Sustained-release preparations of quinolone antibiotics and method for preparation thereof
Abstract
The present invention relates to a preparation for oral administration containing a quinolone antibiotic which releases the active ingredient in a delayed manner. A preferred embodiment relates to preparations which, as an active ingredient, contain the mixture of a free quinolone base and its salt. With particular preference are mixtures of ciprofloxacin hydrochloride and ciproflozacin-betaine.
Term
No projected expiry on record.
- Priority
- Filed
- Granted
- Today
33 claims: 31 independent, 2 dependent
- 1Claims Reivindicaciones 1. Orally administrable preparation comprising a quinolone antibiotic, characterized in that it contains a mixture of 1. Preparación oralmente administrable comprendiendo un antibiótico quinolona, caracterizado porque contiene una mezcla de a) Agua-polímero con capacidad de hincharse a) Water-polymer capable of swelling b) a mixture of at least two quinolone antibiotic derivatives. b) una mezcla de al menos dos derivados del antibiótico quinolona.
- 3Preparation according to claims 1 or 2, characterized in that it additionally contains an adjuvant selected from the group containing organic acid, disintegrant, glidant and lubricant. 3. Preparación de acuerdo a las reivindicaciones 1 ó 2, caracterizada porque adicionalmente contiene un adjuvante seleccionado del grupo que contiene ácido orgánico, desintegrante, glidante y lubricante.
- 4Preparation according to any of the preceding claims, characterized in that it is a combined preparation comprising part of an instant release (IR) and a part of a controlled release (CR). 4 . Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada porque es una preparación combinada que comprende parte de un liberador instantáneo (IR) y una parte de un liberador controlado (CR).
- 5Preparation according to any of the preceding claims, characterized in that the IR part contains quinolone antibiotic, disintegrant, glidant and lubricant. 5. Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada porque la parte IR contiene antibiótico quinolona, desitegrante, glidante y lubricante.
- 6Preparation according to any of the preceding claims, characterized in that the CR part contains quinolone antibiotic, polymer, organic acid, glidant and lubricant. 6. Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada la parte CR contiene antibiótico quinolona, polímero, ácido orgánico, glidante y lubricante.
- 8Preparation according to any of claims 4 to 7, characterized in that each IR and CR part contains a mixture of two quinolone antibiotic derivatives. 8. Preparación de acuerdo a cualesquiera de las reivindicaciones 4 a la 7, caracterizada porque cada parte IR y CR contiene una mezcla de dos derivados de antibiótico de quinolona.
- 11Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada porque contiene una mezcla de dos derivados de antibiótico de quinolona, una mezcla de una sal con la base libre. eleven. Preparation according to any of the preceding claims, characterized in that it contains a mixture of two quinolone antibiotic derivatives, a mixture of a salt with the free base.
- 12Preparation according to any of the preceding claims, characterized in that it contains a mixture of two quinolone antibiotic derivatives, a mixture of two salts. 12. Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada porque contiene una mezcla de dos derivados de antibiótico de quinolona, una mezcla de dos sales.
- 13Preparation according to any of the preceding claims, characterized in that the quinolone antibiotic is ciprofloxacin. 13. Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada porque el antibiótico quinolona es ciprofloxacina.
- 14Preparation according to any of the preceding claims, characterized in that the two derivatives are ciprofloxacin hydrochloride and ciprofloxacin betaine. 14. Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada porque los dos derivados son hidrocloruro de ciprofloxacina y betaína de ciprofloxacina.
- 15Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada porque el hidrocloruro de ciprofloxacina y betaína de ciprofloxacina son incluidos en un radio peso de 1:20 y 20:1. fifteen. Preparation according to any of the preceding claims, characterized in that ciprofloxacin hydrochloride and ciprofloxacin betaine are included in a weight radius of 1:20 and 20: 1.
- 16Preparation according to any of the preceding claims, characterized in that the polymer is selected from the group comprising polysaccharides, cellulose ethers, alkali metal salts, dextrins, dextran, pectins, polious, gum arabic, gum tragacanth, carrageenan, galactomannans, algin, alginates, polypeptides, proteins, chitin derivatives, completely synthetic polymers and mixtures thereof. 16. Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada porque el polímero es seleccionado del grupo comprendiendo polisacáridos, éters de celulosa sales metálicas alcalinas, dextrinas, dextrana, pectinas, poliosas, goma arábiga, goma tragacanto, carragenato, galactomananos, algina, alginatos, polipéptidos, proteínas, derivados de quitina, polímeros completamente sintéticos y mezclas de los mismos.
- 17Preparation according to any of the preceding claims, characterized in that the polymer is hydropropylmethylcellulose. 17. Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada porque el polímero es hidropropilmetilcelulosa.
- 18Preparation according to any one of the preceding claims, characterized in that it contains an organic acid having 2 to 10 carbon atoms and 1 to 4 carboxyl groups. 18. Preparación de acuerdo a una cualesquiera de las reivindicaciones precedentes, caracterizada porque contiene un acido orgánico que posee de 2 a 10 átomos de carbono y de 1 a 4 grupos carboxilos.
- 19Preparation according to any of the preceding claims, characterized in that the organic acid is selected from the group comprising acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid and citric acid. 19. Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada porque el ácido orgánico es seleccionado del grupo que comprende ácido acético, ácido malónico, ácido succinico, ácido fumárico, ácido tartárico y ácido cítrico.
- 20Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada porque contiene un enrejado de polívinilpirrolidona como desintegrante. twenty. Preparation according to any of the preceding claims, characterized in that it contains a polyvinylpyrrolidone lattice as a disintegrant.
- 21Preparación de acuerdo a cualesquiera de las reivindicaciones precedentes, caracterizada porque contiene un glidante seleccionado de el grupo que comprende sílica coloidal, aceites vegetales hidrogenados, ácido esteárico, talco y mezclas de los mismos. twenty-one. Preparation according to any of the preceding claims, characterized in that it contains a glycer selected from the group comprising colloidal silica, hydrogenated vegetable oils, stearic acid, talc and mixtures thereof.
- 2222 Preparation according to any of the preceding claims, characterized in that it contains magnesium stearate as a lubricant. 22. Preparación de acuerdo con cualquiera de las reivindicaciones anteriores, caracterizada porque contiene estearato de magnesio como lubricante.
- 232. 3. Preparation according to any of the preceding claims, characterized in that the polymer has a viscosity of at most 75 x 10 3 Pa.s (75 cP), measured as 2% of the force by weight of an aqueous solution at 2 ° C. 23. Preparación de acuerdo con cualquiera de las reivindicaciones anteriores, caracterizada porque el polímero tiene una viscosidad de a lo sumo 75 x 10 3 Pa.s (75 cP), medidos como un 2% de la fuerza por peso de una solución acuosa a 2 0°C.
- 24Preparation according to the preceding claim, characterized in that the hydroxypropyl methylcellulose has a viscosity of at most 75 x 10 "3 Pa.s (75 cP), measured as 2% of the force by weight of an aqueous solution at 20 ° C. 24. Preparación de acuerdo con la reivindicación anterior, caracterizada porque la hidroxipropilmetilcelulosa tiene una viscosidad de a lo sumo 75 x 10“3 Pa.s (75 cP), medidos como un 2% de la fuerza por peso de una solución acuosa a 20°C.
- 25Preparation according to the preceding claim, characterized in that the hydroxypropyl methylcellulose has a viscosity of at most 50 x 103 Pa.s (50 cP), measured as 2% of the force by weight of an aqueous solution at 20 ° C. 25. Preparación de acuerdo con la reivindicación anterior, caracterizada porque la hidroxipropilmetilcelulosa tiene una viscosidad de a lo sumo 50 x 103 Pa.s (50 cP), medidos como un 2% de la fuerza por peso de una solución acuosa a 20°C.
- 26Preparation according to any of the preceding claims, characterized in that it contains from 2 to 20 parts by weight of the mixture of the active compound per part by weight of the polymer. 26. Preparación de acuerdo con cualquiera de las reivindicaciones anteriores, caracterizada porque contiene de 2 a 20 partes por peso de la mezcla del compuesto activo por parte por peso del polímero.
- 27Preparation according to any of the preceding claims, characterized in that it contains hydroxypropylmethylcellulose as a polymer and from 2 to 20 parts by weight of the mixture of the active component per part by weight of the hydroxypropylmethylcellulose. 27. Preparación de acuerdo con cualquiera de las reivindicaciones anteriores, caracterizada porque contiene hidroxipropilmetilcelulosa como polímero y de 2 a 20 partes por peso de la mezcla del componente activo por parte por peso de la hidroxipropilmetilcelulosa.
- 28Preparation according to any of the preceding claims, characterized in that it contains 500 to 1000 mg of quinolone antibiotic, counted as betaine, per unit dose form. 28. Preparación de acuerdo con cualquiera de las reivindicaciones anteriores, caracterizada porque contiene 500 a 1000 mg de antibiótico quinolona, contado como betaína, por forma de dosis unitaria.
- 29Process for the production of a preparation according to any of the preceding claims, according to which a part of the active compound is mixed with a disaggregate, granulated and mixed with a glidant and a lubricant (IR part), and another part of active compound it is mixed with organic acid and polymer, granulated and mixed with lubricant and glidant (part CR), and part IR and part CR are tabletted to obtain combined tablets and optionally the resulting tablets are coated. 29. Proceso para la producción de una preparación de acuerdo con cualquiera de las reivindicaciones anteriores, según la cual una parte del compuesto activo es mezclado con un desagregante, granulado y mezclado con un glidante y un lubricante (parte IR), y otra parte de compuesto activo es mezclado con ácido orgánico y polímero, granulado y mezclado con lubricante y glidante (parte CR), y parte IR y parte CR son tableteados para obtener tabletas combinadas y opcionalmente las tabletas resultantes son recubiertas.
- 3030 Process according to the preceding claim, characterized in that a part of the active compound is mixed with a disaggregator, granulated and mixed with a glidant and a lubricant (IR part), and another part of the active compound is mixed with acid and with hydroxypropyl methylcellulose, granulated and mixed with lubricant and glidant (part CR), and part IR and part CR are tableted to obtain combined tablets and optionally the resulting tablets are coated. 30. Proceso de acuerdo a la reivindicación anterior, caracterizado porque una parte del compuesto activo es mezclado con un desagregante, granulado y mezclado con un glidante y un lubricante (parte IR) , y otra parte del compuesto activo es mezclado con ácido y con hidroxipropilmetilcelulosa, granulado y mezclado con lubricante y glidante (parte CR), y parte IR y parte CR son tableteados para obtener tabletas combinadas y opcionalmente las tabletas resultantes son recubiertas.
- 31Process according to any of claims 29 and 30, characterized in that the IR part and the CR part are tabletted to obtain a two-layer tablet. 31. Proceso de acuerdo con cualquiera de las reivindicaciones 29 y 30, caracterizado porque la parte IR y la parte CR son tableteadas para obtener una tableta de dos capas.
- 33Preparation according to any of the preceding claims characterized in that it releases 80% of the active compound both in 0.IN hydrochloric acid and in acetate buffer at pH 4.5 in the USP XXIV Paddle test at 50 revolutions per minute / 37 ° C in the course of 1 to 4 hours. 33. Preparación de acuerdo a cualquiera de las reivindicaciones anteriores caracterizada porque la misma libera 80% del compuesto activo tanto en ácido hidrocloridrico 0.IN como en buffer acetato a pH 4.5 en el test Paddle de la USP XXIV a 50 revoluciones por minuto/37°C en el transcurso de 1 a 4 horas.
Independent claims31
210 paragraphs, as filed
Delayed antibiotic release preparations .. of quinolone and procedure for its preparation
The present invention relates to solid matrix preparations of orally administered quinolone antibiotics with delayed release and to a process for their preparation.
The active substances of the quinolone class have long been used as broad-spectrum antibiotics and numerous forms of administration can be acquired on the market, such as tablets, infusion solutions, eye drops, etc.
For many medications - as well as for the quinolone class - formulations are desirable which, after a once-daily administration, guarantee a controlled, prolonged and regular release of the active substance. In this way the desired concentration of the active ingredient in the plasma (hereinafter: plasma level) and the therapeutic effect can be maintained without large fluctuations for a prolonged period. Formulations that release the active substance in this way for a prolonged period are called delayed or controlled release preparations (retard or controlled release (CR)).
However, it is very difficult to develop oral quinolone preparations that, despite being administered only once a day, guarantee a sufficiently high antibiotic activity; the patient must therefore take at least two doses daily. But it is desirable to reduce the frequency of taking such quinolone antibiotics once a day.
Several techniques are known in principle for the preparation of controlled active ingredient release preparations. Thus, it is often intended that the preparation remains a prolonged time in the stomach to allow rapid and total resorption of the active ingredient that is delayed in the resorption window (i.e. in the section of the gastrointestinal tract in which absorption takes place) . The residence time in the stomach however depends strongly on the type and nutritional value of the food found in the stomach (SS Davis in G. Hardy et al., Drug Delivery to the Gastrointestinal Tract, Ellis Holwood Ltd., Chichester, England 1989). To prolong the time spent in the stomach, different methods have been tried that either
a) increase the density of the preparation (EP-A 265 061)
b) use special additives such as ammonium myristate which is known to retard the progress of preparations in the gastrointestinal tract (R.
<td></td><td>Groning;</td><td>G. Heung,</td><td>Int. J. Pharm. 56. 111</td>
<td></td><td> (1989)),</td><td></td><td></td>
<td>c)</td><td>use</td><td>prepared</td><td>that swell in the</td>
<td></td><td>stomach</td><td>(tablets</td><td>balloon) (Agyilirah et al.,</td>
<td></td><td>Int. J.</td><td colspan="2">Pharm 7 ¿, 241 (1991)),</td>
<td>d)</td><td>use</td><td>prepared</td><td>with greater dilation</td>
Space (EP-A 235 718) or
e) use bioadhesive preparations that should preferably adhere to the mucous membranes of the gastrointestinal tract (R. Khosla, SS Davis, J. Pharm. Pharmacol. 39. 47 (1987)).
Another delay technique uses a matrix of hydrophilic polymers and, where appropriate, pharmaceutical adjuvants, in which the active ingredient is included. In an aqueous environment, the polymer swells into a gel that then either (together with the poorly soluble active ingredient) erodes slowly or through it the active substance (of good solubility) diffuses. The polymer can be hydrophilic, hydrophobic or mixed hydrophilic / hydrophobic. Meanwhile matrix tablets have become highly appreciated because they are comparatively cheap, well tolerated and can be prepared in usual facilities.
Another method consists in the use of buffered or pH sensitive envelopes that allow a controlled release in certain sections of the gastrointestinal tract.
A technically expensive method consists in the use of osmotic systems (OROS) that work according to the following principle: through a water permeable membrane water penetrates slowly into the tablet and causes the swelling of an ingredient that swells with water; The pressure that is formed by increasing the volume drives the active principle out of the purchase through a hole provided for this purpose.
All these techniques have drawbacks, especially expensive and complicated manufacturing methods, inter-individual and intra-individual variability or dependence on the desired effect of body posture.
In the preparation of delayed-release preparations, attention must also be paid to where resorption of the active ingredient can take place: the smaller the resorption window, the more difficult the preparation of delayed-release preparations becomes. Quinolones such as ciprofloxacin, for example, are predominantly reabsorbed in the upper part of the small intestine (duodenum); the resorption in the lower section of the small intestine and in the large intestine is significantly lower (S. Harder et al., Br. J. clin. Pharmacol. 30, 35-39, (1990)). Therefore, to achieve maximum bioavailability, the active substance must be released before the preparation leaves this resorption window. In addition, the strong influence of the pH of the environment on the solubility of quinolone active ingredients must be taken into account; This is reduced by increasing the pH.
It has therefore been the task of the invention to provide simple preparations for the delayed release of quinolone antibiotics that, once a day, guarantee sufficient therapeutic action.
Accordingly, the object of the invention is an oral antibiotic matrix preparation containing an active substance of quinolone, characterized in that it releases 801 of the active substance both in 0.1 N hydrochloric acid and also in acetate buffer at pH 4.5 in the USP-XXIV paddle test at 50 revolutions per minute / 37 ° C over the course of 1 to 4 hours. To prevent the deletion of the tablet, it can be placed in a wire rack as described, e.g. in the Japanese pharmacopoeia.
The term quinolone active ingredients designates β
Within the framework of the present invention the class of substances that can be used as anti-infectives with a basic quinolone structure, especially quinoloncarboxylic acids. Preferred quinolone active ingredients include ciprofloxacin, olamufloxacin, clinafloxacin, trovafloxacin, cadrofloxacin, alatrofloxacin mesylate, gatifloxacin, rufloxacin, esparfloxacin, levofloxacin, irloxacin, grepafloxacin, moxifloxacin, pruphoxacin, lupifloxacin, lufifloxacin, lufiflocinacin
The preferred active substance of quinolone is ciprofloxacin and its hydrates.
In the context of the present invention, the term quinolone active ingredients also includes quinolone derivatives that only release the active substance in the body (called prodrugs), eg esters of a quinoloncarboxylic acid.
According to a preferred embodiment, the preparation according to the invention contains as an active principle a combination, preferably a mixture, of two different quinolone derivatives. It would be an example of a gemífloxacin, amifloxacin, nitrosoxacin-A.
embodiment according to the similar invention a preparation containing as active ingredient a mixture of two different quinolone salts.
A preferred embodiment refers to preparations which as an active ingredient contain the mixture of a free quinolone base and its salt. Mixtures of ciprofloxacin hydrochloride and ciprofloxacin-betaine are especially preferred.
Ciprofloxacin hydrochloride dissolves well for example at low pH values; but the solubility at the pH value of the intestinal tract (> 6.5) is significantly reduced. However, it has been shown that mixtures of ciprofloxacin hydrochloride and ciprofloxacin base (betaine) in a weight ratio of 1:20 to 20: 1, especially 1:10 to 10: 1, are widely released from the preparation. pH independent (in the pH range from 1 to 4.5). An effect in the same direction can also be achieved using mixtures of other derivatives, eg salts, bases or prodrugs of the active ingredient. Mixtures of stereoisomers, on the other hand, do not fall within the scope of the invention in the term combining two different quinolone derivatives but mixtures of hydrate and anhydrate.
A special embodiment of the preparations according to the invention refers to matrix tablets. Preferred matrix tablets contain a delayed release part (CR part) and a rapid release part (IR part). Polymers that swell with water are suitable as retarding polymers for the matrix, eg. polysaccharides such as starch and starch derivatives (corn starch, wheat, rice, potatoes, carboxymethyl starches, sodium starchondylolates), cellulose ethers such as alkyl celluloses, hydroxyalkylcelluloses, carboxy alkylcelluloses and their alkali metal salts (methyl-, hydroxymethyl-hydroxyethyl hydroxyethyl hydroxyethyl hydroxyethyl hydroxyethyl , sodium carboxymethyl celluloses, cross-linked carboxymethyl celluloses), dextrins, dextran, pectins, poliosae, gum arabic, tragacanth, carcinogen, galactomannans such as guar gum, algina, alginic acid and alginates, polypeptides and proteins such as gelatin and casein, in addition to chitin derivatives such as chitosan, fully synthetic polymers such as copolymers of (meth) acrylic acid (copolymers of methyl methacrylate, hydroxymethyl methacrylate 1), polyvinyl alcohol , uncrosslinked polyvinylpyrrolidone and vinyl pyrrolidone copolymers and mixtures of the indicated compounds. Since polymers that swell with water form gels in the presence of water, they can also be called gel-forming polymers.
Frequently, high viscosity polymers are used for delayed release preparations. In the present invention, however, it has been found that low viscosity polymers positively influence the release behavior of the preparations. In principle, all low viscosity hydrophilic polymers can be used for the purpose of delay. The term low viscosity in the context of the present invention means a (apparent) viscosity of 5 to 400 mPa.s (cP), preferably a maximum of 75 cP, especially a maximum of 50 cP, measured with a rotation viscometer. as a 2% aqueous solution by weight at 20 ° C.
Hydroxypropylmethylcellulose (HPMC) is especially preferred. Especially preferred is hydroxypropyl methylcellulose of specification 2910 of USP XXIV, that is to say with a proportion of methoxy of 28 to 30% by weight and a proportion of hydroxypropoxy of 7 to 12% by weight, for example Metolose® 60 SH (Shinetsu, Japan). The desired degree of delay of the preparation can be adjusted by selecting the viscosity and quantity of the HPMC.
P, the HPMC preferably has a viscosity of 5 to 400 cP, preferably a maximum of 7 5 cP, especially a maximum of 50 cP (respectively measured with a rotation viscometer as a 2% by weight aqueous solution at 20 ° C).
The proportion of the hydrophilic polymer, preferably HPMC, can be varied within wide limits. Preferably, however, 1 part by weight of hydrophilic polymer is used for 2 to 20, preferably for 5 to 15, parts by weight of active ingredient.
To guarantee the release of the active substance from the dosage form also in the small intestine and to maintain the pH value of the outer layer and the environment of the preparation in the acidic range and therefore avoid the risk of precipitation of the active ingredient in the higher pH value of the intestinal fluid to the greatest extent possible, an organic acid can be incorporated into the preparation (if preferably present in the delayed release part); in this way the active ingredient is provided in a more accessible way for resorption. For this purpose, preferred organic acids have 2 to 10 C atoms and 1 to 4 carboxyl groups, such as acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid and citric acid.
In addition to the active substance, hydrophilic polymer retardant and, if necessary, organic acid, the preparations according to the invention may also contain disintegrants, eg cross-linked polyvinyl pyrrolidone such as ® Kollidon CL, slip agents, eg colloidal silicon dioxide such as ® Aerosil, hydrogenated vegetable oils, stearic acid, talc or mixtures thereof, lubricants. eg magnesium stearate, as well as other adjuvants. Both the sliding agents and the lubricants are preferably incorporated into the granulate before the tablet formation phase.
The tablets can then be lacquered if necessary to mask a bitter taste of the active substance, protect the active substance from the influence of light and / or make the tablet aesthetically pleasing. The lacquering can be carried out, for example, by spraying an aqueous suspension of: film former, eg HPMC, plasticizer, eg polyethylene glycol, and light dispersing and light absorbing pigments, eg titanium dioxide. For drying the water, hot air can be directed over the bed of tablets during lacquering.
With the described components, delayed release preparations can be manufactured. In addition to the delayed-release part (CR part) a quick-release part (IR part) can also be used to obtain a rapid rise and a higher plasma level. In the context of the present invention, rapid-release (IR) preparations are understood as those which release the active ingredient in USP-XXIV pallet test rapidly at will, preferably within 3 minutes to less than 60 minutes. The rapid release can be controlled by variation of the composition, eg by variation of the proportion of disintegrant, or by manufacturing parameters within certain limits. The quick-release portions of the preparations according to the invention must not contain two different quinolone derivatives.
It is thus possible to prepare combination preparations containing in a unit dose form preparations with different release profiles: thus, preparations with different release profile can be used to precisely control the plasma level over time. Combination preparations within the meaning of the invention should not only be understood as unit dose forms (called fixed combinations) and combination packages containing respective separate preparations with different release profile (kit-of-parts, kit of parts) ) but also IR and CR parts respectively, administered simultaneously or temporarily outdated, as long as they are used for the treatment or prophylaxis of the same disease.
The object of the present invention is also a combination preparation having a quick release part and a delayed release part, eg in the form of a double layer tablet.
The quick-release portion may contain the active substance of quinolone (eg ciprofloxacinabetaine), disintegrant (eg cross-linked polyvinylpyrrolidone such as Kollidon® CL), slip agent (colloidal silicon dioxide, eg Aerosil®) and lubricant (eg magnesium stearate) as well as organic acid or other adjuvants. The delayed-release part may contain active ingredient (ciprofloxacin hydrochloride and ciprofloxacin-betaine), the retarding polymer (e.g. Low density HPMC), organic acid (eg succinic acid), a slip agent (eg colloidal silicon dioxide) and a lubricant (eg magnesium stearate) and, where appropriate, other adjuvants. The starting materials for the quick-release and the delayed-release part can be granulated (eg by wet or dry granulation techniques) before the tabletting process. The granulate can be mixed with gliding agents and lubricants and the compressible granulate (ready-to-compress) of both layers can (eg using conventional double-layer tablet making machines) be processed to obtain double-layer tablets. A part of the sliding agent could also be granulated.
Since the addition of an organic acid can increase the release rate of the active substance, especially ciprofloxacin hydrochloride and ciprofloxacin-betaine, it may also be advisable to add organic acid to the IR part.
Delayed-release preparations according to the invention conveniently contain 500 to 1000 mg of active ingredient, calculated as betaine, per unit dose form. By unit dose forms are meant those preparations that are administered as single doses, eg tablets, dragees or capsules.
For the preparation of the delayed release preparations with IR part and CR part according to the invention, for example, the following procedure can be used: for the preparation of the IR part, the active ingredient (preferably as a mixture of two derivatives) is mixed with the disintegrant, especially Kollidon CL, and granulated and mixed with the sliding agent, especially Aerosil, and the lubricant, in special magnesium stearate, to obtain first compressible IR granules (readyto-compress).
For the delayed release part, the active ingredient (as a mixture of two derivatives) is mixed with the acid, eg succinic acid, and the gel-forming polymer, especially HPMC, and granulated. This CR granulate is mixed with the sliding agent, especially Aerosil®, and the lubricant, especially magnesium stearate, to obtain the compressible CR granulate (ready-to-compress). The CR granulate and IR (ready-to-compress) granulate are processed with conventional double layer tablet manufacturing machines to obtain a double layer tablet. The tablet obtained can then be lacquered.
The following examples of embodiment will illustrate the object of the invention by means of double-layer tablets without however being limited.
Examples Example 1
<td>Amount in mg</td><td>Substances used</td>
<td> 366,70</td><td>Ciprofloxacin hydrochloride</td>
<td> 41,70</td><td>Ciprofloxacin-betaine</td>
<td> 46,700</td><td>Kollidon CL * **</td>
<td> 4,30</td><td>Aerosil 200 ***</td>
<td> 4,70</td><td>Magnesium stearate</td>
<td> 464,10</td><td>IR subtotal</td>
<td> 302,70</td><td>Ciprofloxacin hydrochloride</td>
<td> 464,30</td><td>Ciprofloxacin-betaine</td>
<td> 125,40</td><td>Succinic acid</td>
<td> 103,10</td><td>Hydroxypropyl methylcellulose 50 cP *</td>
<td> 5,20</td><td>Aerosil 200 ***</td>
<td> 9, 30</td><td>Magnesium stearate</td>
<td> 1010,00</td><td>Subtotal part CR</td>
<td> 18,00</td><td>Hydroxypropyl methylcellulose 15 cP *</td>
<td> 6, 00</td><td>Titanium dioxide</td>
<td> 6, 00</td><td>Polyethylene Glycol 400 ****</td>
<td> 30,00</td><td>Lacquer Subtotal</td>
<td>23 x 9.5 mm</td><td>Oblong tablet</td>
* Viscosity respectively measured as 2% aqueous solution by weight at 20 ° C ** Cross-linked polyvinylpyrrolidone *** Colloidal silicon dioxide, specific surface 200 m<sup>2</sup>/ g **** Nuneric data refers to the average molecular weight
Example 2
<td>Amount in mg</td><td>Substances used</td>
<td> 183,40</td><td>Ciprofloxacin hydrochloride</td>
<td> 20, 90</td><td>Ciprofloxacin-betaine</td>
<td> 22,30</td><td>Kollidon CL</td>
<td> 2,30</td><td>Magnesium stearate</td>
<td> 1, 10</td><td>Spray 200</td>
<td> 230,00</td><td>IR subtotal</td>
<td> 151,40</td><td>Ciprofloxacin hydrochloride</td>
<td> 232,10</td><td>Ciprofloxacin-betaine</td>
<td> 64,00</td><td>Succinic acid</td>
<td> 52,30</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 7, 60</td><td>Magnesium stearate</td>
<td> 2,60</td><td>200 spray</td>
<td> 510,00</td><td>Subtotal part CR</td>
<td> 12,00</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 4,00</td><td>Polyethylene Glycol 400</td>
<td> 4,00</td><td>Titanium dioxide</td>
<td> 20,00</td><td>Lacquer Subtotal</td>
<td>19 x 8 mm</td><td>Oblong tablet</td>
Example 3
<td>Amount in mg</td><td>Substances used</td>
<td> 183,40</td><td>Ciprofloxacin hydrochloride</td>
<td> 20,90</td><td>Ciprofloxacin-betaine</td>
<td> 22,30</td><td>Kollidon CL</td>
<td> 2, 30</td><td>Magnesium stearate</td>
<td> 1, 10</td><td>200 spray</td>
<td> 230,00</td><td>IR subtotal</td>
<td> 151,40</td><td>Ciprofloxacin hydrochloride</td>
<td> 232,10</td><td>Ciprofloxacin-betaine</td>
<td> 65,10</td><td>Succinic acid</td>
<td> 73,00</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 10,70</td><td>Magnesium stearate</td>
<td> 2,70</td><td>200 spray</td>
<td> 535,00</td><td>Subtotal part CR</td>
<td> 12,00</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 4,00</td><td>Polyethylene Glycol 3350</td>
<td> 4,00</td><td>Titanium dioxide</td>
<td> 20,00</td><td>Lacquer Subtotal</td>
<td>19 x 8 mm</td><td>Oblong tablet</td>
Example 4
<td>Amount in mg</td><td>Substances used</td>
<td> 183,40</td><td>Ciprofloxacin hydrochloride</td>
<td> 20, 90</td><td>Ciprofloxacin-betaine</td>
<td> 22,30</td><td>Kollidon CL</td>
<td> 2, 30</td><td>Magnesium stearate</td>
<td> 1,10</td><td>200 spray</td>
<td> 230,00</td><td>IR subtotal</td>
<td> 151,40</td><td>Ciprofloxacin hydrochloride</td>
<td> 232,10</td><td>Ciprofloxacin-betaine</td>
<td> 64,00</td><td>Succinic acid</td>
<td> 72,00</td><td>Hydroxypropyl methylcellulose 50 cP</td>
<td> 7, 90</td><td>Magnesium stearate</td>
<td> 2,60</td><td>200 spray</td>
<td> 530,00</td><td>Subtotal part CR</td>
<td> 12,00</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 4,00</td><td>Polyethylene Glycol 400</td>
<td> 4,00</td><td>Titanium dioxide</td>
<td> 20,00</td><td>Lacquer Subtotal</td>
<td>19 x 8 mm</td><td>Oblong tablet</td>
Example 5
<td>Amount in mg</td><td>Substances used</td>
<td> 262,00</td><td>Ciprofloxacin hydrochloride</td>
<td> 29, 80</td><td>Ciprofloxacin-betaine</td>
<td> 8,90</td><td>Succinic acid</td>
<td> 42,20</td><td>Kollidon CL</td>
<td> 1,80</td><td>200 spray</td>
<td> 5,30</td><td>Magnesium stearate</td>
<td> 350,00</td><td>IR subtotal</td>
<td> 116,40</td><td>Ciprofloxacin hydrochloride</td>
<td> 178,50</td><td>Ciprofloxacin-betaine</td>
<td> 134,00</td><td>Succinic acid</td>
<td> 87,80</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 2,70</td><td>200 spray</td>
<td> 10,60</td><td>Magnesium stearate</td>
<td> 530,00</td><td>Subtotal part CR</td>
<td> 12,00</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 4,00</td><td>Polyethylene Glycol 400</td>
<td> 4,00</td><td>Titanium dioxide</td>
<td> 20,00</td><td>Lacquer Subtotal</td>
<td>19 x 8 mm</td><td>Oblong tablet</td>
Example 6
<td>Amount in mg</td><td>Substances used</td>
<td> 183,40</td><td>Ciprofloxacin hydrochloride</td>
<td> 20,90</td><td>Ciprofloxacin-betaine</td>
<td> 6,20</td><td>Succinic acid</td>
<td> 24,70</td><td>Kollidon CL</td>
<td> 1,20</td><td>200 spray</td>
<td> 3,60</td><td>Magnesium stearate</td>
<td> 240,00</td><td>IR subtotal</td>
<td> 151,40</td><td>Ciprofloxacin hydrochloride</td>
<td> 232,10</td><td>Ciprofloxacin-betaine</td>
<td> 174,00</td><td>Succinic acid</td>
<td> 95,70</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 3,40</td><td>200 spray</td>
<td> 13,40</td><td>Magnesium stearate</td>
<td> 670,00</td><td>Subtotal part CR</td>
<td> 12,00</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 4,00</td><td>Polyethylene Glycol 400</td>
<td> 4,00</td><td>Titanium dioxide</td>
<td> 20,00</td><td>Lacquer Subtotal</td>
<td>19 x 8 mm</td><td>Oblong tablet</td>
Example 7
<td>Amount in mg</td><td>Substances used</td>
<td> 366,70</td><td>Ciprofloxacin hydrochloride</td>
<td> 41,70</td><td>Ciprofloxacin-betaine</td>
<td> 46, 60</td><td>Kollidon CL</td>
<td> 4,70</td><td>Magnesium stearate</td>
<td> 2,30</td><td>200 spray</td>
<td> 462,00</td><td>IR subtotal</td>
<td> 302,70</td><td>Ciprofloxacin hydrochloride</td>
<td> 464,30</td><td>Ciprofloxacin-betaine</td>
<td> 125,30</td><td>Succinic acid</td>
<td> 103,00</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 20,50</td><td>Magnesium stearate</td>
<td> 5,20</td><td>200 spray</td>
<td> 1021,00</td><td>Subtotal part CR</td>
<td> 18,00</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 6, 00</td><td>Polyethylene Glycol 3350</td>
<td> 6, 00</td><td>Titanium dioxide</td>
<td> 30,00</td><td>Lacquer Subtotal</td>
<td>23 x 9.5 mm</td><td>Oblong tablet</td>
Comparative Example A
<td>Amount in mg</td><td>Substances used</td>
<td> 357,00</td><td>Ciprofloxacin-betaine</td>
<td> 58,00</td><td>Kollidon CL</td>
<td> 6, 00</td><td>Magnesium stearate</td>
<td> 4,00</td><td>200 spray</td>
<td> 425,00</td><td>IR subtotal</td>
<td> 833,00</td><td>Ciprofloxacin-betaine</td>
<td> 108,00</td><td>Succinic acid</td>
<td> 108,00</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 16, 00</td><td>Magnesium stearate</td>
<td> 10,00</td><td>200 spray</td>
<td> 1075,00</td><td>Subtotal part CR</td>
<td> 18,00</td><td>Hydroxypropyl methylcellulose 15 cP</td>
<td> 6, 00</td><td>Polyethylene Glycol 400</td>
<td> 6,00</td><td>Titanium dioxide</td>
<td> 30,00</td><td>Lacquer Subtotal</td>
<td>23 x 9.5 mm</td><td>Oblong tablet</td>
Comparative Example B
65 members in 41 offices
Priority claims4
| Document | Office | Kind | Date |
|---|---|---|---|
| 10031043 | Germany | A | |
| 10031043 | Germany | A | |
| DE20001031043 | – | – | – |
| DE2000131043 | – | – | – |
Members65
| Document | Office | Kind | |
|---|---|---|---|
| HN2001000132A | Honduras | A | |
| WO0200219A1 | World Intellectual Property Organization (WIPO) | A1 | |
| AU7057301A | Australia | A | |
| GT200100126A | Guatemala | A | |
| DE10031043A1 | Germany | A1 | |
| PE20020207A1 | Peru | A1 | |
| DOP2001000199A | Dominican Republic | A | |
| SV2002000505A | El Salvador | A | |
| NO20026160D0 | Norway | D0 | |
| NO20026160L | Norway | L | |
| CA2414271A1 | Canada | A1 | |
| KR20030023883A | Republic of Korea | A | |
| MA25761A1 | Morocco | A1 | |
| SK18212002A3 | Slovakia | A3 | |
| EP1296685A1 | European Patent Office (EPO) | A1 | |
| CZ20024216A3 | Czechia | A3 | |
| BR0111911A | Brazil | A | |
| MXPA02012727A | Mexico | A | |
| IL153333D0 | Israel | D0 | |
| AR029688A1 | Argentina | A1 | |
| CN1438889A | China | A | |
| HU0300953A2 | Hungary | A2 | |
| BG107372A | Bulgaria | A | |
| US2004024018A1 | United States of America | A1 | |
| ZA200210350B | South Africa | B | |
| JP2004504278A | Japan | A | |
| HK1058479A1 | Hong Kong, China | A1 | |
| HRP20030050A2 | Croatia | A2 | |
| EE200200707A | Estonia | A | |
| NZ523352A | New Zealand | A | |
| PL360632A1 | Poland | A1 | |
| CA2414271C | Canada | C | |
| AT355062T | Austria | T | |
| CN1273138C | China | C | |
| EP1296685B1 | European Patent Office (EPO) | B1 | |
| US2007065509A1 | United States of America | A1 | |
| DE50112123D1 | Germany | D1 | |
| TWI279232B | Taiwan Province of China | B | |
| DK1296685T3 | Denmark | T3 | |
| PT1296685E | Portugal | E | |
| SI1296685T1 | Slovenia | T1 | |
| US2007237824A1 | United States of America | A1 | |
| ES2282270T3 | Spain | T3 | |
| CU23264B7This record | Cuba | B7 | |
| EE04992B1 | Estonia | B1 | |
| NO325415B1 | Norway | B1 | |
| UA83616C2 | Ukraine | C2 | |
| RU2332204C2 | Russian Federation | C2 | |
| HU0300953A3 | Hungary | A3 | |
| PL203710B1 | Poland | B1 | |
| KR100939617B1 | Republic of Korea | B1 | |
| MY140994A | Malaysia | A | |
| US7709022B2 | United States of America | B2 | |
| BG65914B1 | Bulgaria | B1 | |
| IL153333A | Israel | A | |
| CZ301812B6 | Czechia | B6 | |
| SK287384B6 | Slovakia | B6 | |
| US7780986B2 | United States of America | B2 | |
| HRP20030050B1 | Croatia | B1 | |
| US8187632B2 | United States of America | B2 | |
| JP4958373B2 | Japan | B2 | |
| CY1107574T1 | Cyprus | T1 | |
| HU229806B1 | Hungary | B1 | |
| BRPI0111911B1 | Brazil | B1 | |
| BRPI0111911B8 | Brazil | B8 |
Numbers
- Publication, DOCDB
- 23264
- Publication, EPODOC
- CU23264
- Application
- 333
- Application, DOCDB
- 20020333
- Application, EPODOC
- CU20020000333
Titles2
- Spanish
- PREPARADOS DE LIBERACION RETARDADA DE ANTIBIOTICOS DE QUINOLONA Y PROCEDIMIENTO PARA SU PREPARACION
- English
- PREPARED FOR DELAYED DELIVERY OF QUINOLONE ANTIBIOTICS AND PROCEDURE FOR PREPARATION
Classification
- CPC, 9
- A61K9/209
- A61K31/496
- A61K9/2027
- A61K9/2054
- A61K31/47
- A61K31/495
- C07D401/04
- A61P31/00
- A61P31/04
- IPC, 9
- A61K9 20
- A61K9 22
- A61K9 24
- A61K31 495
- A61K31 496
- A61K47 30
- A61K47 38
- A61P31 00
- A61P31 04