Pharmaceutical formulation comprising an antibiotic, a triazole and a corticosteroid

ES 2 320 360 T3

DESCRIPTION

Pharmaceutical formulation comprising an antibiotic, a triazole, and a corticosteroid.

Background of the invention

Otomax ear suspension^® contains Gentamicin Sulfate, USP; betamethasone valerate, USP and clotrimazole, USP. The Mometamax ear suspension^® Contains Gentamicin Sulfate, USP, Clotrimazole, USP, and Mometasone Furoate Monohydrate.

There is a problem with these products regarding the potential for ototoxicity due to the aminoglycosides that are often used in such products. Accordingly, there is a need for new combination products for the treatment of infections in animals not suffering from these diseases.

Summary of the invention

Accordingly, pharmaceutical compositions are disclosed for the treatment of an infection in an animal comprising orbifloxacin or a pharmaceutically acceptable salt thereof; an antifungal effective amount of the compound represented by chemical structural formula I comprising:

<img file="ES2320360T3_D0001.tif" />

mometasone furoate monohydrate and at least one pharmaceutically acceptable carrier, wherein said composition is a suspension.

Also described are pharmaceutical compositions for the treatment of an infection in an animal comprising orbifloxacin or a pharmaceutically acceptable salt thereof; an antifungally effective amount of a pharmaceutical acceptable triazole compound, mometasone furoate monohydrate, and at least one pharmaceutically acceptable carrier, wherein said composition is a suspension.

Detailed description of the invention

The present invention relates to a pharmaceutical composition for the treatment of an infection in an animal comprising orbifloxacin or one of its pharmaceutically acceptable salts; an antifungal effective amount of the compound represented by the chemical structural formula comprising:

<img file="ES2320360T3_D0002.tif" />

mometasone furoate monohydrate and a pharmaceutically acceptable carrier, in which the composition is a suspension.

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Mometasone furoate monohydrate is a synthetic steroid hormone from the glucocorticoid family. Glucocorticoid hormones are powerful anti-inflammatory agents. It also shows antipruritic and vasoconstrictor actions. It is used topically in the treatment of corticosteroid-sensitive dermatoses such as psoriasis and atopic dermatitis. Mometasone furoate, the active component in ELOCON® lotion, cream, and ointment, is an anti-inflammatory corticosteroid that has the chemical name, 9,21-dichloro-11 (beta), 17-dihydroxy-16 (alpha) -methylpregna -1,4-diene-3,20-dione 17- (2furoate). It is practically insoluble in water, slightly soluble in methanol, ethanol, and isopropanol; soluble in acetone and chloroform; and frankly soluble in tetrahydrofuran. Its partition coefficient between octanol and water is greater than 5000. Mometasone can exist in various hydrated, crystalline, and enantiomeric forms, for example, as a monohydrate. This product is available from Schering-Plow Corporation, Kenilworth, New Jersey. Mometasone furoate monohydrate may be present in amounts of about 0.01 to about 1%, preferably about 0.1%. Other corticosteroids for use in the present invention include dexamethasone, butoxicart, rofleponide, budesonide, deflazacort, ciclesonide, fluticasone, beclomethasone, beta-methasone, fluocinolone, prednisone, prednisolone ,lotprednol, or triamcinolone.

This invention also relates to stable formulations containing an antifungal effective amount of the micronized compound represented by the chemical structural formula I:

<img file="ES2320360T3_D0003.tif" />

US Patent No. 5,661,151 describes the compound of formula I and its potent antifungal activity against a wide range of fungi such as Aspergillis, Candida, Cryptococcus, Fusarium, and other opportunistic fungi. US Patent Nos. 5,834,472 and 5,846,971 describe oral pharmaceutical compositions in capsule form of the compound of structural formula I coated on inert beads together with a binder. This product is available from Schering-Plow Corporation, Kenilworth, New Jersey. Posaconazole can be present in amounts from about 0.01% to about 1%, preferably about 0.11%.

Other triazole antifungal compounds for use in the present invention include voriconazole, ketoconazole, fluconazole, itraconazole, saperconazole, neticonazole, oxiconazole, isoconazole, sulconazole, tercanazole, toconazole, and / or the pharmaceutically acceptable salts thereof.

Orbifloxacin is a potent, broad-spectrum synthetic antibacterial agent classified as a derivative of quinolone carboxylic acid. It is safe and effective for the management of diseases in dogs and cats associated with bacteria susceptible to orbifloxacin. Quinolones and derivatives thereof useful in the practice of the present invention include, but are not limited to, orbifloxacin, ciprofloxacin, danofloxacin, enoxacin, grepafloxacin, levofloxacin, lomefloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, enrbofloxacin. , garenoxacin, T-3811M1, T-3811M4, T3811 M6, gatifloxacin, gemifloxacin, morofloxacin, difloxacin, rufloxacin, pradofloxacin and trovafloxacin mesylate and / or metabolites thereof. Other quinolones useful in the practice of the present invention are described in WO 96/16055 published May 30, 1996; US Patent No. 5,104,868 issued April 14, 1992; US Patent No. 5,496,947 issued March 5, 1996; US Patent No. 5,498,615 issued March 12, 1996; US Patent No. 5,770,597 issued June 23, 1998; US Patent No. 5,840,333 issued November 1998; US Patent No. 5,672,600 issued September 30, 1997; US Patent No. 5,491,139 issued February 13, 1996; US Patent No. 5,530,118 issued June 1996; and US Patent No. 5,646,163 issued July 8, 1997, all of which are incorporated herein by reference.

Quinolone compounds useful in the practice of the present invention comprise from about 0.01% to about 30% by weight of the pharmaceutical compositions of the present invention. Preferably, the quinolone compounds useful in the practice of the present invention comprise from about

ES 2 320 360 T3

0.1% to about 10% by weight of the pharmaceutical compositions of the present invention. More preferably, the quinolone compounds useful in the practice of the present invention comprise from about 0.5% to 5% by weight of the pharmaceutical compositions of the present invention.

Orbifloxacin can be present in amounts from about 0.1% to about 10%, preferably about 1%.

Fluorine-containing antibiotic analogs chloramphenicol and thiamphenicol have been shown to have antibiotic activity, both against organisms sensitive to and resistant to chloramphenicol and thiamphenicol. See Schafer, TW et al., "Novel Fluorine-Containing Analogs of Chloramphenicol and Thiamphenicol: Antibacterial and Biological Properties," in CURRENT CHEMOTHERAPY AND INFECTIOUS DISEASE PROCEEDINGS OF THE 11THICC AND THE 19TH ICAAC AMERICA SOCIETY OF MICROBI-4OLOGY 1980. Examples of such compounds and methods for their manufacture are described and claimed in US Patent No. 4,235,892. The medical profession is increasingly concerned about the transfer of bacterial resistance to humans when antibiotics useful for human treatment are administered to livestock. As the chloramphenicol group of antibiotics is now infrequently used to treat humans, its derivatives are particularly suitable for veterinary use. Of particular interest are the 3-fluoro, 3-deoxy derivatives having the following Formula II:

<img file="ES2320360T3_D0004.tif" />

where R is a member selected from the group consisting of methyl or ethyl or a halogenated derivative thereof, dihalogenodeuteriomethyl, 1-halogeno-1-deuterioethyl, 1,2-dihalogeno-1-deuterioethyl, azidomethyl, and methylsulfonylmethyl;

each of X and X 'is a member independently selected from the group consisting of NO₂, SO₂R_BSORi, SR_i, SONH₂, SO₂NH₂, SONHRi, SO-NIIR ,, CORi, ORi, R_i, CN, halogen, hydrogen, phenyl, and halogen substituted phenyl, NO₂, R_i, OR_i, PO₂R_i, CONHR_i, NHR_i, NR_iR₂, CONR_iR₂ or OCOR_i, where each of R_i and R2 is a member independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, isobutyl, and phenyl; and Z is hydrogen or an acyl group of a hydrocarbon carboxylic acid (preferably a hydrocarbon dicarboxylic acid) having up to 16 carbon atoms or an acyl group of an amino hydrocarbon carboxylic acid having up to 12 carbon atoms; and the pharmaceutically acceptable salts of said acyl groups.

Halogenated groups contemplated for the R moiety in Formula II include mono-, di- and tri-fluoro, mono-, di- and tri-chloro-, mono- and di-bromo-, and iodo-methyl groups. as well as the mono- and di-fluoro-, mono- and di-chloro-, mono- and di-bromo-, and iodoethyl groups in which the halogen substituents are preferably on the alpha carbon relative to the carbonyl function. Also included are mixed dihaloalkyl groups in which both halogens are preferably linked via the alpha carbon to carbonyl groups, for example groups such as fluorochloro-, fluorobromo-, and chlorobromo-methyl and -ethyl, as well as trihalogeno-methyl groups. such as dichlorofluoro- and difluorochloromethyl.

Compounds of Formula II also include ester derivatives, for example 1-hydrocarbon carboxylates of Formula II in which Z is an acyl group of a hydrocarbon carboxylic acid having up to 16 carbon atoms which can be saturated, unsaturated, chain straight or branched chain, aliphatic, cyclic, cyclicaliphatic, aromatic, aryl-aliphatic, or alkyl-aromatic and can be substituted with hydroxy, alkoxy containing 1 to 5 carbon atoms, carboxyl, NO₂, NHR_i, NR_iR₂, MR_i, SOR_i, or halogen, where R_i and R₂ they are as defined above.

Other antibacterially active ester derivatives of Formula II are those in which Z is an acyl group of an amino acid containing up to 12 carbon atoms which can be saturated, unsaturated, straight chain, branched chain or cyclic, which can contain aromatic groups. and that it can be substituted with hydroxyl groups.

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Preferred ester derivatives include those derived from dibasic hydrocarbon carboxylates, for example the 1-succinate and 1-palmitate esters, which provide pharmaceutically acceptable, water-soluble cationic salts, for example the sodium or potassium salts as well as salts with amine, for example trimethylamine. .

Also preferred are amino acid ester derivatives which provide pharmaceutically acceptable water soluble acid addition salts with mineral or organic acids, for example the addition salts of hydrochloric acid, sulfuric acid, or succinic acid.

As used herein the term "pharmaceutically acceptable salts" therefore includes salts in which the acidic hydrogen in the dibasic hydrocarboncarboxylate esters of this invention is replaced by a cation (eg, D- (threo) - Sodium 1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propyl hemisuccinate) as well as salts in which acidic hydrogen forms an acid addition salt with an amino (for example, the N-trimethylamine salt of D- (threo) -1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propyl hemisuccinate). Also included are acid addition salts formed between mineral or organic acids and the amine in amino acid esters of compounds of Formula II (for example, D- (threo) -1-p-nitrophenyl-2-dichloroacetamido hydrochloride. -3-fluoro-1-propyl glycinate).

Among the pharmaceutically acceptable cationic salts of the dibasic hydrocarboncarboxylate esters included in Formula II are the alkali and alkaline earth metal salts (eg, sodium, potassium, calcium, aluminum) and salts with an amine such as trialkylamines, procaine, dibenzylamine , N-benzyl-beta-phenethylamine, N, N'-dibenzylethylenediamine, N-lower alkyl piperidines (eg, N-ethylpiperidine), and N-methyl glucamine.

Preferably, R is a halogenated derivative of methyl or ethyl, Z is hydrogen, X is phenyl, CORi, or SO₂R₁, R₁ is methyl, and X 'is hydrogen. More preferably R is CHCl₂ or CHF₂.

A preferred antibiotic compound is florfenicol (D- (threo) -1-p-methylsulfonyl phenyl-2-dichloroacetamido-3-fluoro-1-propanol). Another preferred antibiotic compound is D- (threo) -1-p-methylsulfonyl phenyl-2-difluoroacetamido-3-fluoro1-propanol. The processes for the manufacture of these preferred antibiotic compounds, and the intermediates useful in such processes, are described in US Patent Nos. 4,311,857; 4,582,918; 4,973,750; 4,876,352; 5,227,494; 4,743,700; 5,567,844; 5,105,009; 5,382,673; 5,352,832; and 5,683,361.

Tetracyclines are also preferred antibiotics. Chlorotetracycline and oxytetracycline are particularly preferred.

Compounds such as amoxicillin, ampicillin, ampicillin trihydrate, ampicillin sodium, apalycillin, aspoxicillin, azlocillin, bacampicillin, carbenicillin, carbenicillin sodium, carphecillin, carindacillin, cycloxacillin, cloxacillin sodium, dicxacillin sodium, dicxacillin sodium, can also be used in the present invention. , flucloxacillin, hetacillin, lenampicillin, mecillin, am, metampicillin, methicillin, mezlocillin, nafcillin, nafcillin sodium, oxacillin, penicylic acid, penicillin G, benzathine penicillin G, potassium penicillin G, sodium penicillin G, penicillin V, pheneticillin, potassium pheneticillin, piperacillin, sodium piperacillin, pivampicillin, sulbenicillin, sultamicillin, talampicillin, ticarcillil, cefaxadrochlorin, cefahydrochloride , cefamandole nanfate, cefamandol sodium, cefazaflur, cefazedone, cefazolin, cefazolin sodium, cephalidin, cefdinir, cefepime, cefetamet, cefixime, cefluprenam, cefmenoxime, Cefmetazole Sodium, Cefodizime, Cefonicid, Cefoperazone, Cefoperazone Sodium, Ceforanide, Cefoselis, Cefotaxime, Cefotaxime Sodium, Cefotiam, Cefozopran, Cefpimizole, Cefpimizole Sodium, Cefpimizole, Cefadximexime, Cefodimethylpyrome, Cefodimezime, Cefodimexime, Cephynimexime, Cefadzime, Cefodroxime ceftazidime pentahydrate, ceftezole, ceftibuten, ceftiolene, ceftizoxime, ceftriaxone, disodium salt of ceftriaxone, ceftriaxone sodium, cefuroxime, cefuzonam, cefacetrile, cephalexin, cephaloridin, cephalosporin C, cephalothin, cephalothin sodium, cephapirin, cephapirin sodium, cephradine, loracarbef, cefbuperazone, cefoxitin, cefoxitin sodium, cefminox, cefmetazole, cefotetan, alone or in combination with beta-lactavulabactase inhibitors, such as beta-lactavulabactase inhibitors, , iodopenicillanic acid, 6-bromopenicillanic acid, forgettable acids, and tazobactam.

Macrolide antibiotics such as azithromycin, brefeldin, clarithromycin, erythromycin, erythromycin stolate, erythromycin ethyl succinate, erythromycin stearate, josamycin, chitasamycin and tulathromycin can also be used in the present invention.

Another preferred antibiotic compound is tilmicosin. Tilmicosin is a macrolide antibiotic that is chemically defined as 20-dihydro-20-deoxy-20- (cis-3,5-dimethylpiparidin-1-yl) -desmicosin and that is described and reported in US Patent No. 4,820,695. Also disclosed in US Patent No. 4,820,695 is an aqueous, injectable formulation comprising 50% (by volume) propylene glycol, 4% (by volume) benzyl alcohol, and 50 to 500 mg / ml of active ingredient. Tilmicosin can be present as the base or as a phosphate. Tilmicosin has been found to be useful in the treatment of respiratory infections, particularly Pasteurella haemolytica infections in cattle when administered by injection over a 4 day treatment period.

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Another suitable antibiotic for use in the present invention is tulathromycin. Tulathromycin has the following chemical structure:

<img file="ES2320360T3_D0005.tif" />

Tulathromycin can be identified as 1-oxa-6-azacyclopentadecan-15-one, 13 - [[2,6-dideoxy-3-C-methyl-3-0methyl-4-C - [(propylamino) methyl] - α- L-ribo-hexopyranosyl] oxy] -2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11 [[3,4,6-trideoxy-3- (dimethylamino ) -j6-D-xyl-hexopyranosyl] oxy] -, (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R). Tulathromycin can be prepared according to the procedures shown in United States Publication No. 2003/0064939 A1, which is incorporated by reference in its entirety. Tulathromycin can be present in injectable dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. Tulathromycin is most desirably administered in dosages ranging from about 0.2 mg per kg of body weight per day (mg / kg / day) to about 200 mg / kg / day in single or divided doses (i.e., 1 to 4 doses per day), and more preferably 1.25, 2.5 or 5 mg / kg once or twice a week, although variations will necessarily occur depending on the species, weight and condition of the subject being treated. Tulathromycin can be present in injectable dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.

There are five reasons why this otic product that is intended for use in companion animals is novel. The antibiotic fluoroquinolone (orbifloxacin) has not been used in this type of product previously (although it is available in member states in tablet form for the treatment of urinary tract infections in dogs). Furthermore, the usual antibiotic in this class of medicines is gentamicin (or other aminoglycosides) which have been associated with a higher frequency of deafness, particularly in dogs. Therefore, this product can be expected to have a better safety profile.

The anti-inflammatory drug is preferably mometasone. It is the first in the class of corticosteroids. Therefore, this product is expected to be safer than other topical corticosteroid preparations currently used in veterinary medicine.

The antifungal drug is preferably posaconazole, a drug with 10-400x the antifungal activity of traditional antifungal compounds used in veterinary medicine such as clotrimazole, miconazole, nystatin. It will be the first use of an antifungal triazole in veterinary medicine. The combination for this proposed otic product is new. The product requires only one application per day. In summary, the justification for using the centralized procedure is:

• New antibiotic in an otic preparation without the ototoxicity of the aminoglycosides often used in these products;

• New corticosteroid, with a better safety profile when compared to other corticosteroids used in otic preparations;

• Powerful triazole antifungal drug;

o New combination of the three drugs described above;

o A single daily application.

Other inert ingredients can be added to the present composition, as desired. Such ingredients include preservatives, chelating agents, antioxidants, and stabilizers. Exemplary preservatives include methyl p-hydroxybenzoate (methyl paraben) and propyl p-hydroxybenzoate (propyl paraben). Exemplary chelating agents include sodium edetate. Exemplary antioxidants include butylated hydroxyanisole and sodium monothioglycerol.

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To prepare the suspension compositions of the present invention, the vehicle (s) or a portion of the vehicle (s) is added to the combination container, followed by the remaining excipients and active compounds. Additives, such as those listed above, can also be included in the container and mixed into the formulation (the order of addition is not critical).

The compositions can be administered once a day or divided into multiple doses. Often a single dose will suffice to treat the infection. In some circumstances a dose followed by a second dose will be required 48 hours later to treat the animal. Alternatively, the medication can be administered once a day for up to 7 days. The precise dose will depend on the stage and severity of the infection, the susceptibility of the infecting organism to the composition, and the individual characteristics of the animal species being treated, as will be understood by one of ordinary skill in the art.

As noted above, pharmaceutically acceptable excipients include, but are not limited to, resins, fillers, binders, lubricants, solvents, emollients, disintegrants, co-solvents, surfactants, preservatives, buffer systems, pharmaceutical grade colorants or pigments, and agents. viscosity enhancers.

Preferred buffer systems include, but are not limited to, NaOH, acetic, boric, carbonic, phosphoric, succinic, maleic, tartaric, citric, benzoic, lactic, glyceric, gluconic, glutaric and glutamic acids and their sodium, potassium and ammonium salts. The pharmaceutical composition of the present invention generally contains 0.1% to 20% buffer systems.

Preferred surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrose monoesters and lanolin esters and ethers, alkyl sulfate salts, sodium, potassium, and ammonium salts of fatty acids.

Preferred preservatives include, but are not limited to, phenol, alkyl esters of parahydroxybenzoic acid, sorbic acid, and methyl paraben, o-phenylphenol benzoic acid and the salts thereof, chlorobutanol, benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride, methyl paraben, and propyl paraben. Sorbic acid is particularly preferred. The compositions of the present invention generally include 0.01% to 5% preservatives.

Preferred viscosity enhancing agents include, but are not limited to, methyl cellulose, sodium carboxymethyl cellulose, hydroarylpropyl methyl cellulose, hydroxypropyl cellulose, sodium alginate, carbomer, povidone, acacia, guar gum, xanthan gum, and tragacanth. Methyl cellulose, carbomer, xanthan gum, guar gum, povidone, sodium carboxymethyl cellulose, and magnesium aluminum silicate are particularly preferred. The compositions of the present invention include 0.1% to 5% viscosity agents.

A particularly preferred thickening agent is Plastibase 50 W: it is available from Bristol-Myers Squibb, Plastibase^® 50 W contains 5% polyethylene in 95% mineral oil. Polyethylene is an inert hydrocarbon with a high molecular weight and a high melting point. It is used as a thickening agent to increase the viscosity of mineral oil. Other preferred thickening agents include carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose, laponite, and water soluble cellulose salt ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as karaya gum, xanthan gum, acacia, and gum tragacanth can also be used. Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening agent to further improve the texture.

Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil. Physiological saline, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol can be included. Such compositions and preparations generally contain at least 0.1% by weight of the compound.

A preferred class of thickening or gelling or suspending agent includes a class of crosslinking homopolymers of acrylic acid with an alkyl ether of pentaerythritol or an alkyl ether of sucrose, or carbomers. Carbomers are commercially available from BF Goodrich as the Carbopol® series. Particularly preferred carbopols include Carbopol 934, 940, 941, 956, and mixtures thereof. Copolymers of lactide and glycolide monomers, the copolymer having a molecular weight in the range of about 1,000 to about 120,000 (number average), are useful in delivering the active compounds. These polymers are described in US Patent No. 5,198,220, issued March 30, 1993 and US Patent No. 5,242,910, issued September 7, 1993, both to Damani, and US Patent No. United States No. 4,443,430, Mattei, issued April 17, 1984.

Thickening agents can be used in an amount of from about 0.1% to about 15%, preferably from about 2% to about 10%, more preferably from about 4% to about 8%, by weight of the composition. total. Higher concentrations can be used for stamps, non-abrasive gels, and subgingival gels.

The compositions of the present invention may optionally contain lactose, mannitol, sorbitol, tribasic calcium phosphate, dibasic calcium phosphate, compressible sugar, starch, calcium sulfate, dextrocellulose, and cellulose.

ES 2 320 360 T3 microcrystalline, magnesium stearate, stearic acid, talc, colloidal silicon dioxide, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, and microcrystalline cellulose, acacia, tragacanth, hydroxypropyl cellulose, gelatinized starch, gelatinized starch, gelatinized starch ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and methyl cellulose.

The present invention is more particularly described in the following example which is intended to be illustrative only as numerous modifications and variations thereto will be apparent to those skilled in the art.

Example 1

<td>Ingredient</td><td>mg / g</td>

<td>Micronized Orbifloxacin</td><td> 10,0*</td>

<td>Micronized mometasone furoate monohydrate</td><td> 1,0**</td>

<td>Micronized Posaconazole</td><td></td>

<td>USP mineral oil (40 centistokes)</td><td> 685,0</td>

<td>Plasticized Hydrocarbon Gel - Base Ointment (Plastibase 50W)</td><td>cs up 1.0 g ****</td>

The actual amount of orbifloxacin has to be determined based on the assay and the moisture content of the batch to be used. The actual amount of mometasone furoate monohydrate has to be determined based on the assay and the moisture content of the batch to be used. The actual amount of posaconazole has to be determined based on the assay and the moisture content of the batch to be used. The formulation can be prepared as is known to one of ordinary skill in the art.

Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications can be made to the disclosed embodiments without departing from the spirit and scope of the invention. Accordingly, the invention is intended to be limited only to the extent required by the appended claims and applicable rules of law.