WO2006121429A1 - Compositions de clindamycin et systeme d'administration pour ces compositions - Google Patents

Compositions de clindamycin et systeme d'administration pour ces compositions Download PDF

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Publication number
WO2006121429A1
WO2006121429A1 PCT/US2005/015775 US2005015775W WO2006121429A1 WO 2006121429 A1 WO2006121429 A1 WO 2006121429A1 US 2005015775 W US2005015775 W US 2005015775W WO 2006121429 A1 WO2006121429 A1 WO 2006121429A1
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WO
WIPO (PCT)
Prior art keywords
composition
clindamycin
compositions
water
chamber
Prior art date
Application number
PCT/US2005/015775
Other languages
English (en)
Inventor
Mohan Vishnupad
Naomi Vishnupad
Original Assignee
Imaginative Research Associates, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Imaginative Research Associates, Inc. filed Critical Imaginative Research Associates, Inc.
Priority to PCT/US2005/015775 priority Critical patent/WO2006121429A1/fr
Publication of WO2006121429A1 publication Critical patent/WO2006121429A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

Definitions

  • BPO benzoyl peroxide
  • antibiotics such as clindamycin phosphate
  • BENZACLIN ® (available from Dermik Laboratories, Berwyn, PA). BENZACLIN is provided to pharmacies as a kit (with the active ingredients in separate containers) and compounding instructions.
  • the kit includes a vial containing clindamycin powder and a separate container containing a BPO gel. To fill a prescription, the pharmacist dissolves the clindamycin salt by adding a measured amount of water to the vial containing the clindamycin powder. The clindamycin solution is then poured into the jar containing the BPO gel, and the contents are mixed with a spatula for uniform blending. This pharmacy-compounded, three component product has an expiration date of three months at room temperature. Another brand name product that contains BPO and clindamycin phosphate is
  • DUAC ® (available from Stiefel Laboratories, Inc., Coral Gables, FL). DUAC has the same combination of BPO and clindamycin phosphate in a specific gel formulation mixed together. Due to the incompatibility of the two actives at elevated temperatures, the combined product requires refrigeration. Thus, once made, DUAC must be refrigerated at the production plant, during shipment, and in the pharmacy's inventory until the product is dispensed to a consumer. Once dispensed, DUAC has a 60 day expiration date at room temperature. Refrigeration of the inventory and during shipment is quite expensive and substantially drives up the cost of the product. Clindamycin salts, such as clindamycin phosphate, are commonly used in aqueous solutions.
  • U.S. Patent No. 6,117,843 discloses a two-component kit containing an aqueous solution of clindamycin and an aqueous benzoyl peroxide suspension wherein the aqueous solution of clindamycin has a clindamycin concentration in the range from 2% to 15% by weight and a pH within a range from 3.5 to 7, preferably within a range from 6 to 6.5, in order to inhibit precipitation of the clindamycin from the solution, particularly when the solution is exposed to cold temperatures during storage.
  • compositions contain a solution of water, clindamycin and glycerin, wherein the amount of water is insufficient alone to solubilize the clindamycin, hi some embodiments, the compositions contain water, clindamycin phosphate and glycerin, the weight ratio of clindamycin phosphate to water being from about 1 : 1.5 to about 1 : 16.5, and optionally a water soluble emulsifier.
  • the present compositions contain water, clindamycin in an amount greater than 6% by weight based on the weight of the water, and a co-solvent in which clindamycin is not soluble, the co-solvent being present in an amount sufficient to solubilize the clindamycin in the water.
  • the co- solvent may be glycerin.
  • the compositions optionally contain an emulsifier. hi particularly useful embodiments, the compositions contain water in an amount of about 25% to about 35% by weight of the composition, glycerin in an amount of about 65% to about 75% by weight of the composition, clindamycin in an amount of about 1.5 to about 10% by weight of the composition; and optionally a water soluble emulsifier.
  • an apparatus in another aspect, includes a first chamber containing a first composition containing clindamycin, water, a co-solvent such as glycerin and optionally an emulsifier, a second chamber containing a second composition that contains benzoyl peroxide, and at least one outlet for dispensing the first and second compositions.
  • a method in another aspect, includes providing a first composition, the first composition containing clindamycin, water, a co-solvent such as glycerin and optionally an emulsifier; providing a second composition comprising benzoyl peroxide; storing the first and second compositions separately from each other in first and second chambers, respectively of an apparatus comprising first and second chambers; mixing the first and second compositions within the apparatus; and dispensing the first and second compositions.
  • Fig. 1 is a vertical cross-sectional of a chamber in chamber single pump dispenser.
  • Fig. 2 is a vertical cross-sectional view showing the configuration of the chamber in chamber single pump dispenser of Figure 1 when the contents of the two chambers are being mixed prior to use.
  • Fig. 3 is a vertical cross-sectional view showing the configuration of the chamber in chamber single pump dispenser of Figure 1 at the time of dispensing.
  • the elevated temperature drug incompatibility may be overcome.
  • the small chamber 14 which has a small capacity, contains a composition (A).
  • Composition (A) may contain one of the active ingredients, such as antibiotic solution, or antibiotic powder blend.
  • This chamber 14 is inserted into a main chamber 2, which contains a composition (B).
  • Composition (B) may contain the other active ingredient, such as a benzoyl peroxide suspension or emulsion.
  • the ratio of both actives is calculated in accordance with embodiments of the present disclosure for this system to deliver the combination of BPO and antibiotics at a concentration that has already been established commercially and is approved by the FDA.
  • the small chamber 14 is locked inside the main chamber 2. The two active drugs never come in contact with each other until the consumer activates the system before use.
  • compositions (A) and (B) may be specially formulated with low viscosity to facilitate quick and uniform blending.
  • the user can then use the pump delivery mechanism (as shown in Figure 3) to dispense the mixed contents (C).
  • mixed contents (C) contains the powder or solution of composition (A) blended with the suspension or emulsion of composition (B) to deliver the combination of both actives for treating the skin.
  • the shelf life or expiration date for such products, from the time of manufacturing to the time of patient's total consumption of the dispensed product, may exceed two years. This expiration date is economical for the marketer and desirable for the FDA.
  • the small chamber has a limited capacity.
  • the active concentrations in both chambers should be accurately balanced and maintained in order to deliver the desirable concentrations for product efficacy and FDA compliance.
  • a higher concentration of antibiotics in the small chamber which when diluted with the main chamber containing BPO, provides the desirable concentrations for skin application.
  • compositions containing a concentration of clindamycin phosphate higher than 6% are desirable.
  • solutions containing concentrations of clindamycin in excess of 6% in a minimum amount of water may be prepared by using co-solvents such as glycerin. Clindamycin phosphate by itself is not soluble in glycerin alone.
  • the present compositions may contain a solution of water, clindamycin and glycerin, wherein the amount of water is insufficient alone to solubilize the clindamycin.
  • the term "solubilize" as used with respect to solubilizing clindamycin refers to the ability to dissolve clindamycin and optionally with heating and stirring and maintaining clindamycin in solution at room temperature for at least 24 hours.
  • Clindamycin phosphate solutions prepared in accordance with the present disclosure using water and glycerin as a co-solvent do not precipitate upon long-term storage at room temperature or at cold temperatures of, for example, about 2 to about 10 0 C.
  • the present methods make it possible to dissolve the salt in a small amount of water.
  • the ratio of water to co-solvent can be from about In accordance with the present methods, 1 gram of clindamycin phosphate dissolves in 4.2 grams of water (24% solution) by using glycerin as a co-solvent. Due to the limited solubility of clindamycin phosphate in water, this concentration is not soluble in water alone.
  • the co-solvent system includes at least 25% water, with the balance being glycerin. Glycerin acts as a co-solvent, rendering a clear solution.
  • the small chamber can contain, for example, 5 grams of the unique 6.05% clindamycin solution, delivering 1.00% of active clindamycin in the final blended product.
  • Composition (B) can be any benzoyl-peroxide containing composition.
  • the composition (B) can be an aqueous emulsion or suspension containing benzoyl peroxide.
  • Formulations for benzoyl-peroxide containing aqueous emulsions and suspensions can be readily formulated by those skilled in the art and typically contain benzoyl peroxide in an amount from about 1% to about 20%, water in an amount from about 5% to about 80%.
  • Composition (B) can also be a substantially anhydrous benzoyl-peroxide containing composition.
  • substantially anhydrous benzoyl- peroxide containing compositions are described, for example, in U.S. Patent No. 5,632,996, the entire disclosure of which is incorporated herein by this reference.
  • optional components such as, for example, humectants, emollients, dyes, medicaments, texture modifiers, fillers and the like may be included in composition (A) or composition (B) or both.
  • the distribution in the mixed contents (C) may not be uniform, resulting in a non functional product.
  • an emulsif ⁇ er may optionally be included in composition (A) or composition (B) or both to ensure uniform blending of the compositions when generating mixed contents (C).
  • the present compositions may contain from about 0.01% to about 10%, more typically from about 0.1% to about 5%, of emulsifier, based on the weight of the composition. Any emulsifier may be used.
  • the emulsifier may be nonionic, anionic or cationic. Suitable emulsifiers are disclosed, for example, in McCutcheon's Detergents and Emulsifiers, North American Edition, pages 317-324 (1986), the disclosure of which is incorporated herein in its entirety by this reference. Suitable emulsifiers include, but are not limited to ethoxylated fatty acids, ethoxylated esters, phosphated esters, polyoxyethylene fatty ether phosphates, fatty acid amides, acyl lactylates, soaps and mixtures thereof.
  • Non-limiting examples of such emulsifiers include polyoxyethylene (8) stearate, myristyl ethoxy (3) myristate, polyoxyethylene (100) monostearate, lauric diethanolamide, stearic monoethanolamide, hydrogenated vegetable glycerides, sodium stearoyl-2-lactylate, calcium stearoyl-2-lactylate. Soaps are also acceptable emulsifiers.
  • the soaps may be alkali metal or triethanolamine salts of long chain fatty acids. Such soaps include sodium stearate, triethanolamine stearate and the similar salts of lanolin fatty acids.
  • emulsifying surfactants having an HLB value from about 3 to below 12 such as steareth-2, PEG-5 soya sterol oil, PEG-IO soya sterol oil, diethanolamine cetyl phosphate, sorbitan monostearate (SPAN 60), diethyleneglycol monostearate, glyceryl monostearate, and mixtures thereof can be used.
  • emulsifying surfactants can be used that have an HLB value of 12 or above (or about 12 and above) such as Steareth-21, polyoxyethylene sorbitan tristearate (TWEEN 65), polyethylene glycol 20 sorbitan monostearate, polyethylene glycol 60 sorbitan monostearate, polyethylene glycol 80 sorbitan monostearate, Steareth-20, Ceteth-20, PEG-100 stearate, sodium stearoyl sarcosinate, hydrogenated lecithin, sodium cocoylglyceryl sulfate, sodium stearyl sulfate, sodium stearoyl lactylate, PEG-20 methyl glucoside sesquistearate, PEG-20 glyceryl monostearate, sucrose monostearate, sucrose polystearates (having a high proportion of sucrose monostearate), polyglyceryl 10 stearate, polyglyceryl 10 myristate, Steareth-10,
  • the present compositions may include an emulsifying surfactant having an HLB value about 12 or below and an emulsifying surfactant having an HLB value of about 12 or above.
  • HLB is well known to one of ordinary skill in the art and means hydrophobic lipophilic balance. See, “The HLB System, A Time-Saving Guide to Emulsifier Selection, "ICI Americas Inc., August (1984) the disclosure of which is incorporated herein by reference in its entirety.
  • polysorbate is added as an emulsifier to the clindamycin/glycerin/ water solution in the small chamber.
  • Suitable polysorbates are commercially available under the trqdename TWEEN®, such as TWEEN 20® or TWEEN 8®. Upon releasing this solution from the small chamber into the larger chamber containing the BPO suspension or emulsion, and shaking the bottle, the actives may advantageously be uniformly blended.
  • the weight ratio of composition (A) to composition (B) can be from about 1:2 to about 1 :20, typically from about 1 :3 to about 1:10. In particularly useful embodiments, the weight ratio of composition (A) to composition (B) can be from about 1:4.
  • Example 1 The inner, smaller chamber of a chamber in a chamber package is filled with clindamycin phosphate composition and the larger, main chamber is filled with a BPO suspension.
  • the formulation for each composition is as follows: Small, inner chamber (Composition A - clindamycin phosphate solution)
  • the inner, smaller chamber of a chamber in a chamber package is filled with clindamycin phosphate composition and the larger, main chamber is filled with a BPO emulsion.
  • the formulation for each composition is as follows:
  • Composition A clindamycin solution
  • Composition B BPO Emulsion
  • Alkyl benzoate (FINSOLV TN®) 7.00 DiH 2 O 75.98
  • Composition B 80.00% Final concentration of actives in the blend: Clindamycin: 1.00% BPO: 5.00%
  • Example 3 The inner, smaller chamber of a chamber in a chamber package is filled with clindamycin phosphate composition and the larger, main chamber is filled with a BPO suspension.
  • the formulation for each composition is as follows:
  • composition A Clindamycin solution
  • Composition B BPO Emulsion
  • Emulsifier 10 1.00 cetyl stearyl alcohol 1.52
  • Composition B 80.00% Final concentration of actives in the blend: Clindamycin: 1.00% BPO: 5.00%
  • a high concentration clindamycin powder blend can be used in the small chamber and blended with the BPO emulsion or suspension.
  • the concentration of the high concentration clindamycin powder blend is calculated to achieve the 1.0% clindamycin and 5.0% BPO in the final blended composition.
  • the chamber in a chamber delivery system is also desirable to formulate water incompatible compounds such as ascorbic acid, green tea extract, hydroquinone, 2,4,6-cycloheptraxien-l-one, w-hydroxy-4- (1-methyethyl) or other skin bleaching agents, that discolor in the presence of light, heat, and oxidation.
  • water incompatible compounds such as ascorbic acid, green tea extract, hydroquinone, 2,4,6-cycloheptraxien-l-one, w-hydroxy-4- (1-methyethyl) or other skin bleaching agents, that discolor in the presence of light, heat, and oxidation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des compositions de clindamycin qui contiennent de l'eau et un co-solvant et éventuellement un émulsifiant.
PCT/US2005/015775 2005-05-06 2005-05-06 Compositions de clindamycin et systeme d'administration pour ces compositions WO2006121429A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2005/015775 WO2006121429A1 (fr) 2005-05-06 2005-05-06 Compositions de clindamycin et systeme d'administration pour ces compositions

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Application Number Priority Date Filing Date Title
PCT/US2005/015775 WO2006121429A1 (fr) 2005-05-06 2005-05-06 Compositions de clindamycin et systeme d'administration pour ces compositions

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993020796A1 (fr) * 1992-04-09 1993-10-28 Allergan, Inc. Procede et composition pour le traitement de l'acne
US6462025B2 (en) * 2000-12-12 2002-10-08 Imaginative Research Associates, Inc. Antibiotic/benzoyl peroxide dispenser
US20020176891A1 (en) * 2000-08-03 2002-11-28 Dow Gordon J. Topical gel delivery system
US20030180366A1 (en) * 2002-03-20 2003-09-25 Kirschner Mitchell I. Bioadhesive drug delivery system
WO2003099295A1 (fr) * 2002-05-20 2003-12-04 Imaginative Research Associates, Inc. Distributeur double d'administration esthetiquement acceptable de compositions anhydres pour le traitement de la peau
US20050255131A1 (en) * 2004-05-11 2005-11-17 Mohan Vishnupad Clindamycin compositions and delivery system therefor

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993020796A1 (fr) * 1992-04-09 1993-10-28 Allergan, Inc. Procede et composition pour le traitement de l'acne
US20020176891A1 (en) * 2000-08-03 2002-11-28 Dow Gordon J. Topical gel delivery system
US6462025B2 (en) * 2000-12-12 2002-10-08 Imaginative Research Associates, Inc. Antibiotic/benzoyl peroxide dispenser
US20030180366A1 (en) * 2002-03-20 2003-09-25 Kirschner Mitchell I. Bioadhesive drug delivery system
WO2003099295A1 (fr) * 2002-05-20 2003-12-04 Imaginative Research Associates, Inc. Distributeur double d'administration esthetiquement acceptable de compositions anhydres pour le traitement de la peau
US20050255131A1 (en) * 2004-05-11 2005-11-17 Mohan Vishnupad Clindamycin compositions and delivery system therefor

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