Phospholipid gel compositions for drug delivery and methods of treating conditions using same
Abstract
This record has no abstract on file.
Term
Term ended
Projected expiry passed 23 June 2025, 1.3 years ago.
- Priority
- Filed
- Published
- Projected expiry
- Today
41 claims: 1 independent, 40 dependent
- 1Zastrzeżenia patentowe 1. Kompozycja farmaceutyczna zawierająca:(i) fosfolipid;(ii) polarny aprotonowy rozpuszczalnik organiczny;(iii) polarny protonowy rozpuszczalnik organiczny;(iv) hydroksypropylometylocelulozę;i (v) środek farmaceutycznie czynny, przy czym kompozycja farmaceutyczna jest w formie żelu.
- 2Kompozycja farmaceutyczna według zastrzeżenia 1, w której stosunek polarnego protonowego rozpuszczalnika organicznego do polarnego aprotonowego rozpuszczalnika organicznego waha się od 90:10 do 10:90.
- 3Kompozycja farmaceutyczna według zastrzeżenia 2, w której stosunek polarnego protonowego rozpuszczalnika organicznego do polarnego aprotonowego rozpuszczalnika organicznego waha się od 60:40 do 40:60.
- 4Kompozycja farmaceutyczna według zastrzeżenia 1, w której polarny aprotonowy rozpuszczalnik jest wybrany z grupy obejmującej węglan propylenu, dimetylosulfotlenek, dimetyloacetamid, dimetyloformamid, triacetynę i N-metylo-2-pirolidon, a polarny protonowy rozpuszczalnik wybiera się z grupy obejmującej formal gliceryny, glikol propylenowy i 1,4-butanodiol.
- 5Kompozycja farmaceutyczna według zastrzeżenia 1, w której polarnym protonowym rozpuszczalnikiem organicznym jest formal gliceryny i polarnym aprotonowym rozpuszczalnikiem organicznym jest węglan propylenu.
- 6Kompozycja farmaceutyczna według zastrzeżenia 5, w której fosfolipid ma ogólną budowę:Rj-O-|h 2 Bi-O-CH O I II + CH2 - O-P-O-CHjCHj—N(CHjh R ' w której R1 oznacza -O- i R2 i R3 oznaczają każda niezależnie grupy stearoilowe lub grupy palmitoilowe, gdzie stosunek grup stearoilowych do grup palmitoilowych wynosi około 85:15.
- 7Kompozycja farmaceutyczna według zastrzeżenia 1, która to kompozycja farmaceutyczna ma lepkość w zakresie od 1000 cP do 75 000 cP w 20°C.
- 8Kompozycja farmaceutyczna według zastrzeżenia 1, w której fosfolipid jest obecny w ilości w zakresie od 0,5 procent do 7 procent wagowych kompozycji farmaceutycznej.
- 9Kompozycja farmaceutyczna według zastrzeżenia 8, w której fosfolipid jest obecny w ilości w zakresie od 1 procent do 4 procent wagowych kompozycji farmaceutycznej.
- 10Kompozycja farmaceutyczna według zastrzeżenia 1, w której hydroksypropylometyloceluloza jest obecna w ilości w zakresie od 0,1 do 10 procent wagowych kompozycji farmaceutycznej.
- 11Kompozycja farmaceutyczna według zastrzeżenia 10, w której hydroksypropylometyloceluloza jest obecna w ilości w zakresie od 1 do 7,5 procent wagowych kompozycji farmaceutycznej.
- 12Kompozycja farmaceutyczna według zastrzeżenia 11, w której hydroksypropylometyloceluloza jest obecna w ilości w zakresie od około 1,5 do 5 procent wagowych kompozycji farmaceutycznej.
- 13Kompozycja farmaceutyczna według zastrzeżenia 1, która to kompozycja zawiera wodę w ilości mniejszej niż 2 procent wagowych kompozycji farmaceutycznej.
- 14Kompozycja farmaceutyczna według zastrzeżenia 1, w której fosfolipid jest obecny w ilości w zakresie od 1 do 4 procent wagowych kompozycji farmaceutycznej i hydroksypropylometyloceluloza jest obecna w ilości w zakresie od około 1,5 do 5 procent wagowych kompozycji farmaceutycznej.
- 15Kompozycja farmaceutyczna według zastrzeżenia 1, w której środkiem farmaceutycznie czynnym jest połączenie środka przeciwbakteryjnego, środka przeciwgrzybiczego i steroidu.
- 16Kompozycja farmaceutyczna według zastrzeżenia 5, w której środek farmaceutycznie czynny zawiera środek przeciwbakteryjny, środek przeciwgrzybiczy i steroid, a fosfolipid ma ogólną budowę:’Τ R ' _o_ r ι · CHj—O-P-O-CHiC^—N(CHj)3 Ri w której R1 oznacza -O- i R2 i R3 oznaczają każda niezależnie grupy stearoilowe lub grupy palmitoilowe, gdzie stosunek grup stearoilowych do grup palmitoilowych wynosi około 85:15.
- 17Kompozycja farmaceutyczna według zastrzeżenia 16, w której stosunek węglanu propylenu do formalu gliceryny waha się od 60:40 do 40:60.
- 18Kompozycja farmaceutyczna według zastrzeżenia 17, w której fosfolipid jest obecny w ilości w zakresie od 1 do 4 procent wagowych kompozycji.
- 19Kompozycja farmaceutyczna według zastrzeżenia 16, w której (i) środek przeciwbakteryjny jest wybrany z grupy obejmującej tobramycynę lub jej farmaceutycznie dopuszczalną sól i florfenikol lub jego farmaceutycznie dopuszczalny ester;(ii) środkiem przeciwgrzybiczym jest terbinafina lub jej farmaceutycznie dopuszczalna sól;(iii) steroidem jest betametazon lub jego farmaceutycznie dopuszczalny ester.
- 20Kompozycja farmaceutyczna według zastrzeżenia 19, w której stosunek węglanu propylenu do formalu gliceryny waha się od 60:40 do 40:60.
- 21Kompozycja farmaceutyczna według zastrzeżenia 20, w której fosfolipid jest obecny w ilości w zakresie od 1 do 4 procent wagowych kompozycji.
- 22Kompozycja farmaceutyczna według zastrzeżenia 19, w której hydroksypropylometyloceluloza jest obecna w ilości w zakresie od 1 do 7,5 procent wagowych kompozycji farmaceutycznej.
- 23Kompozycja według zastrzeżenia 19, w której środek przeciwbakteryjny jest obecny w ilości w zakresie od 1 do 3% wagowych kompozycji;terbinafina lub jej farmaceutycznie dopuszczalna sól jest obecna w ilości w zakresie od 1 do 3% wagowych kompozycji;i betametazon lub jego farmaceutycznie dopuszczalny ester jest obecny w ilości w zakresie od 0,05 do 0,3% wagowych kompozycji.
- 24Kompozycja farmaceutyczna według zastrzeżenia 23, w której stosunek węglanu propylenu do formalu gliceryny waha się od 60:40 do 40:60.
- 25Kompozycja farmaceutyczna według zastrzeżenia 24, w której fosfolipid jest obecny w ilości w zakresie od 1 do 4 procent wagowych kompozycji.
- 26Kompozycja farmaceutyczna według zastrzeżenia 23, w której hydroksypropylometyloceluloza jest obecna w ilości w zakresie od 1 do 7,5 procent wagowych kompozycji farmaceutycznej.
- 27Kompozycja farmaceutyczna według zastrzeżenia 23, w której fosfolipid jest obecny w ilości w zakresie od 1 do 4 procent wagowych kompozycji; stosunek węglanu propylenu do formalu gliceryny waha się od 60:40 do 40:60;i hydroksypropylometyloceluloza jest obecna w ilości w zakresie od 1 do 7,5 procent wagowych kompozycji farmaceutycznej.
- 28Kompozycja farmaceutyczna według zastrzeżenia 27, w której środkiem przeciwbakteryjnym jest tobramycyna lub jej farmaceutycznie dopuszczalna sól.
- 29Kompozycja farmaceutyczna według zastrzeżenia 27, w której środkiem przeciwbakteryjnym jest florfenikol lub jego farmaceutycznie dopuszczalny ester.
- 30Kompozycja farmaceutyczna według zastrzeżenia 16, w której (i) środkiem przeciwbakteryjnym jest gentamycyna lub jej farmaceutycznie dopuszczalna sól;(ii) środkiem przeciwgrzybiczym jest klotrimazol lub jego farmaceutycznie dopuszczalny ester;(iii) steroidem jest betametazon lub jego farmaceutycznie dopuszczalny ester.
- 31Kompozycja farmaceutyczna według zastrzeżenia 30, w której stosunek węglanu propylenu do formalu gliceryny waha się od 60:40 do 40:60.
- 32Kompozycja farmaceutyczna według zastrzeżenia 31, w której fosfolipid jest obecny w ilości w zakresie od 1 do 4 procent wagowych kompozycji.
- 33Kompozycja farmaceutyczna według zastrzeżenia 30, w której hydroksypropylometyloceluloza jest obecna w ilości w zakresie od 1 do 7,5 procent wagowych kompozycji farmaceutycznej.
- 34Kompozycja według zastrzeżenia 30, w której gentamycyna lub jej farmaceutycznie dopuszczalna sól jest obecna w ilości w zakresie od 1 do 3% wagowych kompozycji;klotrimazol lub jego farmaceutycznie dopuszczalna sól jest obecna w ilości w zakresie od 1 do 3% wagowych kompozycji;i betametazon lub jego farmaceutycznie dopuszczalny ester jest obecny w ilości w zakresie od 0,05 do 0,3% wagowych kompozycji.
- 35Kompozycja farmaceutyczna według zastrzeżenia 34, w której stosunek węglanu propylenu do formalu gliceryny waha się od 60:40 do 40:60.
- 36Kompozycja farmaceutyczna według zastrzeżenia 35, w której fosfolipid jest obecny w ilości w zakresie od 1 do 4 procent wagowych kompozycji.
- 37Kompozycja farmaceutyczna według zastrzeżenia 34, w której hydroksypropylometyloceluloza jest obecna w ilości w zakresie od 1 do 7,5 procent wagowych kompozycji farmaceutycznej.
- 38Kompozycja farmaceutyczna według zastrzeżenia 34, w której fosfolipid jest obecny w ilości w zakresie od 1 do 4 procent wagowych kompozycji; stosunek węglanu propylenu do formalu gliceryny waha się od 60:40 do 40:60;i hydroksypropylometyloceluloza jest obecna w ilości w zakresie od 1 do 7,5 procent wagowych kompozycji farmaceutycznej.
- 39Kompozycja według jednego z zastrzeżeń 1 do 38 do zastosowania w leczeniu infekcji bakteryjnych, grzybiczych lub drożdżakowych.
- 40Kompozycja farmaceutyczna według zastrzeżenia 1, którą to kompozycję wytwarza się przez (i) połączenie środka farmaceutycznie czynnego, hydroksypropylometylocelulozy, polarnego aprotonowego rozpuszczalnika organicznego i polarnego protonowego rozpuszczalnika organicznego z uzyskaniem mieszaniny;(ii) mieszanie mieszaniny, aż środek farmaceutycznie czynny i hydroksypropylometyloceluloza rozpuszczą się z uzyskaniem roztworu;(iii) dodanie fosfolipidu do roztworu z uzyskaniem mieszaniny fosfolipidowej;i (iv) ogrzewanie mieszaniny fosfolipidowej do temperatury niższej niż 70°C.
- 41Kompozycja farmaceutyczna według zastrzeżenia 27, którą to kompozycję wytwarza 20 się przez (i) połączenie środka przeciwbakteryjnego, środka przeciwgrzybiczego, steroidu, hydroksypropylometylocelulozy, polarnego aprotonowego rozpuszczalnika organicznego i polarnego protonowego rozpuszczalnika organicznego z uzyskaniem mieszaniny; (ii) mieszanie mieszaniny, aż środek przeciwbakteryjny, środek przeciwgrzybiczy, steroid, i hydroksypropylometyloceluloza rozpuszczą się z uzyskaniem roztworu; (iii) dodanie fosfolipidu do roztworu z uzyskaniem mieszaniny fosfolipidowej; i (iv) ogrzewanie mieszaniny fosfolipidowej do temperatury niższej niż 70°C. IDEXX LABORATORIES, INC. Pełnomocnik:
Independent claims41
893 paragraphs in 9 sections, as filed
[0001] The present invention relates to pharmaceutical compositions in the form of a gel for the controlled or sustained release of a pharmaceutically active agent and methods of treating or preventing a condition in an animal by administering to an animal in need thereof a pharmaceutical composition. The pharmaceutical compositions are suitable for oral, topical, ear and ocular applications. One particular type of condition for which pharmaceutical compositions are useful is a microbial infection, e.g., of the skin, ear or eye, especially in veterinary applications.
1.2. DESCRIPTION OF RELATED TECHNIQUE [0002] It is often desirable to administer drugs using controlled or sustained release formulations that can maintain at least a minimum therapeutic level, for example, a blood level of the drug for a long time. These controlled or sustained release formulations reduce the frequency of dosing, for greater convenience and compliance, as well as a reduction in the severity and frequency of side effects. For example, by maintaining essentially constant blood levels and avoiding fluctuations in drug levels in the blood, such as those associated with conventional immediate release preparations that are administered several times a day, controlled or sustained release preparations may provide a better therapeutic profile than that achieved with conventional immediate preparations release.
[0003] Known methods of controlled or sustained release of a drug include implantable devices, such as osmotic pumps, and a drug dispersed in a biocompatible polymer matrix that can be implanted, administered orally, or injected. Examples of biocompatible polymers used in such applications include poly (lactic acid) and poly (lactic acid-co-glycolic acid). The polymer typically undergoes slow hydrolysis in vivo, continuously releasing the entrapped drug over time. Polymer degradation products are non-toxic and absorbed or metabolized by the body. For example, when the biologically compatible polymer is poly (lactic acid) or poly (lactic acid-co-glycolic acid), the degradation products are parent acids, lactic acid and glycolic acid, which are absorbed by the body.
[0004] In US Patent No. 5,110,809 Wang et al. discloses stable anhydrous gel formulations for topical antifungal use containing imidazole, a steroid, a cosolvent system containing mono- and dihydroxy alcohols, and a hydroxyalkyl cellulose gelling agent.
[0005] International publication no. WO 00/09117 discloses topical pharmaceutical compositions containing nimesulfide, a nonsteroidal anti-inflammatory agent having poor water solubility.
[0006] US Patent No. 6,214,339 Pellico discloses a therapy for otitis externa in cats and dogs that involves administering a substantially non-aqueous, two-enzyme therapeutic composition in a liquid or gel gel carrier. An illustrative composition contains glucose, glucose oxidase, potassium iodide and lactoperoxidase in a liquid mixture of glycerin and propylene glycol.
[0007] Eurasian Patent No. EA 0002978 B1 claims in a main independent claim a method for producing a phospholipid suspension.
[0008] US Patent Application No. US 2004/0220264 discloses compositions, methods of making compositions, and the use of compositions that contain a molecular complex between an acid pharmaceutical drug and a functional substance. The functional substance may be a basic amino acid, amino acid amide, amino acid ester or related amino acid. The compositions are intended to be useful for delivering a drug to skin tissue.
[0009] US Patent Application No. US 2004/0197408 discloses diblock copolymer formulations having a hydrophobic block and hydrophilic block, an additive selected from amino acids, and an oligopeptide. The preparations, when mixed with water, form drug delivery vehicles in the form of micelles.
[0010] There remains, however, a need in the art for drug-containing pharmaceutical compositions, especially pharmaceutical compositions containing a drug suitable for oral, topical, ear-and-ocular use that provide controlled and / or sustained release of the drug contained therein.
[0011] Citation of any literature entry in Section 1 of this application should not be interpreted so that such entry is prior art to the present application.
2. SUMMARY OF THE INVENTION [0012] These and other features and advantages of the present invention will become apparent in the light of the remainder of the disclosure, in particular the following detailed description of preferred embodiments, all of which illustrate by way of example the principles of the invention.
[0013] The invention relates to pharmaceutical compositions providing sustained or controlled release of a pharmaceutically active compound.
[0014] In one embodiment, the pharmaceutical compositions comprise (i) a phospholipid or sphingomyelin; (ii) a polar aprotic organic solvent; (iii) a polar protic organic solvent; and (iv) a pharmaceutically active agent, wherein the pharmaceutical composition is in the form of a gel.
[0015] In one embodiment, the pharmaceutical compositions comprise (i) a phospholipid or sphingomyelin, (ii) a solvent selected from the group consisting of propylene glycol substantially free of other organic solvents and glycerol formal substantially free of other organic solvents, and (iii) a pharmaceutical agent active, wherein the pharmaceutical composition is in the form of a gel. In one embodiment, the solvent is glycerol formal substantially free of other organic solvents. In one embodiment, the solvent is propylene glycol substantially free of other organic solvents.
[0016] The invention further relates to a method of treating a condition in an animal comprising administering to an animal in need thereof a pharmaceutical composition according to the invention.
3. BRIEF DESCRIPTION OF THE DRAWINGS [0017] Not applicable.
4. DETAILED DESCRIPTION OF THE INVENTION [0018] The invention relates to pharmaceutical compositions for the controlled or sustained release of a pharmaceutically active agent. In one embodiment, the pharmaceutical compositions comprise (i) a phospholipid or sphingomyelin, (ii) a first organic solvent, (iii) a second organic solvent, and (iv) a therapeutically effective amount of a pharmaceutically active agent in relative amounts sufficient to cause gel formation.
[0019] In another embodiment, the pharmaceutical compositions comprise (i) a phospholipid or sphingomyelin, a solvent selected from the group consisting of propylene glycol substantially free of other organic solvents, and glycerol formal substantially free of other organic solvents, and (iii) a therapeutically effective amount of a pharmaceutical agent active in relative amounts sufficient to cause gel formation.
[0020] The invention further relates to a method of treating or preventing a condition in an animal. The method comprises administering to a animal in need thereof a therapeutically effective amount of a pharmaceutically active agent by orally, topically, by ear, and / or intraocular administration of the pharmaceutical composition of the invention.
4.1 Definitions [0021] As used herein, the term "gel" means material having an average viscosity of at least about 1000 centipoise ("cP"), preferably at least about 2000 cP, more preferably at least about 5000 cP, even more preferably at least about 7500 cP , and most preferably at least about 10,000 cP but less than about 100,000 cP, preferably less than about 75,000 cP at 20 ° C. Typically, the gel exhibits constant and / or dynamic interactions between its components, e.g., in the form of association complexes, which are generally reversible using force (e.g., shear) and / or temperature to obtain flow.
[0022] As used herein, the term "phospholipid" means a compound having the general formula:
R<sub>3</sub>-O-CH<sub>2</sub>
AND
R<sub>2</sub>-o-CH O
I II
CH, -R 4 -OPO
AND
Ri in which
R1 is -OH or -O<sup>-</sup>;
R2 means:
(i) -H, or (ii) C2-C36 saturated or unsaturated, linear or branched acyl;
R3 means:
(i) -H, (ii) C2-C36 saturated or unsaturated, linear or branched acyl; or (iii) -C = C-R9 where R9 is a C1-C22 saturated or unsaturated, linear or branched hydrocarbon group, optionally substituted with one or more nitrogen-containing groups;
and at least one of R2 or R3 is not -H;
R4 means:
(i) -H;
(i) - (CH2) n-R5, where R5 is -N (R6) (R7) or -N<sup>+</sup>(R6) (R7) (R8),
R6, R7, and R8 are independently -H, a C1-C3 alkyl group, or R6 and R7 are joined to form a 5- or 6-membered nitrogen heterocyclic ring, and n is an integer in the range of 1 to 4, preferably 2;
(Iii)
<img file="PL1781256T3_D0001.tif" />
(Iv)
<img file="PL1781256T3_D0002.tif" />
wherein each R10 is independently -H or -P (O) (OH) 2; or 20 (v) -CH2CH (OH) CH2 (OH).
[0023] As used herein, the term "saturated or unsaturated, linear or branched C2 - C36 acyl" means a group of formula -OC (O) -R, wherein R is a C1 - C35 hydrocarbon group which may be saturated or unsaturated , linear or branched.
[0024] As used herein, the term "sphingomyelin" means a compound having the general formula:
<img file="PL1781256T3_D0003.tif" />
wherein
R1 is -OH or -O-;
R4 means:
(i) -H; or (i) - (CH2) n-R5, wherein R5 is N (R6) (R7) or -N<sup>+</sup>(R6) (R7) (R8),
R6, R7, and R8 are independently -H, C1-C3 alkyl, or R6 and R7 are joined to form a 5- or 6-membered nitrogen heterocyclic ring, and
n is an integer in the range of 1 to 4, preferably 2; and
R11 is C1 - C22 saturated or unsaturated, linear or branched hydrocarbon group optionally substituted with one or more nitrogen containing groups.
[0025] As used herein, the term "fatty acid" means a carboxylic acid of formula RC (O) OH, wherein R is a C6-C22 linear or branched, saturated or unsaturated hydrocarbon group. Representative fatty acids include, but are not limited to, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, ricinoleic acid, oleopalmitic acid, oleic acid, linoleic acid and linolenic acid.
[0026] As used herein, the term "organic solvent" means any organic compound or mixture of organic compounds that is fluid in about
20 ° C or above, preferably at about 10 ° C or above, more preferably at about 0 ° C or above, most preferably at about -10 ° C or above. Typical organic solvents have a molecular weight of not more than about 500 g / mol and preferably not more than 100 g / mol. When organic solvents are administered to an animal, preferably organic solvents are compounds that do not significantly induce excessive undesirable effects such as excessive toxicity, irritation or an allergic reaction in proportion to a reasonable benefit / risk ratio (i.e., "pharmaceutically acceptable organic solvents").
[0027] As used herein, the term "polar aprotic organic solvent" means an organic solvent that has a dielectric constant greater than about 20, preferably greater than about 30, and more preferably greater than about 50, and does not contain an OH function.
[0028] As used herein, the term "polar protic organic solvent" means an organic solvent that has a dielectric constant greater than about 20, preferably greater than about 30, and more preferably greater than about 50, and contains a -OH functional group.
[0029] As used herein, the term "pharmaceutically active agent" means a compound that exerts a pharmacological effect in an animal. Typically, the pharmacological action is to treat or prevent an animal's condition. The pharmaceutically active agent may preferably comprise a drug in its biologically active form, a prodrug in such a form that the biologically active form of the drug is formed in vivo in an animal, a drug metabolite, or a pharmaceutically acceptable salt or ester of the biologically active drug.
[0030] The term "animal" as used herein includes, without limitation, humans, dogs, cats, horses, cattle, sheep, pigs, amphibians, reptiles and birds. Representative animals include, without limitation, cow, horse, sheep, pig, ungulate animal, chimpanzee, monkey, baboon, hen, turkey, mouse, rabbit, rat, guinea pig, dog, cat and human. In one embodiment, the animal is a mammal. In one embodiment, the animal is a human. In one embodiment, the animal is a dog, cat, horse, ox, sheep, or pig.
[0031] The term "condition" as used herein means interruption, termination or disorder of body, system or organ function, and includes diseases, defects, and disorders.
Representative conditions include, but are not limited to, infections such as bacterial, viral, fungal, yeast, and parasitic infections; diseases such as cancer;
inflammation; diabetes; and organ failure.
[0032] The terms "effective amount" and "therapeutically effective amount" as used herein, mean an amount sufficient to treat or prevent a condition in an animal.
[0033] The phrases "treatment" "therapy" and the like include alleviating or interrupting the condition.
[0034] The phrases "prevention" and "prevention" and the like include avoiding the onset of the condition.
[0035] The phrase "pharmaceutically acceptable salt", as used herein, means a salt formed from the acid and basic nitrogen group of a pharmaceutically active agent. Illustrative salts include, without limitation, sulfate; citrate, acetate; oxalate; chloride; bromide; iodide; nitrate; bisulfate; phosphate; hydrogen; isonicotinate; lactate; salicylate; acid citrate; tartrate; oleate; tannate; pantothenate; hydrogen; askobinian; succinate; maleate; gentisinate; fumarate; gluconate;
glucuronide; saccharate; formate; benzoate; glutamate; methanesulfonate; ethanesulfonate; benzene; p-toluenesulfonate; pamoate (i.e., 1,1'-methylene bis- (2-hydroxy-3-naphthoate)); and fatty acid salts such as capronate, laurate, myristate, palmitate, stearate, oleate, linoleate, and linolate. The phrase "pharmaceutically acceptable salt" also refers to a salt prepared from a pharmaceutically active agent having an acid functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, alkali metal hydroxides such as sodium, potassium and lithium; alkaline earth metal hydroxides such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonium and organic amines such as unsubstituted or hydroxy substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis- or tris- (2-hydroxy-lower alkylamines) such as mono-, bis- or tris- (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine, or tris (hydroxymethyl) methylamine , N, N, -di-lower alkyl-N- (hydroxy lower alkyl) amines such as N, N, -dimethyl-N- (2-hydroxyethyl) amine, or tri- (2-hydroxyethyl) amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.
[0036] The phrase "substantially free of" as used herein means less than about 5 weight percent, preferably less than about 2 weight percent, more preferably less than about 1 weight percent, even more preferably less than about 0.5 weight percent, and most preferably less than about 0.2 percent by weight. For example, the phrase "propylene glycol (or glycerol formal) substantially free of other organic solvents" means that the amount of other organic solvents in the propylene glycol (or glycerol formal) is less than about 5 weight percent, preferably less than about 2 weight percent, more preferably less than about 1 weight percent, even more preferably less than about 0.5 weight percent, and most preferably less than about 0.2 weight percent of the combined amount of propylene glycol (or glycerol formal) and other organic solvents.
4.2 Phospholipid [0037] Any pharmaceutically acceptable phospholipid may be used in the pharmaceutical compositions of the invention.
[0038] Representative, pharmaceutically acceptable phospholipids include, without limitation:
phosphatidic acids of the general formula:
Rg-- O <sup>1</sup>CK2
<img file="PL1781256T3_D0004.tif" />
CH<sub>2</sub>-OPO - H
AND
R1 in which R1, R2, and R3 are as defined above. Suitable phosphatidic acids for use in the compositions and methods of the invention include, but are not limited to, 1-acyl-2-acyl-sn-glycerol-3-phosphates and 1,2-diacyl-sn-glycerol-3-phosphates available in trade with Avanti Polar Lipids Inc. from Alabaster, AL.
phosphatidylethanolamine of general formula r<sub>3</sub>-O-CH<sub>2</sub>
R<sub>2</sub>-O-CH O
I II, ch<sub>2</sub> 0-P-O-CH<sub>2</sub>ch<sub>2</sub>-NH<sub>2</sub>
R1 wherein R1, R2, and R3 are as defined above. Suitable phosphatidylethanolamines for use in the compositions and methods of the invention include, but are not limited to, 1-acyl-2-acyl-sn-glycero-3-phosphoethanolamine and 1,2-diacyl-sn-glycerol-311 phosphoethanolamine commercially available from Avanti Polar Lipids Inc. from Alabaster, AL.
phosphatidylcholines of the general formula r<sub>3</sub>-O-CH<sub>2</sub>
AND
R<sub>2</sub>-o -— CH O
I II.
CH<sub>2</sub>-OPO-CH<sub>2</sub>CH<sub>2</sub>-N (CH<sub>3</sub>)<sub>3</sub>
R1 in which R1, R2, and R3 are as defined above. Suitable phosphatidylcholines for use in the compositions and methods of the invention include, but are not limited to, 1-acyl-2-acyl-sn-glycero-3-phosphocholine, 1,2-diacyl-sn-glycerol-3-phosphoethanolamine (saturated series) , and 1,2-diacyl-sn-glycero-3-phosphoethanolamine (unsaturated series), commercially available from Avanti Polar Lipids Inc. from Alabaster, AL and
Phospholipon® -50PG, Phospholipon®-53MCT, Phospholipon® -75SA, Phospholipon 10® -80, Phospholipon® -90NG, Phospholipon® -90H, and Phospholipon® -100H, commercially available from Phospholipid GmbH from Cologne, Germany. In one embodiment, the phospholipid is Phospholipon ® -90H. phosphatidylserines of the general formula
<img file="PL1781256T3_D0005.tif" />
wherein R1, R2, and R3 are as defined above. Suitable phosphatidylserines for use in the compositions and methods of the invention include, but are not limited to, 1-acyl-2-acyl-sn-glycero-3- [phospho-L-serine] and 1,2-diacyl-sn-glycerol 3 [phospho-L-serine] commercially available from Avanti Polar Lipids Inc. from Alabaster, AL.
plasmalogens of general formula r<sub>3</sub>-O-CH<sub>2</sub>
R<sub>2</sub>-O-CH O
<img file="PL1781256T3_D0006.tif" />
ch<sub>2</sub>OP-CH<sub>2</sub>ch<sub>2</sub>-NH<sub>2</sub>
.........<sup>R</sup>1 · Wherein R1 and R2 are as defined above and R3 is -C = C-R9, where R9 is
CH<sub>2</sub>OH
AND
CH-OH as defined above. Suitable plasmalogens for use in the compositions and methods of the invention include, but are not limited to, C16 (Plasm) -12: 0
NBD PC, C16 (Plasm) -18: 1 PC, C16 (Plasm) -20: 4 PC, C16 (Plasm) -22: 6 PC, C16 (Plasm) 18: 1 PC, C16 (Plasm) -20: 4 PE, and C16 (Plasm) -22: 6 PE, commercially available from Avanti Polar
Lipids Inc. from Alabaster, AL.
phosphatidylglycerols of the general formula "3-Ο-ρ R<sub>2</sub>-Ο-CH Ο
I II ch<sub>2</sub>-Ο-Ρ-ο-ch<sub>2</sub>
AND
R1 in which R1, R2, and R3 are as defined above. Suitable phosphatidylglycerols for use in the compositions and methods of the invention include, but are not limited to, 1-acyl-2-acyl-sn-glycero-3- [phospho-rac- (1-glycerol)] and 1,2-diacyl snglicero-3- [phospho-rac- (1-glycerols)], commercially available from Avanti Polar Lipids Inc. from Alabaster, AL.
phosphatidylinositols of the general formula
<img file="PL1781256T3_D0007.tif" />
wherein R1, R2, R3, and R10 are as defined above. Suitable phosphatidylinositols for use in the compositions and methods of the invention include, but are not limited to, phosphatidylinositol, phosphatidylinositol-4-phosphate, and phosphatidylinositol4,5-bisphosphate, commercially available from Avanti Polar Lipids Inc. from Alabaster, AL.
[0039] The amount of phospholipid in a pharmaceutical composition typically ranges from about
0.1 percent to 10 percent by weight of the pharmaceutical composition.
[0040] In one embodiment, the amount of phospholipid in the pharmaceutical composition ranges from about 0.5 percent to 7 percent by weight of the pharmaceutical composition.
[0041] In one embodiment, the amount of phospholipid in the pharmaceutical composition ranges from about 1 percent to 4 percent by weight of the pharmaceutical composition.
[0042] In one embodiment, the amount of phospholipid in the pharmaceutical composition ranges from about 2 percent to 4 percent by weight of the pharmaceutical composition.
[0043] In one embodiment, the amount of phospholipid in the pharmaceutical composition is greater than about 1 weight percent of the pharmaceutical composition.
[0044] In one embodiment, the amount of phospholipid in the pharmaceutical composition is greater than about 2 weight percent of the pharmaceutical composition.
[0045] Typically, the higher the phospholipid concentration in the pharmaceutical composition, the higher the viscosity of the pharmaceutical composition. Accordingly, it is possible to change the viscosity of a pharmaceutical composition by varying the amount of phospholipid present in the pharmaceutical composition.
[0046] An average person skilled in the art will, however, note that the amount of phospholipid present in the pharmaceutical compositions of the invention may vary widely depending on the organic solvents present, the pharmaceutically active agent present, and / or other additional ingredients present in the pharmaceutical composition.
[0047] Phospholipids are commercially available or can be obtained by methods well known to those skilled in the art. Representative methods for obtaining phospholipids are described in Sandra Pesch et al., Properties of Unusual Phospholipids Bearing Acetylenic Fatty Acids, Tettrahedron, Vol. 15, No. 43, 14,627-14634 (1997); Sepp D.
Kohlwein, Phospholipid Synthesis, Sorting, Subcellular Traffic - The Yeast Approach, Trends in Cell Biology, vol. 6, 260-266 (1996), Serguei V. Vinogradov, Synthesis of Phospholipids - Oligodeoxyribonucleotide Conjugates, Tett. Lett., Vol. 36, No. 14, 24932496 (1995), and the literature cited therein.
4.3 Sphingomyelin [0048] Any pharmaceutically acceptable sphingomyelin can be used in the pharmaceutical compositions of the invention.
[0049] In one embodiment, the sphingomyelin is
<img file="PL1781256T3_D0008.tif" />
wherein R11 is C1-C24 linear, saturated or unsaturated hydrocarbon and R4 is -CH2CH2N (CH3) 3<sup>+</sup>. In another embodiment, R11 is C8-C24 linear, saturated or unsaturated hydrocarbon and R4 is -CH2CH2N (CH3) 3<sup>+</sup>. In another embodiment, R11 is a C16-C24 linear, saturated or unsaturated hydrocarbon, and R4 is -CH2CH2N (CH3) 3<sup>+</sup>.
[0050] Suitable sphingomyelins include, but are not limited to, C 2 -fingomyelin, C 6 -sphingomyelin, C 18 -sphingomyelin, C 6-NBD-sphingomyelin, and C 12-NBD sphingomyelin, commercially available from Avant Polar Lipids Inc. from Alabaster, AL.
4.4 Pharmaceutically active agent [0051] Any pharmaceutically active agent compatible with phospholipid or sphingomyelin and polar aprotic organic solvent and polar protic organic solvent or compatible with phospholipid or sphingomyelin and propylene glycol substantially free of other organic solvents or a glycerol formal essentially free of other solvents can be used in the pharmaceutical compositions of the invention.
[0052] In one embodiment, the pharmaceutically active agent is present as a pharmaceutically acceptable salt of the pharmaceutically active agent.
[0053] In one embodiment, the pharmaceutically active agent is a zwitterion.
[0054] In one embodiment, the pharmaceutically active agent is a basic compound.
[0055] In one embodiment, the pharmaceutically active agent is an acidic compound.
[0056] In one embodiment, the pharmaceutically active agent is an inert compound.
[0057] The amount of pharmaceutically active agent in the pharmaceutical compositions typically ranges from about 0.01 to 30 percent by weight of the pharmaceutical composition.
[0058] In one embodiment, the amount of pharmaceutically active agent in the pharmaceutical compositions ranges from about 0.01 to 25 percent by weight of the pharmaceutical composition.
[0059] In one embodiment, the amount of pharmaceutically active agent in the pharmaceutical compositions ranges from about 0.01 to 20 percent by weight of the pharmaceutical composition.
[0060] In one embodiment, the amount of pharmaceutically active agent in the pharmaceutical compositions ranges from about 0.01 to 15 percent by weight of the pharmaceutical composition.
[0061] The amount of pharmaceutically active agent in the pharmaceutical compositions typically ranges from about 0.01 to 10 percent by weight of the pharmaceutical composition.
[0062] In one embodiment, the amount of pharmaceutically active agent in the pharmaceutical compositions ranges from about 0.05 to 7.5 weight percent of the pharmaceutical composition.
[0063] In one embodiment, the amount of pharmaceutically active agent in the pharmaceutical composition is from about 0.05 to 5 percent by weight of the pharmaceutical composition.
[0064] In one embodiment, the amount of pharmaceutically active agent in the pharmaceutical composition is from about 0.1 to 3 weight percent of the pharmaceutical composition.
[0065] In one embodiment, the amount of pharmaceutically active agent in the pharmaceutical composition is from about 0.1 to 2 weight percent of the pharmaceutical composition.
[0066] In one embodiment, the amount of pharmaceutically active agent in the pharmaceutical composition is from about 0.1 to 1 weight percent of the pharmaceutical composition.
[0067] The average person skilled in the art will recognize, however, that the amount of pharmaceutically active agent in the pharmaceutical compositions of the invention may vary widely depending on the active pharmaceutical agent and any other ingredients present in the pharmaceutical composition.
[0068] Examples of pharmaceutically active agents useful in the composition and methods of the invention include, but are not limited to, α-adrenergic agonists, β-adrenergic agonists, α-adrenergic blockers, βadrenergic blockers, aldose reductase inhibitors, anabolics, analgesics (narcotic and non-narcotic) ), androgens, anesthetics, anti-anorexia, anthelmintics (e.g., tapeworm, nematode, river blindness nematode, schistosoma, and the like), antiallergic agents, anti-amoebas, anti-thrush agents, anti-androgenic agents, anti-angina agents, anti-arrhythmics, anti-arteriosclerosis agents, anti-arthritis agents, antibiotics and other anti-bacterial agents, anti-cholinergic agents, anti-convulsants, anti-depressants, anti-depressants. anti-diarrheal agents, anti-diuretics, anti-estrogens, anti-fungal agents, anti-glaucoma agents, anti-gonadotropins, anti-gout agents, antihistamines, anti-hyperlipoproteinemic agents, antihypertensive agents, anti-thyroid agents, anti-hypertrophic agents, anti-hypotensive agents, anti-hypothyroid agents, anti-inflammatory agents, anti-malarial agents, anti-microbial agents, anti-migraine agents, anti-nausea agents, anti-nausea agents, antioxidants, anti-parasite agents, anti-Parkinson agents, anti-pigmented agents, anti-Pneumocystis agents, antiproliferative agents, antiprotozoal agents (e.g., leishmanas, trichomonias, bipers, and the like), antipruritic agents, anti-psoriatic agents, antipsychotic agents, antipyretics, anti-rheumatic agents, anti-angiotic agents, anti-angiotic agents antiseptics, antispastics, anticoagulants, antitussives, anti-ulcer agents, anti-urolithiasis, anti-viral agents, antiviral agents, anxiolytic agents, benzodiazepine antagonists, bronchodilators, calcium channel blockers, calcium regulators, cardiotonic agents, chelating agents, chemotherapeutic agents, cholecystokinin antagonists, gallstone dissolving agents, bile secreting agents, cholinergic agents, cholinesterase inhibitors, cholinesterase reactivators, central nervous system agents and stimulators, anti-edematous agents, diuretics, dopamine receptor agonists, drugs for the treatment or prevention of pain, agents against external parasites, enzymes, enzyme inducers, estrogens, gastric secretion inhibitors, glucocorticoids, sex stimulants, gonadotropic hormones, growth hormones, growth hormone releasing agents, growth stimulants, haemolytic agents, heparin agonists, liver protection agents, sleeping pills, immune system enhancers, immunomodulators, immunosuppressants, lactation stimulating hormones, LH-RH stimulants, lipotropic agents, suppressive lupus erythematosus, mineralocorticoids, miosis, monoamine oxidase inhibitors, mucolytics, muscle relaxants , neuroprotective agents, neotropic agents, ovarian hormones, oxytocides, pepsin inhibitors, peristalsis stimulators, progestrogens, prolactin inhibitors, protoglandins, prostaglandin analogues, protease inhibitors, respiratory stimulants, sclerosants, sedatives, steroids, blood clot dissolving agents, thyrotropic hormones, skin penetration enhancers, uricosuric agents, vasoconstrictors, vasodilators (e.g., cerebral, coronary, peripheral, and the like), vasoprotectants, vitamins, vitamin source extracts, wound care products (including among others, listed in US Patent No. 5,719,197, the full disclosure of which is incorporated herein by reference), and combinations thereof. Other additional or alternatively acceptable pharmaceutically active agents can be found, e.g., US Patent No. 6,221,383, the full disclosure of which is incorporated herein by reference.
[0069] In one embodiment, the pharmaceutically active agent comprises an antibacterial agent.
[0070] In one embodiment, the pharmaceutically active agent comprises an antifungal agent.
[0071] In one embodiment, the pharmaceutically active agent comprises an anti-parasite agent.
[0072] In one embodiment, the pharmaceutically active agent comprises an anti-yeast agent.
[0073] In one embodiment, the pharmaceutically active agent comprises an antiviral agent.
[0074] In one embodiment, the pharmaceutically active agent comprises a hormone.
[0075] In one embodiment, the pharmaceutically active agent comprises an anti-inflammatory agent.
[0076] In one embodiment, the pharmaceutically active agent comprises a steroid.
[0077] Examples of useful antibacterial agents include, but are not limited to, β-lactam antibiotics such as penicillins, amoxicillin, ampicillin, and cephalosporins; macrolide antibiotics such as oleandomycin and erythromycin;
tetracyclines such as tetracycline, oxytetracycline and chlortetracycline; procaine penicillin G; quinolones such as enrofloxacin, nalidixic acid and norfloxacin;
sulfonamides; chloramphenicol; florfenicol; thiamphenicol, aminoglycosides such as tobramycin, streptomycin, kanamycin, azithromycin and gentamycin; nucleoside antibiotics such as polyoxin B; aktynorodyna; bacitracin; Candicidin A; ceftiofor; clindamycin; cycloheximide; cycloserine; fosfomycin; griseofulvin; metronidazole; monensin; novobiocin; rifampin; streptotrycyna; tetranactin; tilmicosin; tylosin; actinomycin D; adriamycin; bleomycin B2; glycolipids such as moenomycin A; mitomycin C; nojirimycyna; valinomycin; and vancomycin; (see, e.g., Bradford P. Smith, Large Animal Internal Medicine, 2nd ed., Mosby, St. Louis, 1996, p. 644, and S. Birchard and R Sherding, Saunders Manual of Small Animal Practice, WB Saunders Company , Philadelphia, 1994, p. 739).
[0078] Examples of useful antifungal agents include, but are not limited to, terbinafine, amphotericin B, ketaconazole, clotrimazole, miconazole, 5-fluorocytosine, enilconazole, itraconazole, thiabendazole and iodides (see, e.g., Bradford P. Smith, Large Animal Internal Medicine) , 2nd ed., Mosby, St. Louis, 1996, p. 576, and S. Birchard and R Sherding, Saunders Manual of Small Animal Practice, WB Saunders Company, Philadelphia, 1994, p. 576).
[0079] Examples of useful antiviral agents include, but are not limited to, interferon (see, e.g., Bradford P. Smith, Large Animal Internal Medicine, 2nd Edition, Mosby, St. Louis, 1996, p. 646).
[0080] Examples of useful anti-parasite agents include, but are not limited to, benzimidazoles; such as thiabendazole, fenbendazole, mebendazole, nitazoxanide (NTZ), oxfendazole, oxybendazole, albendazole, parbendazole and febantel; tetrahydropyridines such as morantel tartrate / pirantel pamoate; levamisole, organophosphorus agents such as haloxone, kumafos, trichlorfon and dichlorvos; piperazine salts; ivermectin; and phenothiazine (see, e.g., Bradford P. Smith, Large Animal Internal Medicine, ed. 2, Mosby, St. Louis, 1996, p. 1688).
[0081] Examples of useful anti-inflammatory agents include, but are not limited to, steroids such as betamethasone; corticosteroids such as dexamethasone; antihistamines; and nonsteroidal anti-inflammatory lakes such as aspirin, flunixin meglumine, phenylbutazone, diclofenac and ibuprofin (see, e.g., Bradford P. Smith, Large Animal Internal Medicine, 2nd Edition, Mosby, St. Louis, 1996, p. 645).
[0082] Examples of useful anti-yeast agents include, but are not limited to, aminoglycosides such as tobramycin, streptomycin, kanamycin and gentamicin.
[0083] In one embodiment, the pharmaceutically active agent comprises gentamycin.
[0084] In one embodiment, the pharmaceutically active agent comprises azithromycin.
[0085] In one embodiment, the pharmaceutically active agent comprises tobramycin.
[0086] In one embodiment, the pharmaceutically active agent comprises tobramycin decanoic acid salt.
[0087] In one embodiment, the pharmaceutically active agent comprises a tobramycin oleic acid salt.
[0088] In one embodiment, the pharmaceutically active agent comprises the tobramycin acetic acid salt.
[0089] In one embodiment, the pharmaceutically active agent comprises terbinafine.
[0090] In one embodiment, the pharmaceutically active agent comprises terbinafine decanoic acid salt.
[0091] In one embodiment, the pharmaceutically active agent comprises a terbinafine oleic acid salt.
[0092] In one embodiment, the pharmaceutically active agent comprises terbinafine acetic acid salt.
<td>[0093] W Betamethasone</td><td>one</td><td>example</td><td>implementation, measure</td><td>pharmaceutically</td><td>active</td><td>It contains</td>
<td>[0094] W florfenicol.</td><td>one</td><td>example</td><td>implementation, measure</td><td>pharmaceutically</td><td>active</td><td>It contains</td>
<td>[0095] W thiamphenicol.</td><td>one</td><td>example</td><td>implementation, measure</td><td>pharmaceutically</td><td>active</td><td>It contains</td>
<td>[0096] W clotrimazole.</td><td>one</td><td>example</td><td>implementation, measure</td><td>pharmaceutically</td><td>active</td><td>It contains</td>
[0097] In one embodiment, the pharmaceutically active agent comprises tilmicosin.
[0098] In one embodiment, the pharmaceutically active agent comprises a tetracycline compound.
[0099] In one embodiment, the pharmaceutically active agent comprises ketoconazole.
[0100] In one embodiment, the pharmaceutically active agent comprises diclofenac.
[0101] In one embodiment, the pharmaceutically active agent comprises flunixin.
[0102] In one embodiment, there may be multiple pharmaceutically active agents in a single pharmaceutical composition.
[0103] In one embodiment, the pharmaceutically active agent comprises a combination of an antibacterial agent, an antifungal agent and a steroid.
[0104] Effective amounts of these pharmaceutically active agents are known to those skilled in the art. The specialist's competence is to determine the optimal effective amount range for each pharmaceutically active agent.
[0105] In one embodiment of the invention where multiple pharmaceutically active agents are administered to the animal, the effective amount of each pharmaceutically active agent is less than its effective amount if the other pharmaceutically active agent (s) were not administered. In this case, without being bound by theory, it is believed that many pharmaceutically active agents can be selected to act synergistically to treat or prevent a condition (e.g., bacterial infection).
[0106] In one embodiment, the pharmaceutically active agent comprises a combination of tobramycin, terbinafine and betamethasone.
[0107] In one embodiment, the pharmaceutically active agent comprises a combination of tobramycin decanoic acid salt, terbinafine decanoic acid salt and betamethasone.
[0108] In one embodiment, the pharmaceutically active agent has an amino moiety and is present in the pharmaceutical composition of the invention as a fatty acid salt ("FAS") by converting the amine moiety into an ammonium cation whose counterion is a fatty acid moiety as described in international publication No. WO 03/034988 A2, the full disclosure of which is hereby incorporated by reference.
[0109] Without wishing to be bound by theory, it is believed that the FAS of a pharmaceutically active agent provides additional sustained or controlled release of the pharmaceutically active agent (reflected by more constant blood levels as a function of time). Without wishing to be bound by theory, it is believed that the additional sustained or controlled release of a pharmaceutically active agent obtained by using the FAS pharmaceutically active agent is due to the fact that the FAS pharmaceutically active agent is less water soluble than the pharmaceutically active agent or other non-fatty acid salt a salt of a pharmaceutically active agent, and accordingly is absorbed more slowly by the animal.
[0110] In one embodiment, the FAS salt of the pharmaceutically active agent is a C6-C18 carboxylic acid salt.
[0111] In one embodiment, the FAS salt of the pharmaceutically active agent is a C8-C18 carboxylic acid salt.
[0112] In one embodiment, the FAS salt of the pharmaceutically active agent is a C10-C18 carboxylic acid salt.
[0113] In one embodiment, the FAS salt of the pharmaceutically active agent is a salt of a linear unsaturated fatty acid.
[0114] In one embodiment, the FAS salt of the pharmaceutically active agent is a salt of a linear saturated fatty acid.
4.5 Pharmaceutical compositions
4.5.1 Pharmaceutical compositions containing (i) a phospholipid or sphingomyelin, (ii) a first organic solvent, (iii) a second organic solvent, and (iv) a therapeutically effective amount of a pharmaceutically active agent.
[0115] Any pharmaceutically active agent described above can be used in pharmaceutical compositions.
[0116] Any phospholipid or sphingomyelin described above can be used in pharmaceutical compositions.
4.5.1.1 First organic solvent and second organic solvent [0117] Any pharmaceutically acceptable organic solvents may be used in the pharmaceutical compositions of the invention. However, the first organic solvent and the second organic solvent must mix with each other.
[0118] Suitable organic solvents may contain small amounts of impurities. Typically, organic solvents have a purity greater than 95 weight percent, preferably greater than 97 weight percent, more preferably greater than 98 weight percent, and most preferably greater than 99 weight percent.
[0119] In one embodiment, organic solvents are designated GRAS ("generally considered safe") by the FDA for use or consumption by animals.
[0120] In another embodiment, organic solvents are designated GRAS by the FDA for use or human consumption.
[0121] In one embodiment, the first organic solvent is a polar aprotic solvent and the second organic solvent is a polar protic solvent.
[0122] Representative polar aprotic solvents useful in the compositions and methods of the invention include, but are not limited to, propylene carbonate, dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), dimethylformamide (DMF), triacetin and N-methyl-2-pyrrolidone ( NMP).
[0123] Representative polar protic solvents useful in the compositions and methods of the invention include, but are not limited to, glycerol formal and diols such as propylene glycol and 1,4-butanediol.
[0124] When the first organic solvent is a polar aprotic solvent and the second organic solvent is a polar protic solvent, the ratio of the first organic solvent to the second organic solvent may range from about 90:10 to 10:90. In one embodiment, the ratio of the first organic solvent to the second organic solvent ranges from about 80:20 to 20:80. In one embodiment, the ratio of the first organic solvent to the second organic solvent ranges from about 70:30 to 30:70. In one embodiment, the ratio of the first organic solvent to the second organic solvent ranges from about 60:40 to 40:60. In one embodiment, the ratio of the first organic solvent to the second organic solvent is about 50:50.
[0125] In one embodiment, the first organic solvent and the second organic solvent are substantially free of water. Organic solvents that are substantially free of water are preferred because they do not promote bacterial growth.
Accordingly, typically pharmaceutical compositions that are substantially free of water need not contain a preservative. However, in some embodiments, the non-aqueous pharmaceutical composition of the invention may contain a preservative.
[0126] In one embodiment, the first organic solvent is propylene carbonate and the second organic solvent is glycerol formal.
[0127] In one embodiment, the first organic solvent is propylene carbonate and the second organic solvent is propylene glycol.
[0128] In one embodiment, the first organic solvent is propylene carbonate and the second organic solvent is glycerol formal or propylene glycol and the ratio of the first organic solvent to the second organic solvent ranges from about 80:20 to about 20:80.
[0129] In one embodiment, the first organic solvent is propylene carbonate and the second organic solvent is glycerol formal or propylene glycol and the ratio of the first organic solvent to the second organic solvent ranges from about 75:25 to about 25:75.
[0130] In one embodiment, the first organic solvent is propylene carbonate and the second organic solvent is glycerol formal or propylene glycol and the ratio of the first organic solvent to the second organic solvent ranges from about 60:40 to about 40:60.
[0131] In one embodiment, the first organic solvent is propylene carbonate and the second organic solvent is glycerol formal or propylene glycol and the ratio of the first organic solvent to the second organic solvent ranges from about 50:50.
[0132] The total amount of organic solvent (i.e., first organic solvent and second organic solvent) in the pharmaceutical composition typically ranges from about 20 to about 99 weight percent of the pharmaceutical composition.
[0133] In one embodiment, the total amount of organic solvent in the pharmaceutical composition is from about 35 to about 90 percent by weight of the pharmaceutical composition.
[0134] In one embodiment, the amount of organic solvent in the pharmaceutical composition is at least about 35 weight percent of the pharmaceutical composition.
[0135] In one embodiment, the amount of organic solvent in the pharmaceutical composition is at least about 50 weight percent of the pharmaceutical composition.
[0136] In one embodiment; the amount of organic solvent in the pharmaceutical composition is at least about 75 weight percent of the pharmaceutical composition.
[0137] In one embodiment, the amount of organic solvent in the pharmaceutical composition is at least about 85 percent by weight of the pharmaceutical composition.
4.5.1.2 Representative pharmaceutical preparations.
[0138] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is glycerol formal, and the phospholipid is<sub>3</sub>-O-CH<sub>2</sub>
<img file="PL1781256T3_D0009.tif" />
ch<sub>2</sub>OP-O-CH<sub>2</sub>CH<sub>from</sub>-N (CH<sub>3</sub>)<sub>3</sub>*
R1 in which R2 and R3 are each a stearoyl group or a palmitoyl group and the ratio of all stearoyl groups to palmitoyl groups is about 85:15 and R1 is
ABOUT<sup>-</sup> (Phospholipon® 90H, commercially available from Phospholipid GmbH from Cologne, Germany).
[0139] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is glycerol formal, the phospholipid is Phospholipon® 90H, and the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60.
[0140] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, and the ratio of propylene carbonate to glycerol formal is about 50:50.
[0141] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition.
[0142] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the phospholipid is present in an amount of about 1 to 4 weight percent pharmaceutical composition.
[0143] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the phospholipid is present in an amount of about 3 weight percent of the pharmaceutical composition.
[0144] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the phospholipid is present in an amount of about 3 weight percent pharmaceutical composition.
[0145] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound is at least one of an antibacterial agent, antifungal agent or steroid.
[0146] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the pharmaceutically active compound is at least one of an antibacterial agent, antifungal agent or steroid.
[0147] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the pharmaceutically active compound is at least one of the agent antibacterial, antifungal or steroid.
[0148] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound is at least one of an antibacterial agent, antifungal agent or steroid.
[0149] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 1 to 4 the percent by weight of the pharmaceutical composition and the pharmaceutically active compound is at least one of an antibacterial agent, antifungal agent or steroid.
[0150] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 3 weight percent of the pharmaceutical composition, and the pharmaceutically active compound is at least one of an antibacterial agent, antifungal agent or steroid.
[0151] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 3 percent by weight of the composition pharmaceutical, and the pharmaceutically active compound is at least one of an antibacterial agent, antifungal agent or steroid.
[0152] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises an antibacterial agent, an antifungal agent and a steroid.
[0153] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the pharmaceutically active compound contains antibacterial, antifungal and steroid.
[0154] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the pharmaceutically active compound comprises an antibacterial agent, an agent antifungal and steroid.
[0155] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises an antibacterial agent, an antifungal agent and a steroid.
[0156] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises an antibacterial agent, an antifungal agent and a steroid.
[0157] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 3 weight percent of the pharmaceutical composition, and the pharmaceutically active compound comprises an antibacterial agent, an antifungal agent and a steroid.
[0158] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 3 percent by weight of the composition pharmaceutical compound, and the pharmaceutically active compound comprises an antibacterial agent, an antifungal agent and a steroid.
[0159] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or its pharmaceutically acceptable ester.
[0160] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the pharmaceutically active compound contains tobramycin or a pharmaceutically acceptable salt thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0161] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the pharmaceutically active compound contains tobramycin or a pharmaceutically acceptable drug thereof a salt, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0162] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0163] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 1 to 4 percent by weight of a pharmaceutical composition, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0164] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 3 weight percent of the pharmaceutical composition, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0165] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 3 weight percent of the composition pharmaceutical, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0166] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0167] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the pharmaceutically active compound contains tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0168] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the pharmaceutically active compound contains tobramycin or a pharmaceutically acceptable salt in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to weight percent of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 weight percent of the pharmaceutical composition.
[0169] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0 , 05 to 0.3 percent by weight of the pharmaceutical composition.
[0170] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 1 to 4 percent by weight pharmaceutical composition, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0 , 05 to 0.3 percent by weight of the pharmaceutical composition.
[0171] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 3 weight percent of the pharmaceutical composition, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0 , 05 to 0.3 percent by weight of the pharmaceutical composition.
[0172] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 3 percent by weight of the composition pharmaceutical and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0 , 05 to 0.3 percent by weight of the pharmaceutical composition.
[0173] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 weight percent of the pharmaceutical composition.
[0174] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the pharmaceutically active compound contains tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0175] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the pharmaceutically active compound contains tobramycin or a pharmaceutically acceptable its salt in an amount of about 1 weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0176] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 1 to 4 weight percent of the pharmaceutical composition, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight pharmaceutical composition.
[0177] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 1 to 4 percent by weight pharmaceutical composition, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight pharmaceutical composition.
[0178] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 3 weight percent of the pharmaceutical composition, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight pharmaceutical composition.
[0179] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 3 percent by weight of the composition pharmaceutical and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight pharmaceutical composition.
[0180] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or its pharmaceutically acceptable ester.
[0181] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the pharmaceutically active compound contains florfenicol or a pharmaceutically acceptable ester thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0182] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the pharmaceutically active compound contains florfenicol or a pharmaceutically acceptable salt thereof ester, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0183] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0184] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0185] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 3 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0186] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 3 percent by weight of the composition pharmaceutical, and the pharmaceutically active compound contains florfenicol or a pharmaceutically acceptable ester thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0187] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0188] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the pharmaceutically active compound contains florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0189] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the pharmaceutically active compound contains florfenicol or a pharmaceutically acceptable salt thereof an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0190] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 1 to 4 weight percent of the pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0 , 05 to 0.3 percent by weight of the pharmaceutical composition.
[0191] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 1 to 4 percent by weight pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0 , 05 to 0.3 percent by weight of the pharmaceutical composition.
[0192] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 3 weight percent of the pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0 , 05 to 0.3 percent by weight of the pharmaceutical composition.
[0193] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 3 percent by weight of the composition pharmaceutical and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to
3 a weight percent of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 weight percent of the pharmaceutical composition.
[0194] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 weight percent of the pharmaceutical composition.
[0195] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the pharmaceutically active compound contains florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0196] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the pharmaceutically active compound contains florfenicol or a pharmaceutically acceptable salt thereof an ester in an amount of about 1 weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0197] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight pharmaceutical composition.
[0198] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 1 to 4 percent by weight pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight pharmaceutical composition.
[0199] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 3 weight percent of the pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight pharmaceutical composition.
[0200] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 3 weight percent pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight pharmaceutical composition.
[0201] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises gentamycin or a pharmaceutically acceptable salt thereof, clotrimazole or a pharmaceutically acceptable salt thereof, and betamethasone or its pharmaceutically acceptable ester.
[0202] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable salt thereof, clotrimazole or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0203] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable its a salt, clotrimazole or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0204] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises gentamicin or a pharmaceutically acceptable salt thereof, clotrimazole or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0205] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable salt thereof, clotrimazole or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0206] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 3 weight percent of the pharmaceutical composition, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable salt thereof, clotrimazole or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0207] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 3 weight percent of the composition pharmaceutical, and the pharmaceutically active compound contains gentamicin or a pharmaceutically acceptable salt thereof, clotrimazole or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0208] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises gentamicin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0209] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0210] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable its salt in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0211] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 1 to 4 weight percent of the pharmaceutical composition, and the pharmaceutically active compound comprises gentamicin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0 , 05 to 0.3 percent by weight of the pharmaceutical composition.
[0212] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 1 to 4 percent by weight pharmaceutical composition, and the pharmaceutically active compound comprises gentamicin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0 , 05 to 0.3 percent by weight of the pharmaceutical composition.
[0213] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 3 weight percent of the pharmaceutical composition, and the pharmaceutically active compound comprises gentamicin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0 , 05 to 0.3 percent by weight of the pharmaceutical composition.
[0214] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 3 weight percent of the composition pharmaceutical and the pharmaceutically active compound comprises gentamicin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0 , 05 to 0.3 percent by weight of the pharmaceutical composition.
[0215] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises gentamicin or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 weight percent of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 weight percent of the pharmaceutical composition.
[0216] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable salt thereof in an amount of about 1 weight percent of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0217] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable drug thereof salt in an amount of about 1 weight percent of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0218] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 1 to 4 weight percent of the pharmaceutical composition, and the pharmaceutically active compound comprises gentamicin or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight pharmaceutical composition.
[0219] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 1 to 4 percent by weight pharmaceutical composition, and the pharmaceutically active compound comprises gentamicin or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight pharmaceutical composition.
[0220] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal ranges from about 60:40 to 40:60, the phospholipid is present in an amount of about 3 weight percent of the pharmaceutical composition, and the pharmaceutically active compound comprises gentamicin or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight pharmaceutical composition.
[0221] In one embodiment, the first organic solvent is propylene carbonate, the second organic solvent is a glycerol formal, the phospholipid is Phospholipon® 90H, the ratio of propylene carbonate to glycerol formal is about 50:50, the phospholipid is present in an amount of about 3 percent by weight of the composition pharmaceutical and the pharmaceutically active compound comprises gentamicin or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight pharmaceutical composition.
[0222] In any pharmaceutical composition described in this chapter, glycerol formal can be replaced with propylene glycol.
4.5.2 Pharmaceutical compositions containing (i) a phospholipid or sphingomyelin, a solvent selected from the group consisting of propylene glycol substantially free of other organic solvents and glycerol formal substantially free of other organic solvents, and (iii) a pharmaceutically active agent.
[0223] Any pharmaceutically active agent described above compatible with phospholipid and propylene glycol or glycerol formal can be used in pharmaceutical compositions.
[0224] Any phospholipid or sphingomyelin described above can be used in pharmaceutical compositions.
4.5.2.1 Propylene glycol or glycerol formal [0225] Propylene glycol is an organic solvent represented by the formula:
CH3-CH2 (OH) -CH2-OH or HO-CH2-CH2-CH2-OH.
In one embodiment, the propylene glycol is 1,2-propylene glycol. In another embodiment, the propylene glycol is 1,3-propylene glycol. In one embodiment, the propylene glycol is a mixture of 1,2 propylene glycol and 1,3-propylene glycol.
[0226] Glycerol formal is an organic solvent of formula C4H8O3 and is present as a mixture of 5-hydroxy-1,3-dioxane and 4-hydroxymethyl-1,3-dioxolane in a ratio of about 60:40. Although the solvent, glycerol formal, consists of two chemical compounds, with two chemical compounds present in a certain ratio of about 60:40, it is typically considered a "solvent" rather than a mixture of compounds. This is because 5-hydroxy-1,3-dioxane and 4-hydroxymethyl-1,3-dioxolane are in equilibrium with each other. Correspondingly, the term formal glycerin (i.e., a mixture of 5-hydroxy-1,3-dioxane and 4-hydroxymethyl-1,3-dioxolane in a ratio of about 60:40), as used herein, means an organic solvent substantially free of other organic solvents .
[0227] Propylene glycol and glycerol formal may contain small amounts of impurities.
Typically, propylene glycol and glycerol formal have a purity greater than 95 weight percent, preferably greater than 98 weight percent, more preferably greater than 99 weight percent. The solvent, especially glycerol formal, may contain a stabilizer. Typically, the stabilizer is present in an amount of 0.5% by weight or less, preferably an amount of 0.25% by weight or less, and most preferably an amount of 0.5% by weight or less.
For example, commercially available glycerol formal typically contains ethylenediaminetetraacetate (EDTA), thiodipropionic acid and propyl gallate as stabilizers.
[0228] In one embodiment, the propylene glycol or glycerol formal are substantially free of water. Propylene glycol or glycerol formal substantially free of water are preferred because they do not promote bacterial growth. Accordingly, typically pharmaceutical compositions that are substantially free of water need not contain a preservative. However, in some embodiments, the non-aqueous pharmaceutical composition of the invention may contain a preservative.
[0229] The amount of propylene glycol or glycerol formal in the pharmaceutical composition typically ranges from about 20 to about 99 weight percent of the pharmaceutical composition.
[0230] In one embodiment, the amount of propylene glycol or glycerol formal in the pharmaceutical composition ranges from about 35 to about 90 percent by weight of the pharmaceutical composition.
[0231] In one embodiment, the amount of propylene glycol or glycerol formal in the pharmaceutical composition is at least about 35 weight percent of the pharmaceutical composition.
[0232] In one embodiment, the amount of propylene glycol or glycerol formal in the pharmaceutical composition is at least about 50 weight percent of the pharmaceutical composition.
[0233] In one embodiment, the amount of propylene glycol or glycerol formal in the pharmaceutical composition is at least about 75 percent by weight of the pharmaceutical composition.
[0234] In one embodiment, the amount of propylene glycol or glycerol formal in the pharmaceutical composition is at least about 85 percent by weight of the pharmaceutical composition.
4.5.2.2 Representative Pharmaceutical Preparations [0235] In one embodiment, the solvent is propylene glycol or glycerol formal and the phospholipid is Phospholipon® 90H (commercially available from Phospholipid GmbH from Cologne, Germany).
[0236] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition.
[0237] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition.
[0238] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound is at least one of an antibacterial agent, antifungal agent or steroid.
[0239] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound is at least one of an antibacterial agent, an antifungal agent or steroid.
[0240] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound is at least one of an antibacterial agent, an antifungal agent or steroid.
[0241] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises terbinafine.
[0242] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains terbinafine.
[0243] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains terbinafine.
[0244] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound contains gentamycin.
[0245] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains gentamycin.
[0246] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains gentamycin.
[0247] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises tobramycin.
[0248] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains tobramycin.
[0249] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains tobramycin.
[0250] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound contains azithromycin.
[0251] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains azithromycin.
[0252] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains azithromycin.
[0253] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound contains florfenicol.
[0254] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains florfenicol.
[0255] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains florfenicol.
[0256] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises an antibacterial agent, an antifungal agent and a steroid.
[0257] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises an antibacterial agent, an antifungal agent and a steroid.
[0258] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises an antibacterial agent, an antifungal agent and a steroid.
[0259] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0260] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt, terbinafine or its pharmaceutically acceptable salt, and betamethasone or a pharmaceutically acceptable ester thereof.
[0261] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt, terbinafine or its pharmaceutically acceptable salt, and betamethasone or a pharmaceutically acceptable ester thereof.
[0262] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0263] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains tobramycin or a pharmaceutically acceptable salt thereof 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0264] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains tobramycin or a pharmaceutically acceptable salt thereof 1 to
3 a weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 weight percent of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 weight percent of the pharmaceutical composition.
[0265] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises tobramycin or a pharmaceutically acceptable salt thereof in an amount of about 1 weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof about 1 weight percent of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 weight percent of the pharmaceutical composition.
[0266] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains tobramycin or a pharmaceutically acceptable salt thereof 1 weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0267] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains tobramycin or a pharmaceutically acceptable salt thereof 1 weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0268] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises azithromycin or a pharmaceutically acceptable salt thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0269] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains azithromycin or a pharmaceutically acceptable salt thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0270] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises azithromycin or a pharmaceutically acceptable salt, terbinafine or its pharmaceutically acceptable salt, and betamethasone or a pharmaceutically acceptable ester thereof.
[0271] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises azithromycin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0272] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains azithromycin or a pharmaceutically acceptable salt thereof 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0273] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains azithromycin or a pharmaceutically acceptable salt thereof 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0274] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises azithromycin or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof about 1 weight percent of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 weight percent of the pharmaceutical composition.
[0275] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains azithromycin or a pharmaceutically acceptable salt thereof 1 weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0276] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains azithromycin or a pharmaceutically acceptable salt thereof 1 weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0277] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof, terbinafine or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0278] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester, terbinafine or its pharmaceutically acceptable salt, and betamethasone or a pharmaceutically acceptable ester thereof.
[0279] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester, terbinafine or its pharmaceutically acceptable salt, and betamethasone or a pharmaceutically acceptable ester thereof.
[0280] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0281] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof 1 to 3 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0282] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains florfenicol or a pharmaceutically acceptable ester thereof about 1 to 3 weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0283] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof in an amount of about 1 percent by weight of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof about 1 weight percent of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 weight percent of the pharmaceutical composition.
[0284] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound comprises florfenicol or a pharmaceutically acceptable ester thereof 1 weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0285] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains florfenicol or a pharmaceutically acceptable ester thereof 1 weight percent of the pharmaceutical composition, terbinafine or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0286] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises gentamycin or a pharmaceutically acceptable salt thereof, clotrimazole or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0287] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable salt, clotrimazole or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0288] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable salt, clotrimazole or a pharmaceutically acceptable salt thereof, and betamethasone or a pharmaceutically acceptable ester thereof.
[0289] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises gentamycin or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0290] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable salt thereof 1 to 3 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0291] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable salt thereof 1 to weight percent of a pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 to 3 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.05 to 0.3 percent by weight of the pharmaceutical composition.
[0292] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, and the pharmaceutically active compound comprises gentamycin or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof about 1 weight percent of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 weight percent of the pharmaceutical composition.
[0293] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 4 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable salt thereof 1 weight percent of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
[0294] In one embodiment, the solvent is propylene glycol or glycerol formal, the phospholipid is Phospholipon® 90H, the phospholipid is present in an amount of about 1 to 2 percent by weight of the pharmaceutical composition, and the pharmaceutically active compound contains gentamycin or a pharmaceutically acceptable salt thereof 1 weight percent of the pharmaceutical composition, clotrimazole or a pharmaceutically acceptable salt thereof in an amount of about 1 percent by weight of the pharmaceutical composition, and betamethasone or a pharmaceutically acceptable ester thereof in an amount of about 0.1 percent by weight of the pharmaceutical composition.
4.5.3 General features of pharmaceutical compositions [0295] In one embodiment, the pharmaceutical composition has a viscosity of greater than about 1000 cP at 20 ° C.
[0296] In one embodiment, the pharmaceutical composition has a viscosity greater than about 2000 cP at 20 ° C.
[0297] In one embodiment, the pharmaceutical composition has a viscosity greater than about 5000 cP at 20 ° C.
[0298] In one embodiment, the pharmaceutical composition has a viscosity of greater than about 10,000 cP at 20 ° C.
[0299] In one embodiment, the pharmaceutical composition has a viscosity of greater than about 15,000 cP at 20 ° C.
[0300] In one embodiment, the pharmaceutical composition has a viscosity of greater than about 20,000 cP at 20 ° C.
[0301] In one embodiment, the pharmaceutical composition has a viscosity greater than about 25,000 cP at 20 ° C.
[0302] Typically, the pharmaceutical composition has a viscosity of less than about 100,000 cP at 20 ° C.
[0303] In one embodiment, the pharmaceutical composition has a viscosity of less than about 75,000 cP at 0 ° C.
[0304] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 1000 cP to 100,000 cP at 20 ° C.
[0305] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 2,000 cP to 100,000 cP at 20 ° C.
[0306] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 5000 cP to 100,000 cP at 20 ° C.
[0307] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 10,000 cP to 100,000 cP at 20 ° C.
[0308] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 20,000 cP to 100,000 cP at 20 ° C.
[0309] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 25,000 cP to 100,000 cP at 20 ° C.
[0310] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 1000 cP to 75,000 cP at 20 ° C.
[0311] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 2,000 cP to 75,000 cP at 20 ° C.
[0312] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 5000 cP to 75,000 cP at 20 ° C.
[0313] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 10,000 cP to 75,000 cP at 20 ° C.
[0314] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 20,000 cP to 75,000 cP at 20 ° C.
[0315] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 25,000 cP to 75,000 cP at 20 ° C.
[0316] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 2,000 cP to 25,000 cP at 20 ° C.
[0317] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 5000 cP to 25,000 cP at 20 ° C.
[0318] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 2,000 cP to 18,000 cP at 20 ° C.
[0319] In one embodiment, the pharmaceutical composition has a viscosity that ranges from about 5000 cP to 18,000 cP at 20 ° C.
[0320] Viscosity is determined using a Brookfield DV-E viscometer (commercially available from
Brookfield from Middleboro, MA).
4.5.4 Optional Additives [0321] The present pharmaceutical compositions may optionally contain an appropriate amount of a pharmaceutically acceptable preservative, if desired, to provide additional protection against microbial growth.
[0322] Examples of preservatives useful in the pharmaceutical compositions of the invention include, but are not limited to, potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other parahydroxybenzoic acid esters such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chlorides (e.g., benzethonium chloride).
[0323] In one embodiment, the pharmaceutical compositions of the invention may optionally contain a suitable amount of a pharmaceutically acceptable polymer.
The polymer further increases the viscosity of the pharmaceutical composition. Many pharmaceutical compositions of the invention lose gel properties at temperatures greater than about 40 ° C. After incorporation of the polymer into pharmaceutical compositions, the pharmaceutical compositions retain gel properties at higher temperatures.
[0324] Suitable polymers for use in the compositions and methods of the invention include, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), chitosan, poly (acrylic acid), and poly (methacrylic acid).
[0325] In one embodiment, the polymer is HPMC.
[0326] In one embodiment, the polymer is hydroxypropyl cellulose, [0327] In one embodiment, the polymer is poly (acrylic acid). In one embodiment, the poly (acrylic acid) is a cross-linked poly (acrylic acid) such as Carbomer® (commercially available from Carbomer, Inc. of Westborough, MA).
[0328] In one embodiment, the polymer is poly (methacrylic acid).
[0329] Typically, the polymer is present in an amount ranging from over 0 to 10 percent by weight of the pharmaceutical composition.
[0330] In one embodiment, the polymer is present in an amount ranging from about 0.1 to 10 percent by weight of the pharmaceutical composition.
[0331] In one embodiment, the polymer is present in an amount ranging from about 1 to 7.5 percent by weight of the pharmaceutical composition.
[0332] In one embodiment, the polymer is in an amount ranging from about
1.5 to 5 weight percent of the pharmaceutical composition.
[0333] In one embodiment, the polymer is present in an amount in the range of about 2 to 4 percent by weight of the pharmaceutical composition.
[0334] The components of the pharmaceutical composition (polymer, solvents and pharmaceutically active agent, as well as any other optional ingredients) are preferably biologically compatible and non-toxic, and in time are simply absorbed and / or metabolized by the body.
[0335] In one embodiment, the pharmaceutical compositions of the invention are substantially free of polymers.
[0336] In one embodiment, any additional ingredients added to the pharmaceutical compositions of the invention are designated as GRAS by the FDA for use or consumption by animals.
[0337] In another embodiment, any additional ingredients added to the pharmaceutical compositions of the invention are designated as GRAS by the FDA for use or human consumption.
4.6. Methods for treating the condition in an animal [0338] The pharmaceutical compositions of the invention are useful in human and veterinary medicine.
[0339] In one embodiment, the method of treating or preventing a condition in an animal comprises administering to an animal in need thereof a therapeutically effective amount of a pharmaceutically active agent by oral administration of a pharmaceutical composition of the invention.
[0340] In one embodiment, the method of treating or preventing a condition in an animal comprises administering to a animal in need thereof a therapeutically effective amount of a pharmaceutically active agent by in-ear applying the pharmaceutical composition of the invention.
[0341] In one embodiment, the method of treating or preventing a condition in an animal comprises administering to a animal in need thereof a therapeutically effective amount of a pharmaceutically active agent by ocular application of the pharmaceutical composition of the invention.
[0342] In one embodiment, the method of treating or preventing a condition in an animal comprises administering to a animal in need thereof a therapeutically effective amount of a pharmaceutically active agent by topically applying a pharmaceutical composition of the invention.
[0343] The pharmaceutical compositions of the invention are viscous compositions. Viscous drug-containing compositions are preferable to less viscous (less frequent) liquid preparations for treating or preventing conditions in animals. For example, in topical, in-ear and ophthalmic applications, especially veterinary, thinner liquid formulations are easily washed out or swept out of the targeted delivery area than formulations that are more viscous (denser). For the treatment of conditions such as microbial infections, especially in non-human animals, the benefits of denser pharmaceutical compositions include keeping the pharmaceutically active agent, such as antibiotics, in the target area for a long time.
[0344] The pharmaceutical compositions of the invention are particularly useful in veterinary medicine, especially in ear applications. For example, in the treatment or prevention of otic microbial infections in small animals such as cats and dogs, the pharmaceutical composition is typically administered in an amount of about 0.5 ml per ear. However, larger amounts may be given to larger animals.
[0345] The pharmaceutical compositions of the invention are preferred in veterinary medicine, especially in ear applications, compared to commercially available pharmaceutical compositions. For example, when treating or preventing otic microbial infections in animals using commercially available pharmaceutical compositions, the animal usually shakes its head and moves the composition from the target infected area (and often completely out of the ear). This is easily done with commercially available antibiotic compositions because they have a lower viscosity. However, the pharmaceutical compositions of the invention, having higher viscosities, are not so easily displaced, and therefore are more effective, in delivering the active pharmaceutical agent to the target infected area and remaining for an extended period of time in the infected area to provide controlled or sustained release of the active pharmaceutical agent.
[0346] Preferably, the pharmaceutical compositions of the invention may be used less frequently than commercially available pharmaceutical compositions. Often, only two doses or a single dose of the pharmaceutical compositions of the invention are effective in treating or preventing otic microbial infections in animals. In contrast, commercially available pharmaceutical compositions typically require a much larger number of doses. For example, OTOMAX® (commercially available from
Schering-Plow Animal Health of Union NJ) requires 2 doses per day for 7 days.
[0347] Furthermore, the pharmaceutical compositions of the invention are typically more lipophilic than aqueous or semi-aqueous preparations. Without wishing to be bound by theory, it is believed that the increased lipophilicity of the pharmaceutical compositions of the invention causes them to be more effective than aqueous or hemihydrate formulations, particularly in the treatment or prevention of ear infections in animals, since the pharmaceutical compositions of the invention are more compatible with the highly lipophilic environment of the animal's ear.
[0348] The pharmaceutical compositions of the invention also adhere well to the skin and are accordingly suitable for topical application.
[0349] The pharmaceutical compositions of the invention may also be administered orally. To administer the pharmaceutical compositions orally, the pharmaceutical composition may be, for example, enclosed in a capsule, such as a hard gelatin capsule or soft gelatin capsule, and the capsule administered orally to the animal. Suitable capsules for use in the invention are Shionogi Qualicaps (commercially available from Shionogi & Co., Ltd of Osaka, Japan). Oral dosage forms can be designed to release the pharmaceutically active compound in the stomach immediately or almost immediately, or to provide sustained release of the pharmaceutically active compound in the stomach. Oral dosage forms can also be designed to release the pharmaceutically active compound in the intestines immediately or almost immediately, or to provide sustained release of the pharmaceutically active compound in the intestines. To delay the release of the pharmaceutically active compound until the dosage form reaches the intestines, the capsule is coated with an enteric coating. Typically, the enteric coating is a pH-sensitive polymer such as Eudragit® L-100 (commercially available from DeGussa AG from Frankfurt, Germany). The release rate of the pharmaceutically active compound is varied by varying the amount of phospholipid or sphingomyelin in the pharmaceutical composition and the presence of polymers in the pharmaceutical composition .
[0350] When administered topically, by the ear, or intraocularly, the pharmaceutical compositions of the invention may provide controlled or sustained release of the pharmaceutically active agent in a pharmaceutically effective amount for up to about 15 days and even longer.
[0351] In one embodiment, the pharmaceutical compositions of the invention provide controlled or sustained release of a pharmaceutically active agent in a pharmaceutically effective amount for at least about 4 to about 15 days.
[0352] In another embodiment, the pharmaceutical compositions of the invention provide controlled or sustained release of a pharmaceutically active agent in a pharmaceutically effective amount for at least about 4 to about 10 days.
[0353] In another embodiment, the pharmaceutical compositions of the invention provide controlled or sustained release of a pharmaceutically active agent in a pharmaceutically effective amount for at least about 1 week.
[0354] In a preferred embodiment, the pharmaceutical compositions of the invention, providing controlled or sustained release of a pharmaceutically active agent, have reduced toxicity, especially in small animals such as cats and dogs. Accordingly, the pharmaceutical compositions of the invention have a better therapeutic profile than conventional immediate release formulations. Methods comprising administering a pharmaceutically active agent to an animal by topical, in-ear or ocular application of the pharmaceutical composition of the invention allow the administration of pharmaceutically active agents to animals that could potentially (when administered in currently available dosage forms) cause toxicity and even death of the treated animal. Advantageously, providing controlled or sustained release of pharmaceutically active agents, the pharmaceutical composition of the invention may be administered less frequently, and thus also be easier to use, convenient and more cost effective than conventional modes of administration of pharmaceutically active agents.
[0355] The amount of pharmaceutically active agent (s) effective in treating or preventing a condition, e.g., a bacterial infection, can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be used to help identify optimal dosage ranges. The exact dose used will also depend on the route of administration, the severity of the condition and the animal being treated, and may be determined depending on the judgment of the physician and / or the circumstances of each animal. However, suitable effective dosage levels may typically range from about 0.1 mg / kg body weight to about 100 mg / kg body weight, preferably about 1 mg / kg body weight to about 50 mg / kg body weight, more preferably from about 2 mg / kg body weight to about 30 mg / kg body weight, for example from about 5 mg / kg body weight to about 100 mg / kg body weight. The effective dosage amounts described herein refer to the total amount administered of all pharmaceutically active agents; that is, if more than one pharmaceutically active agent is administered, the effective dosage amounts correspond to the total amount administered.
[0356] Typically, the pharmaceutical composition is administered from about 1 time each day to about 1 time per week until the condition subsides.
[0357] In one embodiment, the pharmaceutical composition is administered once a day until the condition subsides.
[0358] In one embodiment, the pharmaceutical composition is administered twice each day until the condition weakens.
[0359] In one embodiment, the pharmaceutical composition is administered once a week until the condition subsides.
[0360] In one embodiment, the pharmaceutical composition is administered twice each week until the condition subsides.
[0361] In one embodiment, the pharmaceutical composition is administered about every 12 hours until the condition is subdued.
[0362] In one embodiment, the pharmaceutical composition is administered once. In many cases, the pharmaceutical compositions are effective in treating or preventing an animal's condition.
[0363] In one embodiment, the pharmaceutical composition is administered daily for 1 week.
[0364] In one embodiment, the pharmaceutical composition is administered about every 7 days for 4 weeks.
[0365] In one embodiment, the pharmaceutical composition is administered about every 7 days for 3 weeks.
[0366] In one embodiment, the pharmaceutical composition is administered about every 7 days for 2 weeks.
[0367] In one embodiment, the pharmaceutical composition is administered twice with an interval of about 24 hours.
[0368] In one embodiment, the pharmaceutical composition is administered twice with an interval of about 48 hours.
[0369] In one embodiment, about 24 hours for about 4 weeks.
[0370] In one embodiment, about 12 hours for about 4 weeks.
[0371] In one embodiment, about 24 hours for about 2 weeks.
[0372] In one embodiment, about 12 hours for about 2 weeks.
[0373] In one embodiment, about 24 hours for about 1 week.
the pharmaceutical composition is administered every pharmaceutical composition is administered every pharmaceutical composition is administered every pharmaceutical composition is administered every pharmaceutical composition is administered every [0374] In one embodiment, the pharmaceutical composition is administered about every 12 hours for about 1 week.
[0375] In another embodiment, an effective dosage amount is administered daily until the condition subsides. The total dose can optionally be divided into daily doses and / or into about 2 to 4 single doses.
[0376] In one embodiment, the condition is a bacterial infection.
[0377] Representative bacterial infections that can be treated using the pharmaceutical compositions of the invention include, but are not limited to, bacterial infections caused by bacteria of the genus Pasteurella, Haemophilus, Fusobacterium,
Moraxella, Bacteroides, Aeromonas, Escherichia, Enterobacter, Klebsiella, Salmonella, Shigella, Serratia, Ureaplasma, Chlamydia, Actinobacillus, Streptococcus, Edwardsiella, Staphylococcus, Enterococcus, Bordetella, Proteus, Mycoplasma, or
[0378] Representative bacterial infections that can be treated using the pharmaceutically active agents of the present invention include, but are not limited to, bacterial infections caused by Pasteurella haemolytica, Pasteurella multocida, Pasteurella haemolytica, Haemophilus somnus, Actinobacillus pleuropneumoniae, Actinomielsycinasycomesielsycycomesycycline, Pneumonia, Escherichia Faecalis, Escherichia Coli, Staphylococcus Aureaus, Streptococcus Pyogenes, Bacillus Subtilis, Streptococcus spp., Staphylococcus spp., Moraxella spp., Salmonella spp.,
Bacteroides spp., Peptococcus indolicus, Fusobacterium spp., Mycoplasma bovis, Mycoplasma dispar, Ureaplasma spp., Chlamydia spp., Mycoplasma mycoides, Mycoplasma ovipneumonia, Haemophilus influenzae, Klebsielella Bella, Salmonella
[0379] In one embodiment, the condition is a fungal infection.
[0380] In one embodiment, the condition is yeast infection.
[0381] Without wishing to be bound by theory, it is believed that the pharmaceutical compositions of the invention, where the pharmaceutical composition is in the form of a gel containing a pharmaceutically active agent (s) allows for higher contents than achievable for liposome preparations (where the maximum content is believed to be is only about 1 weight percent of the composition comprising liposome). Indeed, a pharmaceutical composition containing uniformly distributed pharmaceutically active agents in an amount as high as about 5 percent by weight of the pharmaceutical composition, or even more, is routinely possible using the compositions of the invention. Indeed, a pharmaceutical composition containing uniformly distributed pharmaceutically active agents in an amount as high as about 25 percent by weight of the pharmaceutical composition is possible. The pharmaceutical compositions of the invention are preferably substantially free of liposomes. In one embodiment, the pharmaceutical compositions of the invention are free of liposomes.
[0382] In one embodiment, the animal is a non-human animal.
[0383] In another embodiment, the animal is a human.
[0384] In another embodiment, the animal is a cat.
[0385] In another embodiment, the animal is a dog.
[0386] In another embodiment, the animal is a cow.
[0387] In another embodiment, the animal is a pig.
[0388] In another embodiment, the animal is a sheep.
[0389] In another embodiment, the animal is a horse.
4.7. Preparation of pharmaceutical compositions [0390] Pharmaceutical compositions of the invention comprising (i) a phospholipid or sphingomyelin; (ii) a first organic solvent; (iii) a second organic solvent; and (iv) a pharmaceutically active agent, can be prepared, for example, simply by adding the pharmaceutically active agent (s) to the mixture of the first organic solvent and the second organic solvent ("solvent mixture") (typically about 90% of the amount of the solvent mixture desired in the final pharmaceutical composition ) and by shaking or stirring the resulting mixture to dissolve the pharmaceutically active agent (s). One or more optional additives can be added simultaneously and / or sequentially and the mixture shaken or mixed until the optional additive (s) dissolve. The phospholipid is then added to the mixture, with shaking or stirring, and optionally with heating, to give a phospholipid mixture. Typically, the mixture is heated at a temperature lower than 100 ° C, preferably lower than 70 ° C, more preferably lower than about 50 ° C, and most preferably about 40 ° C before adding the phospholipid.
An additional solvent mixture is then added to provide the desired concentration of the pharmaceutically active agent (s) in the pharmaceutical composition and the phospholipid mixture is allowed to cool to room temperature to obtain the pharmaceutical composition.
[0391] Similarly, the pharmaceutical compositions of the invention comprising (i) a phospholipid or sphingomyelin, a solvent selected from the group consisting of propylene glycol substantially free of other organic solvents and glycerol formal substantially free of other organic solvents, and (iii) a pharmaceutically active agent can be prepared, for example . simply by adding the pharmaceutically active agent (s) to propylene glycol or glycerol formal (typically about 90% of the amount of solvent desired in the final pharmaceutical composition) and shaking or stirring the resulting mixture, optionally with heating, to dissolve the pharmaceutically active agent (s). One or more optional additives can be added simultaneously and / or sequentially and the mixture shaken or mixed until the optional additive (s) dissolve. The phospholipid is then added to the mixture, with shaking or stirring, and optionally with heating, to give a phospholipid mixture. Typically, the mixture is heated at a temperature lower than 100 ° C, preferably lower than 70 ° C, more preferably lower than about 50 ° C, and most preferably about 40 ° C before adding the phospholipid. Additional propylene glycol or glycerol formal is then added to provide the desired concentration of the pharmaceutically active agent (s) in the pharmaceutical composition and the phospholipid mixture is allowed to cool to room temperature to obtain the pharmaceutical composition.
[0392] A person skilled in the art, however, will readily recognize that modifications to the above-described methods for preparing the pharmaceutical compositions of the invention are possible, for example, the order of adding the ingredients to the solvent (s) can be changed.
4.8 Kits [0393] The invention includes kits that can simplify the administration of a pharmaceutically active agent to an animal. A typical kit of the invention includes the unit dosage form of the pharmaceutical composition of the invention. In one embodiment, the unit dosage form is a container (such as a vial, bag, tube, syringe, or the like) that can preferably be sterile, containing the pharmaceutical composition of the invention. The kit may further include a label or printed instructions informing about the use of a pharmaceutically active agent for the treatment or prevention of a condition. In another embodiment, the kit comprises a unit dosage form of the pharmaceutical composition of the invention and a dropper, syringe or other applicator for administering the pharmaceutical composition. Typically, kit components, for example, unit dosage form and instructions, are included in the appropriate packaging material.
[0394] The following examples are provided to assist in the understanding of the invention and should not be construed as specifically limiting the invention described herein and claimed. Such variations of the invention, including the use of all equivalents currently known or later developed that would be within the competence of those skilled in the art, and changes in formulation or minor changes in experimental designs should be understood to fall within the scope of the invention.
5. EXAMPLES
Example 5.1: Phospholipid pharmaceutical composition in the form of gel [0395] Tobramycin (2.5 g), terbinafine (2.5 g), decanoic acid (6.34 g), betamethasone acetate (250 mg), and benzethonium chloride (50 mg ) was dissolved in 150 ml of stabilized glycerol formal and the resulting mixture was heated to about 40 ° C with stirring to obtain a clear solution. 37.5 ml of stabilized glycerol formal and 62.5 ml of propylene carbonate were added to the resulting solution, and the resulting solution was heated to about 40 ° C with stirring to obtain a clear solution. Phospholipon ® -90H (2.5 g) (commercially available from Phospholipid GmbH from Cologne, Germany) was added in
40 ° C to the solution with stirring to give a clear solution. Hydroxypropyl methylcellulose (5 g) was then added to the solution with stirring at 40 ° C to obtain a clear solution. The solution was allowed to cool to room temperature to give a gel. The resulting gel contains about 1.25% by weight of Phospholipon®.
[0396] The resulting gel contained 1% tobramycin as the decanoic acid salt, 1% terbinafine as the decanoic acid salt, 0.1% betamethasone acetate, and 0.02% benzethonium chloride and had a viscosity of 2346 cP at 20 ° C.
Example 5.2: Phospholipid pharmaceutical composition in the form of gel [0397] Florfenicol (5 g), betamethasone acetate (500 mg), oleic acid (4.8 g), and benzethonium chloride (100 mg) were dissolved in 250 ml of propylene carbonate and the resulting mixture heated to about 40-45 ° C with stirring to give a clear solution.
To the resulting solution, 284.5 g of stabilized glycerol formal was added, and the resulting solution was heated to about 40 ° C with stirring to obtain a clear solution.
Phospholipon®-90H (5 g) (commercially available from Phospholipid GmbH from Cologne, Germany) was then added at 40 ° C to the solution with stirring to give a clear solution.
The solution was allowed to cool to room temperature overnight to give a gel.
The resulting gel had a viscosity of 52.300 cP at 20 ° C.
[0398] The next day, 150 ml of gel was warmed to about 40 ° C to give a liquid and hydroxypropyl methylcellulose (4.5 g) was added to the liquid at 40 ° C, and the resulting mixture was allowed to stir at 40 ° C for about 15 min. The mixture was then cooled to room temperature to give a gel. The resulting gel contains about 2% by weight
Phospholipon ®.
[0399] The resulting gel contained% florfenicol, 1% terbinafine as the oleic acid salt,
0.1% betamethasone acetate, and 0.02% benzethonium chloride and had a viscosity of 17,880 cP at 20 ° C.
Example 5.3: Phospholipid pharmaceutical composition in the form of gel [0400] Tobramycin (5 g), terbinafine (5 g), decanoic acid (6.35 g), acetic acid (2.21 g), betamethasone acetate (500 mg) and chloride benzethonium (100 mg) was dissolved in
375 ml of stabilized glycerol formal and 90 ml of propylene carbonate added to the solution.
The resulting mixture was heated to about 40 ° C and Phospholipon ® -90H (5 g) (commercially available from Phospholipid GmbH from Cologne, Germany) was added with stirring to give a clear solution. Then hydroxypropyl methylcellulose (15 g) was slowly added to the solution with stirring at 40 ° C. The solution was stirred for 15 min. and then allowed to cool to room temperature to give a gel. The resulting gel contains about 2.5% by weight of Phospholipon® and about 3% by weight of hydroxypropyl methylcellulose.
[0401] The resulting gel contained 1% tobramycin as a mixture of the decanoic acid salt and acetic acid salt, 1% terbinafine as a mixture of the decanoic acid salt and acetic acid salt, 0.1% betamethasone acetate, and 0.02% benzethonium chloride, and had a viscosity 3650 cP at 20 ° C.
Example 5.4: Phospholipid pharmaceutical composition in the form of a gel [0402] Florfenicol (5 g), betamethasone acetate (500 mg), oleic acid (4.8 g) and benzethonium chloride (100 mg) were dissolved in 250 ml of propylene carbonate and the resulting mixture was heated to a temperature of about 40-45 ° C with stirring to obtain a clear solution.
To the resulting solution, 284.5 g of stabilized glycerol formal was added, and the resulting solution was heated to about 40 ° C with stirring to obtain a clear solution.
Phospholipon ® -90H (7.5 g) (commercially available from Phospholipid GmbH from Cologne,
Germany) was then added at 40 ° C to the solution with stirring to give a clear solution. The solution was allowed to cool to room temperature overnight to give a gel. The resulting gel contains about 3% by weight of Phospholipon®. The resulting gel contained 1% florfenicol, 1%, 0.1% betamethasone acetate and 0.02% benzethonium chloride and had a viscosity of 65 300 cP at 20 ° C.
Example 5.5: Phospholipid pharmaceutical composition in the form of gel [0403] Tobramycin (2.5 g), terbinafine (2.5 g), decanoic acid (6.35 g), betamethasone acetate (250 mg) and benzethonium chloride (50 mg) dissolved in 187.5 ml stabilized glycerol formal and heated to about 40 ° C. 45 ml of propylene carbonate was added to the solution and the temperature was kept around 40 ° C. Phospholipon ® -90H (2.5 g) (commercially available from Phospholipid GmbH from Cologne, Germany) was then added to the resulting solution with stirring to obtain a clear solution. Hydroxypropyl methylcellulose (10 g) was then slowly added to the solution at 40 ° C with stirring. The solution was stirred for 15 min and then allowed to cool to room temperature to give a gel. The resulting gel contains about 2.5% by weight of Phospholipon® and about 4% by weight of hydroxypropyl methylcellulose.
[0404] The resulting gel contained 1% tobramycin as the decanoic acid salt, 1% terbinafine as the decanoic acid salt, 0.1% betamethasone acetate, and 0.02% benzethonium chloride and had a viscosity of 160 160 cP at 20 ° C.
Example 5.6: Phospholipid pharmaceutical composition in gel form [0405] Florfenicol (10 g), terbinafine (10 g), oleic acid (9.7 g), betamethasone acetate (1 g) and benzethonium chloride (1 g) were dissolved in about 500 ml glycerin formal and the resulting mixture was heated to about 40 ° C with stirring to give a solution. Phospholipon ® -90H (10 g) (commercially available from Phospholipid GmbH from Cologne, Germany) and hydroxypropyl methylcellulose (30 g) were added to the resulting solution at 40 ° C with stirring to give a solution. The solution was then made up to a volume of 1000 ml (at 40 ° C) with glycerol formal. The total amount of glycerol formal was 898.46 g. The solution was allowed to cool to room temperature to give a gel. The resulting gel contains about 1% by weight of Phospholipon®, about 1% by weight of florfenicol, about 1% by weight of terbinafine as the oleic acid salt, about 0.1% by weight of betamethasone acetate, and about 0.1% by weight of benzethonium chloride.
Example 5.7: Phospholipid pharmaceutical composition in the form of a gel [0406] Tobramycin (5 g), terbinafine (5 g), betamethasone acetate (0.5 g), decanoic acid (6.35 g), acetic acid (2.21 g) and benzethonium chloride (0.5 g) was dissolved in about 300 ml of glycerol formal and the resulting mixture was heated to about 40 ° C with stirring to give a solution. Phospholipon® was added to the resulting solution at 40 ° C
-90H (10 g) (commercially available from Phospholipid GmbH from Cologne, Germany) and hydroxypropyl methylcellulose (10 g) with stirring to give a solution. The solution was then made up to a volume of 500 ml (at 40 ° C) with glycerol formal. The total amount of glycerol formal was 568.66 g. The solution was allowed to cool to room temperature to give a gel. The resulting gel contains about 2% by weight of Phospholipon®, about 1% by weight tobramycin as a mixture of the decanoic acid salt and acetic acid salt, about 1% by weight terbinafine as a mixture of the decanoic acid salt and acetic acid salt, about 0.1% betamethasone acetate, and about 0.1% benzethonium chloride.
[0407] A similar formulation may be prepared by replacing tobramycin with azithromycin (8 g).
Example 5.8: Phospholipid pharmaceutical composition in the form of a gel [0408] About 300 ml of glycerol formal was heated to about 40 ° C, and decanoic acid (41.7 g) and tilmicosin (108.2 g, 92.4% pure) were added to the formal glycerin. The resulting mixture was stirred to give a solution. Phospholipon®-90H (15 g) (commercially available from Phospholipid GmbH from Cologne, Germany) was added with stirring to give a solution. Then hydroxypropyl methylcellulose (12 g) was slowly added to the solution at 40 ° C with stirring. Glycerin formal was then added to give a volume of 500 ml (at 40 ° C) and the solution was allowed to cool to room temperature to give a gel. The resulting gel contains about 3% by weight of Phospholipon®, about 2.4% by weight of hydroxypropyl methylcellulose and about 20% by weight of tilmicosin as the decanoic acid salt.
[0409] A similar formulation may be prepared by replacing tilmicosin with azithromycin (100 g).
Example 5.9: Phospholipid pharmaceutical composition in the form of a gel [0410] Tobramycin (5 g), terbinafine (5 g), betamethasone acetate (0.5 g), decanoic acid (6.35 g), acetic acid (2.21 g) and benzethonium chloride (0.5 g) was dissolved in ca.
300 mL glycerol formal and the resulting mixture was heated to about 40 ° C with stirring to give a solution. Phospholipon® 90H (10 g) (commercially available from Phospholipid GmbH from Cologne, Germany) was added to the resulting solution at 40 ° C with stirring to give a solution. The solution was then made up to a volume of 500 ml (at 40 ° C) with glycerol formal. The total amount of glycerol formal was 568.66 g. The solution was allowed to cool to room temperature to give a gel. The resulting gel contains about 2% by weight of Phospholipon®, about 1% by weight tobramycin as a mixture of the decanoic acid salt and acetic acid salt, about 1% by weight terbinafine as a mixture of the decanoic acid salt and acetic acid salt, about 0.1% betamethasone acetate, and about 0.1% benzethonium chloride. This phospholipid pharmaceutical composition in the form of a gel does not contain polymers.
Example 5.10: Phospholipid pharmaceutical composition in the form of a gel [0411] Tobramycin (5 g), terbinafine (5 g), betamethasone acetate (0.5 g), decanoic acid (6.35 g), acetic acid (2.21 g) and benzethonium chloride (0.5 g) was dissolved in about 300 ml of glycerol formal and the resulting mixture was heated to about 40 ° C with stirring to give a solution. Phospholipon ® -90H (10 g) (commercially available from Phospholipid GmbH from Cologne, Germany) was added to the resulting solution at 40 ° C with stirring to give a solution. The solution was then made up to a volume of 500 ml (at 40 ° C) with glycerol formal. The solution was allowed to cool to room temperature to give a gel. The resulting gel contains about 2% by weight of Phospholipon ®, about 1% by weight of tobramycin as a mixture of the decanoic acid salt and acetic acid salt, about 1% by weight of terbinafine as a mixture of the decanoic acid salt and acetic acid salt, about 0.1% of betamethasone acetate and about 0 , 1% benzethonium chloride.
[0412] A similar formulation may be prepared by replacing tobramycin with azithromycin (8 g). Example 5.11: Clinical study [0413] Several dogs with ear infections were administered the pharmaceutical composition of Example 5.1, 5.2, or 5.3.
[0414] The following protocol was followed to evaluate the clinical effectiveness of the pharmaceutical compositions of the invention.
[0415] Dogs with ear infections were examined by a veterinarian on day 0 and each ear was assigned a clinical score based on the following signs associated with otis external: pain, erythema, exudate, swelling, odor and ulceration. The following scale was used:
Ache:
= none = mild / moderate: painful when touched
<td> 2 =</td><td>severe: painful when touching the auricle</td>
<td>Erythema</td><td></td>
<td> 0 =</td><td>lack</td>
<td> 1</td><td>= mild / moderate: barely noticeable to obvious</td>
redness visible under the otoscope = severe: beetroot or cherry red or erythema passes to the pinna
Exudation
<td> 0 =</td><td>lack</td>
<td> 10 1 =</td><td>Mild / moderate: small amount visible in the ear canal</td>
<td> 2 =</td><td>severe: comes out of the ear canal and may be crusted</td>
Swelling
<td> 0 =</td><td>lack</td>
<td> 1 =</td><td>mild to moderate: some closure of the ear canal</td>
<td> 15 2 =</td><td>heavy: the channel is completely closed</td>
<td>Smell</td><td></td>
<td> 0 =</td><td>lack</td>
<td> 1</td><td>= mild / moderate: ugly smell pronounced when lifted</td>
concha
2 = heavy: an unpleasant odor distinct without raising the pinna to expose the ear canal
Sore
<td> 0 =</td><td>lack</td>
<td> 1 =</td><td>mild / moderate: slight abrasions</td>
<td> 25 2 =</td><td>severe: abrasions that may bleed</td>
[0416] Assessment of pain, erythema, exudate, swelling, smell and ulceration was combined to obtain a combined clinical rating in the range of 0 to 12 for 12 for the most severe otitis externa and 0 for the least severe otitis externa.
[0417] On day 0, the dog was also physically examined, an ear rubbing swab was used to determine bacterial and yeast cultures, and a second swab was prepared from an ear swab to identify bacteria and / or yeast. The dog's ear was also cleaned with a cleaning solution free of antimicrobial and anti-inflammatory activity, and excess solution was removed from the ear. 0.5 ml of the pharmaceutical composition of Example 5.1, 5.2, or 5.3 was then administered to each infected ear and the ears were massaged to spread the pharmaceutical composition.
[0418] On day 7 ± 2 days) each ear was re-evaluated using the same scale as used on day 0. On day 7 ± 2) 0.5 ml of the same pharmaceutical composition as administered on day 0 was re-administered to each infected ear and ears were massaged to spread the pharmaceutical composition.
[0419] On day 14 ± 2 days) each ear was re-evaluated using the same scale as used on day 0.
[0420] The study used dogs of different breeds of both sexes, with different body weights and physiological conditions. All dogs were at least 8 weeks old and generally had good health. For inclusion in the study, dogs had a minimum total clinical rating of 6 on day 0, did not take antimicrobial or anti-inflammatory therapy or anti-inflammatory therapy in the last month, had intact eardrums, visible bacteria or yeast on an ear swab, and no concurrent Otodectes cynotis infection.
[0421] The results of the study are shown below in Table I. The dogs in Group A were treated with the pharmaceutical composition of example 5.1, the dogs in Group B were treated with the pharmaceutical composition of example 5.2, and the dogs in Group C were treated with the pharmaceutical composition of example 5.3.
Table I
<td>Animal no</td><td colspan="6">Rating</td>
<td></td><td colspan="2">Day 0</td><td colspan="2">Day 7</td><td colspan="2">Day 14</td>
<td></td><td>Left ear</td><td>Right ear</td><td>Left ear</td><td>Right ear</td><td>Left ear</td><td>Right ear</td>
<td>Group A.<sup>1</sup></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td> 1</td><td> 7</td><td> 7</td><td> 3</td><td> 3</td><td> 1</td><td> 1</td>
<td> 4</td><td> 3</td><td> 6</td><td> 2</td><td> 2</td><td> 0</td><td> 2</td>
<td> 7</td><td> 10</td><td> 0</td><td> 1</td><td> 0</td><td> 0</td><td> 0</td>
<td> 10</td><td> 9</td><td> 9</td><td> 4</td><td> 3</td><td> 2</td><td> 0</td>
<td> 13</td><td> 12</td><td> 12</td><td> 2</td><td> 0</td><td> 1</td><td> 0</td>
<td> 16</td><td> 2</td><td> 9</td><td> 3</td><td> 4</td><td> 0</td><td> 4</td>
<td> 19</td><td> 10</td><td> 6</td><td> 3</td><td> 3</td><td> 1</td><td> 2</td>
<td> 22</td><td> 12</td><td> 12</td><td> 6</td><td> 6</td><td> 5</td><td> 5</td>
<td> 25</td><td> 0</td><td> 12</td><td> 0</td><td> 6</td><td> 4</td><td> 5</td>
<td> 28</td><td> 10</td><td> 9</td><td> 4</td><td> 4</td><td> 2</td><td> 3</td>
<td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Group B<sup>2</sup></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td> 2</td><td> 8</td><td> 8</td><td> 3</td><td> 0</td><td> 0</td><td> 0</td>
<td> 5</td><td> 6</td><td> 8</td><td> 2</td><td> 2</td><td> 2</td><td> 0</td>
<td> 8</td><td> 10</td><td> 0</td><td> 4</td><td> 0</td><td> 6</td><td> 0</td>
<td> 11</td><td> 0</td><td> 12</td><td> 0</td><td> 4</td><td> 0</td><td> 1</td>
<td> 14</td><td> 10</td><td> 10</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>
<td> 17</td><td> 8</td><td> 7</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>
<td> 20</td><td> 0</td><td> 10</td><td> 0</td><td> 2</td><td> 0</td><td> 0</td>
<td> 23</td><td> 9</td><td> 4</td><td> 4</td><td> 3</td><td> 2</td><td> 0</td>
<td> 26</td><td> 8</td><td> 7</td><td> 1</td><td> 2</td><td> 1</td><td> 1</td>
<td> 29</td><td> 7</td><td> 0</td><td> 3</td><td> 0</td><td> 1</td><td> 0</td>
<td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Group C<sup>3</sup></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td> 3</td><td> 0</td><td> 8</td><td> 0</td><td> 6</td><td> 0</td><td> 6</td>
<td> 6</td><td> 8</td><td> 8</td><td> 2</td><td> 2</td><td> 1</td><td> 0</td>
<td> 9</td><td> 0</td><td></td><td> 0</td><td> 2</td><td> 0</td><td> 2</td>
<td> 12</td><td> 10</td><td> 10</td><td> 4</td><td> 4</td><td> 2</td><td> 2</td>
<td> 15</td><td> 0</td><td> 10</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>
<td> 18</td><td> 8</td><td> 8</td><td> 8</td><td> 8</td><td> 8</td><td> 8</td>
(continuation)
<td>Animal no</td><td colspan="6">Rating</td>
<td></td><td colspan="2">Day 0</td><td colspan="2">Day 7</td><td colspan="2">Day 14</td>
<td></td><td>Left ear</td><td>Right ear</td><td>Left ear</td><td>Right ear</td><td>Left ear</td><td>Right ear</td>
<td> 21</td><td> 7</td><td> 6</td><td> 2</td><td> 2</td><td> 0</td><td> 1</td>
<td> 24</td><td> 0</td><td> 12</td><td> 0</td><td> 1</td><td> 0</td><td> 4</td>
<td> 27</td><td> 8</td><td> 8</td><td> 2</td><td> 1</td><td> 2</td><td> 0</td>
<td> 30</td><td> 10</td><td> 8</td><td> 1</td><td> 1</td><td> 1</td><td> 0</td>
<td colspan="7"><sup>1</sup> The dogs in Group A were treated with the pharmaceutical composition of example 5.1. 2<sup>2</sup> The dogs in Group B were treated with the pharmaceutical composition of example 5.2. about<sup>3</sup> The dogs in Group C were treated with the pharmaceutical composition of example 5.3.</td>
[0422] The data in Table I clearly show that the pharmaceutical compositions of the invention are effective in treating microbial ear infections in dogs.
Example 5.12: Clinical trial [0423] Several dogs with ear infections received the pharmaceutical composition of Example 5.6 or Example 5.7. The dogs treated with the pharmaceutical composition of example 5.6 were designated as Group A and the dogs treated with the pharmaceutical composition of example 5.7 were designated as Group B.
[0424] The same protocol as used in Example 5.10 was used to evaluate the clinical effectiveness of the pharmaceutical compositions of the invention.
[0425] Dogs with ear infections were examined by a veterinarian on day 0 and each ear was assigned a clinical grade based on the scale described in Example 5.10. The assessment of pain, erythema, exudate, swelling, odor and ulceration was combined to obtain a combined clinical rating ranging from 0 to 12 for 12 for the most severe otitis externa and 0 for the least severe otitis externa.
[0426] On day 0, the dog was also physically examined, clinical evaluation was assigned to each ear, the ear rubbing swab was used to determine bacterial and yeast cultures (the dacron rod was inserted into the ear canal and then
TM was placed in a Port-A-Cul transport tube<sup>™</sup> (commercially available from BD (Becton,
Dickinson and Company) from Franklin Lakes, NJ) for shipment to a reference laboratory for culture, and a second swab was prepared from an ear swab to identify bacteria and / or yeast (the Q tip was inserted into the ear canal and then rolled on a slide, the slide was heat fixed and stained using Diff-Quick (commercially available from IMEB Inc. of Chicago, IL). 0.5 ml of the pharmaceutical composition of Example 5.6 or Example 5.7 was then administered to each infected ear using a ml syringe and the ears were massaged to spread the pharmaceutical composition.
[0427] On day 7, each ear was re-evaluated using the same scale as used on day 0 and 0.5 ml of the same pharmaceutical composition as administered on day 0 was again given to each infected ear and the ears were massaged to distribute the pharmaceutical composition.
[0428] On day 14, each ear was re-assessed clinical using the same scale as used on day 0.
[0429] The study used dogs of different breeds of both sexes, with different body weights and physiological conditions. All dogs were at least 8 weeks old and generally had good health. For inclusion in the study, dogs had a minimum total clinical rating of 6 on day 0, did not take antimicrobial or anti-inflammatory therapy or anti-inflammatory therapy in the last month, had intact eardrums, visible bacteria or yeast on an ear swab, and no concurrent Otodectes cynotis infection.
[0430] The results of the study are shown in Table II below. The dogs in Group A were treated with the pharmaceutical composition of example 5.6 and the dogs in Group B were treated with the pharmaceutical composition of example 5.7. A final clinical score of 2 in each ear was considered an effective therapy.
Table II
<td>Animal no</td><td colspan="6">Rating</td>
<td></td><td colspan="2">Day 0</td><td colspan="2">Day 7</td><td colspan="2">Day 14</td>
<td></td><td>Left ear</td><td>Right ear</td><td>Left ear</td><td>Right ear</td><td>Left ear</td><td>Right ear</td>
<td>Group A.<sup>1</sup></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>ROB01</td><td> 8</td><td> 8</td><td> 2</td><td> 2</td><td> 1</td><td> 1</td>
<td>ROB03</td><td> 9</td><td> 9</td><td> 3</td><td> 3</td><td> 0</td><td> 0</td>
<td>ROB05</td><td> 6</td><td> 9</td><td> 0</td><td> 3</td><td> 0</td><td> 0</td>
<td>ROB07</td><td> 6</td><td> 8</td><td> 1</td><td> 2</td><td> 0</td><td> 0</td>
<td>ROB09</td><td> 7</td><td> 8</td><td> 2</td><td> 2</td><td> 0</td><td> 0</td>
<td>ROB011</td><td> 7</td><td> 7</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>
<td>Group B<sup>2</sup></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>ROB02</td><td> 9</td><td> 9</td><td> 3</td><td> 3</td><td> 0</td><td> 0</td>
<td>ROB04</td><td> 6</td><td> 6</td><td> 2</td><td> 2</td><td> 0</td><td> 0</td>
<td>ROB06</td><td> 10</td><td> 10</td><td> 3</td><td> 3</td><td> 2</td><td> 0</td>
<td>ROB08</td><td> 8</td><td> 8</td><td> 3</td><td> 3</td><td> 6</td><td> 6</td>
<td>ROB010</td><td> 7</td><td> 7</td><td> 1</td><td> 1</td><td> 0</td><td> 0</td>
<td>ROB012</td><td> 9</td><td> 9</td><td> 3</td><td> 3</td><td> 0</td><td> 0</td>
<td colspan="7"><sup>1</sup> The dogs in Group A were treated with the pharmaceutical composition of Example 5.6. 2<sup>2</sup> The dogs in Group B were treated with the pharmaceutical composition of Example 5.7.</td>
[0431] The data in Table V clearly show that the microbial ear infection in each Group A dog was successfully treated (100%) and that the microbial ear infection in each Group B dog, except for ROB08, was successfully treated (83.3%) . The ROB08 dog, however, showed no improvement. The data in Table V clearly show that the pharmaceutical compositions of the invention are effective in treating microbial ear infections in dogs.
Example 5.13: Stability of pharmaceutical compositions [0432] A pharmaceutical composition prepared as described in Example 5.1, 5.2, and 5.3 was incubated at about 40 ° C or about 70 ° C for up to 7 days to observe the degradation of pharmaceutically active agents as a function of time and temperature. The concentration of pharmaceutically active agents was determined at each time in the following procedure:
200 mg of the pharmaceutical composition is weighed into a 100 ml volumetric flask and the flask is made up to volume with 80:20 hexane: ethanol and shaken for about 1 min.
HMPC precipitates. 2 ml of the resulting solution is then filtered through a 25 mm Acrodisc syringe filter (0.2 µm Ultipore nylon membrane) and 10 g of the filtered solution is injected onto a Phenomenex Luna HPLC analytical column,
5 μm, CN 100A, 250 mm x 4.6 mm. HPLC is performed at a flow rate of ml / min and eluted with 65% hexane and 35% undenatured ethanol 200 degrees for 20 min. The HPLC device is equipped with a UV detector. Terbinafine and florfenicol are detected at 223 nm and betamethasone acetate is detected at 240 nm. Terbinafine has a retention time of about 4.0 min, betamethasone acetate has a retention time of about 4.4 min and florfenicol has a retention time of about 7.1 min.
[0433] The results of three such stability tests are presented in Tables III-V.
Table III Stability of the pharmaceutical composition of Example 5.1
<td>Day</td><td colspan="2">terbinafine</td><td colspan="2">tobramycin</td><td colspan="2">Betainetazone Acetate</td>
<td></td><td>40 ° C</td><td>70 ° C</td><td>40 ° C</td><td>70 ° C</td><td>40 ° C</td><td>70 ° C</td>
<td> 1</td><td> 101,2</td><td> 98,7</td><td>nd<sup>1</sup></td><td>nd</td><td> 85,6</td><td> 81,3</td>
<td> 2</td><td> 101,2</td><td> 98,2</td><td>nd</td><td>nd</td><td> 84,7</td><td> 80,1</td>
<td> 3</td><td> 101,5</td><td> 96,5</td><td>nd</td><td>nd</td><td> 81,8</td><td> 81,1</td>
<td> 4</td><td> 101,2</td><td> 97,4</td><td>nd</td><td>nd</td><td> 80,0</td><td> 79,9</td>
<td> 5</td><td> 97,8</td><td> 94,7</td><td>nd</td><td>nd</td><td> 80,9</td><td> 79,2</td>
<td> 6</td><td> 98,8</td><td> 94,6</td><td>nd</td><td>nd</td><td> 80,7</td><td> 79,5</td>
<td> 7</td><td> 99,1</td><td> 92,0</td><td>nd</td><td>nd</td><td> 80,6</td><td> 79,1</td>
<td colspan="7"><sup>1</sup> na = not specified</td>
Table IV. Stability of the pharmaceutical composition of Example 5.2
<td>Day</td><td colspan="2">terbinafine</td><td colspan="2">florfenicol</td><td colspan="2">Betamethasone acetate</td>
<td></td><td>40 ° C</td><td>70 ° C</td><td>40 ° C</td><td>70 ° C</td><td>40 ° C</td><td>70 ° C</td>
<td> 1</td><td> 99,0</td><td> 101,1</td><td> 102,7</td><td> 113,0</td><td> 100,9</td><td> 101,0</td>
<td> 2</td><td> 99,2</td><td> 99,3</td><td> 102,4</td><td> 105,1</td><td> 101,1</td><td> 98,3</td>
<td> 3</td><td> 98,9</td><td> 97,2</td><td> 104,9</td><td> 101,1</td><td> 101,9</td><td> 97,6</td>
<td> 4</td><td> 98,6</td><td> 97,9</td><td> 100,6</td><td> 99,0</td><td> 100,2</td><td> 97,1</td>
<td> 5</td><td> 100,8</td><td> 92,9</td><td> 104,4</td><td> 96,7</td><td> 99,5</td><td> 97,1</td>
<td> 6</td><td> 98,7</td><td> 92,6</td><td> 97,4</td><td> 97,5</td><td> 100,3</td><td> 98,4</td>
<td> 7</td><td> 98,5</td><td> 92,8</td><td> 104,3</td><td> 107,2</td><td> 100,1</td><td> 97,0</td>
Table V Stability of the pharmaceutical composition of Example 5.3
<td>Day</td><td colspan="2">terbinafine</td><td colspan="2">tobramycin</td><td colspan="2">Betainetazone Acetate</td>
<td></td><td>40 ° C</td><td>70 ° C</td><td>40 ° C</td><td>70 ° C</td><td>40 ° C</td><td>70 ° C</td>
<td> 1</td><td> 99,8</td><td> 98,0</td><td>nd<sup>1</sup></td><td>nd</td><td> 101,6</td><td> 89,6</td>
<td> 2</td><td> 99,3</td><td> 99,1</td><td>nd</td><td>nd</td><td> 99,2</td><td> 88,0</td>
<td> 3</td><td> 99,8</td><td> 99,8</td><td>nd</td><td>nd</td><td> 101,0</td><td> 88,9</td>
<td> 4</td><td> 98,6</td><td> 97,1</td><td>nd</td><td>nd</td><td> 101,3</td><td> 87,4</td>
<td> 5</td><td> 98,6</td><td> 96,5</td><td>nd</td><td>nd</td><td> 96,2</td><td> 87,2</td>
<td> 6</td><td> 98,3</td><td> 96,5</td><td>nd</td><td>nd</td><td> 93,9</td><td> 86,9</td>
<td> 7</td><td> 98,9</td><td> 96,5</td><td>nd</td><td>nd</td><td> 92,3</td><td> 87,1</td>
<td colspan="7"><sup>1</sup>na = not specified</td>
[0434] The data in Tables III, IV, and V indicate that the pharmaceutical compositions of Examples 5.1, 5.2, and 5.3, respectively, have good stability.
5.14 Phospholipid pharmaceutical composition for oral administration [0435] 300 ml of stabilized glycerol formal and 50 ml of propylene glycol were combined and heated to 40 ° C. 41.7 g of decanoic acid was added to the resulting solvent mixture, and the mixture was stirred to give a solution. Tilmicosin (108.2 g, 92.4% purity) was then added to the solution at 40 ° C with stirring to give a solution. Phospholipon ® -90H (15 g) (commercially available from Phospholipid GmbH from
Cologne, Germany) was added at 40 ° C to the solution with stirring to give a solution. Hydroxypropyl methylcellulose (12 g) was then added to the solution with stirring at 40 ° C to give a solution. The solution was made up to a volume of 500 ml at 40 ° C and then allowed to cool to room temperature to give a gel. The resulting gel contains about 3% by weight of Phospholipon®, 2.4% by weight of hydroxypropyl methylcellulose and 20% by weight of tilmicosin as the decanoic acid salt.
[0436] The resulting gel can then be placed in gelatin capsules to obtain a capsule containing tilmicosin as the decanoic acid salt.
5.15 Phospholipid pharmaceutical composition for oral administration [0437] 300 ml of stabilized glycerin formal and 75 ml of propylene carbonate were combined and heated to 40 ° C. 41.7 g of decanoic acid was added to the resulting solvent mixture, and the mixture was stirred to give a solution. Tilmicosin (108.2 g, 92.4% purity) was then added to the solution at 40 ° C with stirring to give a solution.
Phospholipon ® -90H (15 g) (commercially available from Phospholipid GmbH from Cologne,
Germany) was added at 40 ° C to the solution with stirring to give a solution. Hydroxypropyl methylcellulose (12 g) was then added to the solution with stirring at 40 ° C to give a solution. The solution was made up to a volume of 500 ml at 40 ° C and then allowed to cool to room temperature to give a gel. The resulting gel contains about 3% by weight of Phospholipon®, 2.4% by weight of hydroxypropyl methylcellulose and 20% by weight of tilmicosin as the decanoic acid salt.
[0438] The resulting gel can then be placed in gelatin capsules to obtain a capsule containing tilmicosin as the decanoic acid salt.
5.16 Clinical study [0439] Tilmicosin was orally administered to a dog using the pharmaceutical composition of Example 5.14. A sufficient amount of the gel of Example 5.14 was placed in a gelatin capsule to obtain a 20 mg / kg dose for the dog. The dog was then orally administered a gelatin capsule containing the tilmicosin pharmaceutical composition of Example 5.14. Blood was then collected from the dog at various times and the serum concentration of tilmicosin was determined by the following procedure:
(i) An AC-18 cartridge (commercially available from Waters Corp. from Milford, MA) was connected to a 20 ml syringe and a single diaphragm vacuum pump (commercially available from Gast Manufacturing Inc. of Benton Harbor, MI). The C-18 cartridge was conditioned by washing it with 10 ml methanol followed by 10 ml deionized water at a flow rate of less than 5 ml per minute;
(ii) 1 ml of serum was poured into the syringe and eluted through the C-18 cartridge;
(iii) The cartridge was washed with 10 ml 25% aqueous acetonitrile followed by 10 ml water;
(iv) The cartridge was then dried in a desiccator under high vacuum for 10 min;
(v) The cartridge was then eluted into a 2 ml volumetric flask with 5% acetic acid in methanol and the resulting 2 ml sample was stored in the refrigerator overnight; and (vi) The sample was then mixed using a vortex mixer and filtered into an amber high pressure liquid HPLC vial using a Pall Acrodisk syringe filter (commercially available from Pall Corp. from East
Hills, NY) to provide a solution for tilmicosin HPLC analysis.
[0440] HPLC analysis was performed by injecting 100 μΐ of the solution onto a 25 cm x 4.6 mm Phenomenex Sphericlone 5 μm analytical column equipped with a Phenomenex phenyl (phenylpropyl) protective column. HPLC was operated at a flow rate of 1.5 ml / min and eluted using a gradient elution according to the following profile:
<td>Time</td><td>Percentage of pump A (Acetonitrile)</td><td>Percentage of pump B (water)</td><td>Percentage of C pump (20 mM water dibutylamine solution)</td>
<td> 0,0</td><td> 50</td><td> 50</td><td> 0</td>
<td> 3,0</td><td> 50</td><td> 50</td><td> 0</td>
<td> 4,0</td><td> 15</td><td> 85</td><td> 0</td>
<td> 5,0</td><td> 15</td><td> 0</td><td> 85</td>
<td> 25,0</td><td> 25</td><td> 0</td><td> 75</td>
<td> 25,1</td><td> 50</td><td> 50</td><td> 0</td>
<td> 30,0</td><td> 50</td><td> 50</td><td> 0</td>
for 30 min HPLC was equipped with a UV detector operating at 280 nm. Tilmicosin was eluted with a retention time of 13 to 19 min.
[0441] Serum tilmicosin as a function of time is presented in Table VI.
Table VI: Serum tilmicosin as a function of time
<td>Time (hours)</td><td>Tilmicosin concentration (iig / ml)</td>
<td> 6</td><td> 0,3</td>
<td> 12</td><td> 0,23</td>
<td> 24</td><td> 0,18</td>
<td> 48</td><td> 0,1</td>
[0442] The results show that administration of the pharmaceutical composition ensures the presence of tilmicosin in the dog's blood for at least 48 h.
Example 5.17: Phospholipid composition for topical administration [0443] A pharmaceutical composition was prepared in substantially the same manner as the pharmaceutical composition described in Example 5.5 and with the same ingredients except that the pharmaceutical composition contained 0.1% benzethonium chloride.
Example 5.18: Clinical study [0444] Several dogs with ear infections received the pharmaceutical composition of Example 5.17. The following protocol was followed to evaluate the clinical effectiveness of the pharmaceutical composition of Example 5.17.
[0445] Dogs with ear infections were examined by a veterinarian on day 0 and each ear was assigned a clinical grade using the same scale as used in Example 5.11. If both ears were infected, the right ear was taken as the test ear. On day 0, a swab was obtained by inserting a dacron tip swab into the ear canal and then rolling on a slide, followed by fixation by heating and staining the slide with DifQuik. On day 0, culture was obtained from the infected dog's ear by inserting a dacron swab into the ear canal and then placing the swab in a Port-A-Cul transport tube for shipment to a reference laboratory.
[0446] For inclusion in the study, dogs must have been 8 weeks or older, a minimum clinical rating of 6, and intact tympanic membranes. In addition, the presence of yeast or bacteria on the swab was required. Animals were excluded from the study list if the clinical grade was lower than 6; if they have been treated with systemic or ear-borne antimicrobials or parenteral or topical anti-inflammatory agents, including short-acting corticosteroids during the last 14 days; if they have been treated with parenteral or long-acting corticosteroids during the last 28 days; if they had simultaneous Otodectes cynotis infections; or if foreign bodies were found in your ear canal.
[0447] The dogs were divided into two groups, Group A and Group B. The dogs in Group A were given a single dose of 0.5 ml of the pharmaceutical composition of Example 5.17 in each infected ear on day 0 and the dogs in Group B were given a single dose of 1.0 ml of the pharmaceutical composition of Example 5.17 in each infected ear on day 0.
β
The appropriate dose was placed into the ear canal with a 1 cm syringe<sup>3</sup>and then the ear was massaged.
[0448] Dogs of different breeds were used in the study. Tables VII-X describe race, age, gender and weight
Table VII: Study population by race of test animals.
<td>Race</td><td>Group A.</td><td>Group B</td><td>Sum</td>
<td>Basset hound</td><td> 0</td><td> 1</td><td> 1</td>
<td>Cocker spaniel</td><td> 1</td><td> 1</td><td> 2</td>
<td>Collie</td><td> 0</td><td> 2</td><td> 2</td>
<td>Coonhound (Red Tick)</td><td> 1</td><td> 0</td><td> 1</td>
<td>Dachshund</td><td> 0</td><td> 1</td><td> 1</td>
<td>Dalmatian</td><td> 0</td><td> 1</td><td> 1</td>
<td>English Toy Spaniel</td><td> 0</td><td> 1</td><td> 1</td>
<td>German Shepherd</td><td> 0</td><td> 1</td><td> 1</td>
<td>Labrador retriever</td><td> 1</td><td> 0</td><td> 1</td>
<td>Mixed breed</td><td> 3</td><td> 1</td><td> 4</td>
<td>Shih tzu</td><td> 3</td><td> 0</td><td> 3</td>
<td>Big poodle</td><td> 1</td><td> 1</td><td> 2</td>
<td>Together</td><td> 10</td><td> 10</td><td> 20</td>
Table VIII: Study population by age
<td>Age</td><td>Group A.</td><td>Group B</td><td>Sum</td>
<td><1 year</td><td> 3</td><td> 3</td><td> 6</td>
<td>> 1 and <5 years old</td><td> 3</td><td> 3</td><td> 6</td>
<td>> 5 and <10 years</td><td> 3</td><td> 3</td><td> 6</td>
<td>> 10 years</td><td> 1</td><td> 1</td><td> 2</td>
<td>Together</td><td> 10</td><td> 10</td><td> 20</td>
Table IX: Study population by age
<td>Sex</td><td>Group A.</td><td>Group B</td><td>Sum</td>
<td>Female</td><td> 0</td><td> 2</td><td> 2</td>
<td>Castrated female</td><td> 2</td><td> 4</td><td> 6</td>
<td>Male</td><td> 3</td><td> 3</td><td> 6</td>
<td>Castrated male</td><td> 5</td><td> 1</td><td> 6</td>
<td>Together</td><td> 10</td><td> 10</td><td> 20</td>
Table X: Study population by body weight
<td>Body weight</td><td>Group A.</td><td>Group B</td><td>Sum</td>
<td><10 pounds</td><td> 2</td><td> 1</td><td> 3</td>
<td>> 10 pounds and <25 pounds</td><td> 2</td><td> 4</td><td> 6</td>
<td>> 25 pounds and <50 pounds</td><td> 1</td><td> 0</td><td> 1</td>
<td>> 50 pounds</td><td> 5</td><td> 5</td><td> 10</td>
<td>Together</td><td> 10</td><td> 10</td><td> 20</td>
[0449] On day 7 and day 14, clinical scores were reassigned to the infected ear. The results of the study are presented in Table XI below.
Table XI: Clinical results
<td>Dog</td><td>Group<sup>and</sup></td><td>Score day 0</td><td>Day 7 assessment</td><td>Assessment day 14</td>
<td> 1</td><td>AND</td><td> 7</td><td> 3</td><td> 4</td>
<td> 2</td><td>B</td><td> 7</td><td> 2</td><td> 1</td>
<td> 3</td><td>AND</td><td> 9</td><td> 2</td><td> 3</td>
<td> 4</td><td>B</td><td> 7</td><td> 4</td><td> 2</td>
<td> 5</td><td>AND</td><td> 7</td><td> 1</td><td> 1</td>
<td> 6</td><td>B</td><td> 10</td><td> 4</td><td> 1</td>
<td> 7</td><td>AND</td><td> 12</td><td>No visit</td><td> 3</td>
<td> 8</td><td>B</td><td> 8</td><td> 2</td><td> 1</td>
<td> 9</td><td>AND</td><td> 9</td><td> 2</td><td> 0</td>
<td> 10</td><td>B</td><td> 9</td><td> 5</td><td> 2</td>
<td> 11</td><td>AND</td><td> 7</td><td> 0</td><td> 0</td>
<td> 12</td><td>B</td><td> 9</td><td> 3</td><td> 0</td>
<td> 13</td><td>AND</td><td> 7</td><td> 2</td><td> 1</td>
<td> 14</td><td>B</td><td> 8</td><td> 2</td><td> 0</td>
<td> 15</td><td>AND</td><td> 11</td><td> 6</td><td> 2</td>
<td> 16</td><td>B</td><td> 9</td><td> 2</td><td> 1</td>
<td> 17</td><td>AND</td><td> 12</td><td> 7</td><td> 2</td>
<td> 18</td><td>B</td><td> 9</td><td> 2</td><td> 1</td>
<td> 19</td><td>AND</td><td> 10</td><td> 4</td><td> 4</td>
(continuation)
<td>Dog</td><td>Group<sup>and</sup></td><td>Score day 0</td><td>Day 7 assessment</td><td>Assessment day 14</td>
<td> 20</td><td>B</td><td> 8</td><td>FTC<sup>b</sup></td><td>FTC<sup>b</sup></td>
<td colspan="5"><sup>and</sup>Dogs in Group A were given a single dose of 0.5 ml of the pharmaceutical composition of Example 5.17 and dogs in Group B were given a single dose of 0.5 ml of the pharmaceutical composition of Example 5.17 5.17.<sup>b</sup>FTC = Test not completed.</td>
[0450] A final clinical score of 2 or less was considered a successful treatment. The results in Table XI show that 60 percent of the dogs in Group A and 100 percent of the dogs in Group B underwent successful treatment.
[0451] Table XII describes the results of the culture.
Table XII: Culture results
<td>Dog</td><td>Group<sup>and</sup></td><td>Bacteria day 0</td><td>Yeast<sub>day 0</sub><sup>c, d</sup></td><td>Bacteria day 14</td><td>Yeast<sub>day 14</sub><sup>c, d</sup></td>
<td> 1</td><td>AND</td><td>Negative</td><td>Negative</td><td>Negative</td><td>Negative</td>
<td> 2</td><td>B</td><td>Negative</td><td>MZ (2)</td><td>ON</td><td>ON</td>
<td> 3</td><td>AND</td><td>S. intermedius (3)</td><td>MZ (4)</td><td>S. intermedius (2)</td><td>MZ (3)</td>
<td> 4</td><td>B</td><td>S. intermedius (4)</td><td>Negative</td><td>ON</td><td>ON</td>
<td> 5</td><td>AND</td><td>Negative</td><td>MZ (4)</td><td>ON</td><td>ON</td>
<td> 6</td><td>B</td><td>S. intermedius (4)</td><td>Negative <sup>.</sup></td><td>ON</td><td>ON</td>
<td> 7</td><td>AND</td><td>S. intermedius (4)</td><td>MZ (3)</td><td>Not done</td><td>Not done</td>
<td> 8</td><td>B</td><td>S. intermedius (4)</td><td>MZ (3)</td><td>ON</td><td>ON</td>
<td> 9</td><td>AND</td><td>Negative</td><td>Negative</td><td>ON</td><td>ON</td>
<td> 10</td><td>B</td><td>Negative</td><td>Negative</td><td>ON</td><td>ON</td>
<td> 11</td><td>AND</td><td>Negative</td><td>MZ (4)</td><td>ON</td><td>ON</td>
<td> 12</td><td>B</td><td>S intermedius (2)</td><td>MZ (1)</td><td>ON</td><td>ON</td>
<td> 13</td><td>AND</td><td>Negative</td><td>MZ (2)</td><td>ON</td><td>ON</td>
<td> 14</td><td>B</td><td>S. intermedius (1)</td><td>Negative</td><td>ON</td><td>ON</td>
(continuation)
<td>Dog</td><td>Group<sup>and</sup></td><td>Bacteria day 0</td><td>Yeast<sub>day 0</sub><sup>c, d</sup></td><td>Bacteria day 14</td><td>Yeast<sub>day 14</sub><sup>c, d</sup></td>
<td> 15</td><td>AND</td><td>Negative</td><td>MZ (3)</td><td>ON</td><td></td>
<td> 16</td><td>B</td><td>S. intermedius (4)</td><td>Negative</td><td>ON</td><td>ON</td>
<td> 17</td><td>AND</td><td>S. intermedius (4)</td><td>MZ (4)</td><td>ON</td><td>ON</td>
<td> 18</td><td>B</td><td>S. intermedius (4)</td><td>MZ (3)</td><td>ON</td><td>ON</td>
<td> 19</td><td>AND</td><td>S. intermedius (4), streptococcus β-hemolytic</td><td>Negative</td><td>Not done</td><td>not done</td>
<td> 20</td><td>B</td><td>S. intermedius (4)</td><td>MZ (4)</td><td>FTC<sup>b</sup></td><td>FTC</td>
<td colspan="6"><sup>and</sup> A single 0.5 ml dose of the pharmaceutical composition of Example 5.17 was administered to Group A dogs and a single 0.5 ml composition was administered to the dogs in Group B pharmaceutical agent of Example 5.17.</td>
<td colspan="4"><sup>b</sup> FTC = Test not completed.</td><td></td><td></td>
<td colspan="4"><sup>c</sup> MZ stands for Malasezzia pachydermatis</td><td></td><td></td>
<td colspan="4">* Bold entries indicate failed therapies</td><td></td><td></td>
<td colspan="2"><sup>d</sup> 1000 colony grading scale</td><td colspan="4">: 1 = 1 to 10 colonies; 2 = 11 to 100 colonies; 3 = 101 to 1000 colonies; 4 =></td>
[0452] The results in Tables XI and XII clearly show that the pharmaceutical compositions of the invention are effective in treating microbial ear infections in dogs.
5.19: Clinical trial [0453] A male patient suffering from athlete's foot throughout his life received a single dose of the pharmaceutical composition of Example 5.17 on the exposed foot area. Five days after a single application, the area of skin on which the pharmaceutical composition was applied was smooth, regaining its natural color, and non-itchy, while the surrounding area was dry, flaky, irritable and very itchy. The patient found that the pharmaceutical composition of Example 5.17 was more effective than commercially available anti-fungal creams, which he applied twice a day.
5.20: Phospholipid composition for topical administration [0454] Florfenicol (5 g), terbinafine (5 g), oleic acid (4.85 g), betamethasone acetate (500 mg) and benzethonium chloride (100 mg) were suspended in 250 ml (298.4 g) propylene carbonate in a clean dry 1 liter glass beaker. The mixture was heated to 40-45 ° C with stirring to give a clear solution. To the resulting clear solution, kept at 40-45 ° C, was added 284.5 g of stabilized glycerin with stirring. 10 g of Phospholipon® -90H was added to the resulting solution with stirring, maintaining the temperature at 40-45 ° C and obtaining a clear solution. The solution was allowed to slowly cool to room temperature to give a gel.
Example 5.21: Clinical trial [0455] Several dogs with ear infections received the pharmaceutical composition of Example 5.20. The following protocol was followed to evaluate the clinical effectiveness of the pharmaceutical composition of the invention.
[0456] Dogs with ear infections were examined by a veterinarian on day 0 and each ear was assigned a clinical grade using the same scale as used in Examples 5.11 and 5.18. If both ears were infected, the right ear was taken as the test ear. On day 0, a swab was obtained by inserting a dacron tip swab into the ear canal and then rolling on a slide, followed by fixation by heating and staining the slide with DifQuik. On day 0, culture was obtained from the infected dog's ear by inserting a dacron swab into the ear canal and then placing the swab in a Port-A-Cul transport tube for shipment to a reference laboratory. [0457] For enrollment in the study, dogs had to be 8 weeks or more, minimum clinical scores of 6, and have intact tympanic membranes. In addition, the presence of yeast or bacteria on the swab was required. Animals were excluded from the study list if the clinical grade was lower than 6; if they have been treated with systemic or ear-borne antimicrobials or parenteral or topical anti-inflammatory agents, including short-acting corticosteroids during the last 14 days; if they have been treated with parenteral or long-acting corticosteroids during the last 28 days; if they had simultaneous Otodectes cynotis infections; or if foreign bodies were found in your ear canal.
[0458] A single dose of 1.0 ml β pharmaceutical composition was administered to the dogs
Example 5.20 in each infected ear on day 0 using a 1 cm syringe<sup>3</sup>and then massaging the ear. Dogs of different breeds were used in the study. Tables XIII-XVI describe the race, age, sex and weight of test animals.
Table XIII: Study population by race
<td>Race</td><td>number</td>
<td>Beagle</td><td> 1</td>
<td>Boston Terrier</td><td> 1</td>
<td>Breton spaniel</td><td> 1</td>
<td>Cocker spaniel</td><td> 3</td>
<td>Dalmatian</td><td> 1</td>
<td>Dandie Dinmont Terrier</td><td> 1</td>
<td>Golden retriever</td><td> 1</td>
<td>Labrador retriever</td><td> 2</td>
<td>Crossbreed</td><td> 1</td>
<td>Portuguese Water Dog</td><td> 1</td>
<td>Shar pei</td><td> 3</td>
<td>Shih tzu</td><td> 2</td>
<td>Yorkshire Terrier</td><td> 2</td>
<td>Together</td><td> 20</td>
Table XIV: Study population by age
<td>Age</td><td>number</td>
<td><1 year</td><td> 3</td>
<td>> 1 and <5 years old</td><td> 7</td>
<td>> 5 and <10 years</td><td> 2</td>
<td>> 10 years</td><td> 8</td>
<td>Together</td><td> 20</td>
Table XV: Study population by sex
<td>Sex</td><td>number</td>
<td>Female</td><td> 2</td>
<td>Castrated female</td><td> 6</td>
<td>Male</td><td> 5</td>
<td>Castrated male</td><td> 7</td>
<td>Together</td><td> 20</td>
Table XVI: Study population by body weight
<td>Body weight</td><td>number</td>
<td><10 pounds</td><td> 2</td>
<td>> 10 pounds and <25 pounds</td><td> 5</td>
<td>> 25 pounds and <50 pounds</td><td> 8</td>
<td>> 50 pounds and <75 pounds</td><td> 3</td>
<td>> 75 pounds</td><td> 2</td>
<td>Together</td><td> 20</td>
[0459] On day 7 and day 14, clinical scores were re-assigned to the infected ear. The results of the study are presented below in Tables XVII.
Table XVII: Clinical results
<td>Dog</td><td>Score day 0</td><td>Day 7 assessment</td><td>Assessment day 14</td>
<td> 1</td><td> 6</td><td> 1</td><td> 3</td>
<td> 2</td><td> 7</td><td> 4</td><td> 1</td>
<td> 3</td><td> 6</td><td> 2</td><td> 1</td>
<td> 4</td><td> 8</td><td> 8</td><td> 8</td>
<td> 5</td><td> 11</td><td> 2</td><td> 4</td>
<td> 6</td><td> 6</td><td> 6</td><td> 0</td>
<td> 7</td><td> 10</td><td> 5</td><td> 1</td>
<td> 8</td><td> 10</td><td> 4</td><td> 0</td>
<td> 9</td><td> 9</td><td> 3</td><td> 7</td>
<td> 10</td><td> 10</td><td> 4</td><td> 1</td>
<td> 11</td><td> 6</td><td> 2</td><td> 2</td>
<td> 12</td><td> 10</td><td> 6</td><td> 1</td>
(continuation)
<td>Dog</td><td>Score day 0</td><td>Day 7 assessment</td><td>Assessment day 14</td>
<td> 13</td><td> 6</td><td> 1</td><td> 0</td>
<td> 14</td><td> 9</td><td> 2</td><td> 0</td>
<td> 15</td><td> 10</td><td> 0</td><td> 0</td>
<td> 16</td><td> 10</td><td> 3</td><td> 3</td>
<td> 17</td><td> 9</td><td> 5</td><td> 4</td>
<td> 18</td><td> 12</td><td> 6</td><td> 0</td>
<td> 19</td><td> 6</td><td> 2</td><td> 7</td>
<td> 20</td><td> 6</td><td> 1</td><td> 0</td>
[0460] A final clinical score of 2 or less was considered a successful treatment. The results in Table XVII show that 65 percent of dogs underwent successful treatment.
[0461] Table XIX describes the results of the cultures.
Table XIX: Culture results
<td>Dog</td><td>Bacteria day 0</td><td>Yeast<sub>day 0</sub><sup>b, c</sup></td><td>Bacteria day 14</td><td>Yeast<sub>day 14</sub><sup>b, c</sup></td>
<td> 1</td><td>Negative</td><td>MZ (3)</td><td>Negative</td><td>Negative</td>
<td> 2</td><td>S. intermedius (4), streptococcus β-hemolytic (4)</td><td>MZ (2)</td><td>ON</td><td>ON</td>
<td> 3</td><td>S. intermedius (4), streptococcus β-hemolytic (4)</td><td>MZ (2)</td><td>ON</td><td>ON</td>
<td> 4</td><td>P. aeruginosa (4), S. intermedius (3)</td><td>Negative</td><td>P. aeruginosa (4)</td><td>Negative</td>
<td> 5</td><td>Negative</td><td>Negative</td><td>Negative</td><td>Negative</td>
<td> 6</td><td>Negative</td><td>Negative</td><td>ON</td><td>ON</td>
<td> 7</td><td>S. intermedius (4)</td><td>MZ (2)</td><td>ON</td><td>ON</td>
<td> 8</td><td>Negative</td><td>Negative</td><td>ON</td><td>ON</td>
<td> 9</td><td>S. intermedius (1)</td><td>MZ (1)</td><td>Negative</td><td>MZ (1)</td>
<td> 10</td><td>S. intermedius (2)</td><td>MZ (3)</td><td>ON</td><td>ON</td>
<td> 11</td><td>Negative</td><td>Negative</td><td>ON</td><td>ON</td>
(continuation)
<td>Dog</td><td>Bacteria day 0</td><td>Yeast<sub>day 0</sub><sup>b, c</sup></td><td>Bacteria day 14</td><td>Yeast<sub>day 14</sub><sup>b, c</sup></td>
<td> 12</td><td>S. intermedius (2)</td><td>Negative</td><td>ON</td><td>ON</td>
<td> 13</td><td>Negative</td><td>MZ (2)</td><td>ON</td><td>ON</td>
<td> 14</td><td>Negative</td><td>MZ (2)</td><td>ON</td><td>ON</td>
<td> 15</td><td>Negative</td><td>MZ (2)</td><td>ON</td><td>ON</td>
<td> 16</td><td>Negative</td><td>Negative</td><td>Negative</td><td>Pending</td>
<td> 17</td><td>S. intermedius (4)</td><td>Negative</td><td>Negative</td><td>Pending</td>
<td> 18</td><td>Negative</td><td>Negative</td><td>ON</td><td>ON</td>
<td> 19</td><td>S. intermedius (4)</td><td>Negative</td><td>Negative</td><td>Pending</td>
<td> 20</td><td>Negative</td><td>Negative</td><td>ON</td><td>ON</td>
<td colspan="5"><sup>c</sup>MZ stands for Malasezzia pachydermatis<sup>d</sup> Grading scale: 1 = 1 to 10 colonies; 2 = 11 to 100 colonies; 3 = 101 to 1000 colonies; 4 =></td>
<td colspan="3">1000 colonies. * Bold entries indicate failed therapies.</td><td></td><td></td>
[0462] The results in Tables XVII and XIX clearly show that the pharmaceutical compositions of the invention are effective in the treatment of microbial ear infections in dogs.
5.22: Phospholipid composition for topical administration [0463] Florfenicol (10 g), betamethasone acetate (1 g), oleic acid (9.7 g), and benzethonium chloride (1 g) were dissolved in 500 ml of propylene carbonate and the resulting mixture was heated , with stirring, to a temperature of about 40 to 45 ° C. Phospholipon®-90H (10 g) and hydroxypropyl methylcellulose (30 g) were added to the resulting heated solution, and the resulting mixture was stirred for about 10 min to obtain a clear suspension. Propylene glycol was added to the suspension to give a volume of about 1 L and stirring continued to give a clear solution. The resulting solution was allowed to slowly cool to room temperature to give a gel.
Contents9
30 members in 16 offices
Priority claims8
| Document | Office | Kind | Date |
|---|---|---|---|
| 87453204 | United States of America | A | |
| 1921804 | United States of America | A | |
| 05766244 | European Patent Office (EPO) | A | |
| 2005022072 | United States of America | W | |
| EP20050766244 | – | – | – |
| US20040019218 | – | – | – |
| US20040874532 | – | – | – |
| WO2005US22072 | – | – | – |
Members30
| Document | Office | Kind | |
|---|---|---|---|
| US2005287181A1 | United States of America | A1 | |
| US2005287198A1 | United States of America | A1 | |
| US2005287200A1 | United States of America | A1 | |
| AU2005267395A1 | Australia | A1 | |
| CA2571063A1 | Canada | A1 | |
| WO2006012145A1 | World Intellectual Property Organization (WIPO) | A1 | |
| EP1781256A1 | European Patent Office (EPO) | A1 | |
| CN101014323A | China | A | |
| JP2008504271A | Japan | A | |
| AU2005267395B2 | Australia | B2 | |
| US7846472B2 | United States of America | B2 | |
| US7854943B2 | United States of America | B2 | |
| US7858115B2 | United States of America | B2 | |
| US2011034430A1 | United States of America | A1 | |
| EP1781256A4 | European Patent Office (EPO) | A4 | |
| JP4991530B2 | Japan | B2 | |
| CN101014323B | China | B | |
| US8361496B2 | United States of America | B2 | |
| EP1781256B1 | European Patent Office (EPO) | B1 | |
| CA2571063C | Canada | C | |
| PT1781256E | Portugal | E | |
| DK1781256T3 | Denmark | T3 | |
| ES2407812T3 | Spain | T3 | |
| PL1781256T3This record | Poland | T3 | |
| LU92640I2 | Luxembourg | I2 | |
| NL300715I1 | Netherlands (Kingdom of the) | I1 | |
| NL300715I2 | Netherlands (Kingdom of the) | I2 | |
| FR15C0009I2 | France | I2 | |
| HUS1500004I1 | Hungary | I1 | |
| BE2015C011I2 | Belgium | I2 |
Numbers
- Publication, DOCDB
- 1781256
- Publication, EPODOC
- PL1781256T
- Application
- 766244
- Application, DOCDB
- 05766244
- Application, EPODOC
- PL20050766244T
Titles2
- English
- PHOSPHOLIPID GEL COMPOSITIONS FOR DRUG DELIVERY AND METHODS OF TREATING CONDITIONS USING SAME
- Polish
- Fosfolipidowe kompozycje żelowe do dostarczania leku i sposoby leczenia stanów z ich użyciem
Classification
- CPC, 19
- A61K9/06
- A61K9/0017
- A61K9/0046
- A61K9/0048
- A61K31/137
- A61K31/573
- A61K31/7036
- A61K47/24
- A61P3/10
- A61P5/44
- A61P27/16
- A61P29/00
- A61P31/00
- A61P31/04
- A61P31/10
- A61P31/12
- A61P33/00
- A61P35/00
- A61P43/00
- IPC, 8
- A61K47 24
- A61K9 00
- A61K9 06
- A61K9 127
- A61K31 137
- A61K31 573
- A61K31 7036
- A61K31 704