WO2002024170A1 - Compositions pharmaceutiques pour administration par voie rectale et vaginale - Google Patents

Compositions pharmaceutiques pour administration par voie rectale et vaginale Download PDF

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Publication number
WO2002024170A1
WO2002024170A1 PCT/US2000/025634 US0025634W WO0224170A1 WO 2002024170 A1 WO2002024170 A1 WO 2002024170A1 US 0025634 W US0025634 W US 0025634W WO 0224170 A1 WO0224170 A1 WO 0224170A1
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
active ingredient
effervescent
amount
penefration
Prior art date
Application number
PCT/US2000/025634
Other languages
English (en)
Inventor
S. Indiran Pather
Joseph R. Robinson
Jonathan D. Eichman
Rajendra K. Khankari
John Hontz
Original Assignee
Cima Labs 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 Cima Labs Inc. filed Critical Cima Labs Inc.
Priority to EP00961968A priority Critical patent/EP1318790A4/fr
Priority to CA002422424A priority patent/CA2422424C/fr
Priority to JP2002528206A priority patent/JP2004509142A/ja
Priority to AU2000273847A priority patent/AU2000273847C1/en
Priority to PCT/US2000/025634 priority patent/WO2002024170A1/fr
Priority to AU7384700A priority patent/AU7384700A/xx
Publication of WO2002024170A1 publication Critical patent/WO2002024170A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules

Definitions

  • the present application relates to pharmaceutical compositions and methods of delivering active ingredients through the rectum or vagina, and in particular to compositions and methods using effervescent agents as penetration enhancers to promote rectal or vaginal delivery of an active ingredient.
  • Penetration enhancers are typically low molecular weight compounds, which enhance drug absorption across the mucosal membrane.
  • penetration enhancers There are generally five major classes of penetration enhancers: (1) bile salts and their derivatives (e.g., taurcholate, deoxcholate, and glycocholate); (2) chelators (e.g., citric acid, enamines, EDTA); (3) fatty acids and their derivatives (e.g., arachidonic acid, oleic acid, sodium caprylate, monoolein); (4) surfactants (e.g, SDS, polyoxyethylene-20-cetylether); and nonsurfactants (e.g., 1-alkylazacycloalkanone unsaturated ureas).
  • Penetration enhancers are thought to increase drug permeability by affecting the membrane transport pathways and/or reducing the barrier effect of the mucosal lining.
  • penetration enhancers Although generally effective, many of the penetration enhancers referred to in the current literature damage the absorbing tissues, often causing extensive tissue damage. Moreover, some penetration enhancers are also known to be toxic, such as bile salts, and therefore their use has been very limited. Accordingly, due to their side effects, penetration enhancers are often not a practical solution to the problem of poor bioavailability in the administration of active ingredients through rectum, vagina and elsewhere. Therefore, there is a need for safe and effective penetration enhancers for the delivery of active ingredients across the rectal and vaginal mucosa.
  • compositions of the present invention comprise rectal or vaginal dosage forms containing an active ingredient in combination with an effervescent penetration enhancer for improving absorption of the active ingredient across the rectal and vaginal mucosa membranes, respectively.
  • the effervescent agent can be used alone or in combination with a pH adjusting substance that alters the pH of the localized environment of the site of dissolution and absorption in the rectum or vagina to further improve dissolution and absorption.
  • compositions of the present invention comprise rectally and vaginally administrable active ingredients in combination with an effervescent agent for influencing absorption of a drug in the rectum or vagina, respectively.
  • Effervescence leads to an increase in the rate and/or the extent of absorption of the drugs, and in particular, drags that are known or suspected of having poor bioavailability. It is believed that such increase can result from reducing the thickness and/or the viscosity of the mucus layer; alteration of the tight junctions between cells, thus promoting absorption through the paracellular route; inducing a change in the cell membrane structure, thus promoting transcellular absorption; and increasing the hydrophobic environment within the cellular membrane.
  • the pharmaceutical compositions include an active ingredient, which is administerable through the rectum or vagina, depending on the selected route of administration, and an amount of effervescent agent effective to aid in penetration of the drug in the rectum or vagina, respectively.
  • the amount of effervescent employed must not merely permit rapid dispersion of the medicament, but must aid in penetration of the drug across the rectal or vaginal mucosa.
  • the pharmaceutical compositions of the present invention may be distinguished from other effervescent compositions on the basis of the amount of effervescent material that they contain.
  • the term "effervescent penetration enhancer” includes compounds which evolve gas.
  • the preferred effervescent penetration enhancers evolve gas by means of a chemical reaction which takes place upon exposure of the effervescent penetration enhancer to small amounts of water and other fluids in the rectum or vagina, respectively.
  • Such water-activated materials must be kept in a generally anhydrous state and with little or no absorbed moisture or in a stable hydrated form, since exposure to water will prematurely disintegrate the composition.
  • the acid and base sources may be any which are safe for human or mammalian use. Suitable sources include acid and hydrite antacids such as, for example, citric, tartaric, amalic, fumeric, adipic, and succinics.
  • Suitable base sources include carbonate sources, such as dry solid carbonate and bicarbonate salt, such as, preferably, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and the like.
  • carbonate sources such as dry solid carbonate and bicarbonate salt, such as, preferably, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and the like.
  • the effervescent penetration enhancers of the present invention are not, however, limited to those that are based upon a reaction that forms carbon dioxide. Reactants which evolve oxygen or other gases and which are safe for human or mammalian use are also considered within the scope of the present invention.
  • the pharmaceutical compositions of the present invention should preferably contain at least about twice as much base as active ingredient (on a weight basis) together with the proportionate amount of an appropriate acid for generating the effervescent reaction. More preferably, the pharmaceutical compositions should contain at least about three times as much base as active ingredient (on a weight basis) together with the proportionate amount of an appropriate acid. It is particularly preferred that sufficient effervescent material be provided such that the evolved gas is more than 5 cm 3 , upon exposure of the composition to an aqueous environment in the rectum or vagina, respectively. These high concentrations of effervescent agents are needed to generate effervescence in sufficient amounts to promote permeability and absorption of the active ingredient across the rectal and vaginal mucosa. However, the amount of effervescent agent must be optimized for each specific active ingredient and for delivery in the rectum or vagina, respectively.
  • the pharmaceutical compositions may also include one or more pH adjusting substances.
  • the pH of the aqueous environment can influence the relative concentrations of the ionized and the unionized forms of the active ingredient present in solution, according to the Henderson- Hasselbach equation.
  • the pH of solutions in which an effervescent couple with equimolar amounts of base and acid has dissolved is slightly acidic due to the evolution of CO 2 .
  • the pH of the localized environment of the rectum or vagina i.e., the contents of the rectum or vagina in immediate contact with the composition, including any active ingredient dissolved from the composition
  • the pH of the localized environment of the rectum or vagina may be altered to achieve desired relative proportions of ionized and unionized active ingredients by incorporating in the compositions certain pH adjusting substances.
  • Suitable pH adjusting substances include any pH adjusting substance that is safe for mammalian use. More preferably, the pH adjusting substances include any weak acid or weak base. These include, but are not limited to, any of the acids or bases previously mentioned as the effervescent components, including, sodium carbonate, potassium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and the equivalent potassium salts.
  • compositions may be administered in any dosage form suitable for delivery of an active ingredient to the rectum or vagina, respectively.
  • these compositions are preferably in the form of suppositories, tablets, capsules, powders, granules, microgranules, containing, in addition to the active ingredient and the effervescent agent, such carriers as are known in the art.
  • the compositions are preferably in the form of suppositories, vaginal rings, tablets, capsules, powders, granules, microgranules, containing, in addition to the active ingredient and the effervescent agent, such carriers as are known in the art.
  • the suppositories and vaginal rings may be of a type that dissolve completely in the rectum or vagina, respectively, or remain intact following release of the composition, and subsequently removed.
  • the compositions may be prepared by mixing the ingredients using techniques well known to those skilled in the art for producing these dosage forms and for preparing effervescent pharmaceutical compositions, in which the effervescent materials must remain unreacted prior to administration of the composition.
  • the tablets may be matrix tablets, layered tables in which the various components are separated in different layers, or other specialized forms of tablets.
  • the tablets are preferably manufactured by direct compression or any other tablet manufacturing technique known in the art. See, e.g., U.S. Patents Nos. 5,178,878 and 5,223,264, which are incorporated by reference herein.
  • Excipient fillers can be used to facilitate tableting. A filler desirably will also assist in the rapid dissolution of the dosage form.
  • suitable fillers include mannitol, dextrose, lactose, and sucrose.
  • Pellets or other multiparticulates may be manufactured by granulation, layering techniques, extrusion and spheronization or other pellet manufacturing methods.
  • Granules may be made by dry granulation process or any other granulation process known in the art. Capsules can be soft gelatin capsules, hard gelatin capsules and the like made according to methods well known in the art.
  • bases examples include cocoa butter, polyethylene glycols, polyvinyl pyrrohdone, gelatin, gelatin/glycerin combinations, esterfied fatty acids, polyoxyethelene sorbitans and polyoxyethylene sorbitan fatty acid esters.
  • Various additives may be incorporated including surfactants and absorption enhancers such as medium chain (C8 to C12) fatty acids and fatty acid esters including mono-, di-, and triesters of glycol.
  • Various bases which may contain mixtures of different components, are also available. Examples of these are those sold under the trade names Imhausen, Witepsol and Gelucire. Various grades of each of these are available for specific applications.
  • a suppository of the present invention may be comprised of a suitable polyethylene glycol suppository base known in the art. More preferably, the polyethylene glycol suppository base is comprised of polyethylene glycol and polysorbate.
  • a suitable commercially available polyethylene glycol suppository base is POLYBASE, manufactured by Paddock Laboratories, Inc.
  • the polyethylene glycol suppository base is present in the suppository-based delivery system in any suitable amount so as to allow the composition to be in contact with the rectal or vaginal mucous membrane, respectively.
  • the polyethylene glycol suppository base confers a degree of miscibleness with the mucous membrane surfaces of the rectum or vagina, wherein suspended particles of the compositions are in contact with such mucous membrane surfaces.
  • the suppository is preferably inserted into a laminate suppository shell which forms a molded shape.
  • the suppository is stored in the shell until used.
  • the laminate suppository shell is any shell known in the art suitable for packaging of the suppository.
  • the suppository shell must be able to withstand temperatures of 60° C used in manufacturing the suppositories and temperatures of 4° C for long-term storage without compromising the integrity of the mold or reacting with the suppository in an unfavorable manner.
  • the laminate suppository shell is a polyvinyl chloride-polyethylene laminate suppository shell.
  • a suitable commercially available laminate suppository shell is a polyvinyl chloride-polyethylene laminate suppository shell manufactured by Paddock Laboratories, Inc.
  • compositions may be formulated for rapid, immediate, delayed or sustained release or a combination of these release forms.
  • the active ingredient and the effervescent agent may be combined with one or more coatings, matrix materials or membranes, which prevent exposure of the active ingredient and the effervescent agent to the environment of the rectum or vagina, until a predetermined time or predetermined event.
  • Suitable coating and matrix materials include, for example, materials which are responsive to pH changes, materials which are metabolized by enzymes present in the rectum or vagina, respectively, and materials which dissolve after a predetermined time or exposure to a certain volume of liquid.
  • the active ingredients suitable for use in the present invention include any active agent suitable for delivery by either the rectum or the vagina, as desired.
  • Pharmaceutical ingredients suitable for use in the present dosage forms may include, without limitation, analgesics, anti-inflammatories, antipyretics, antibiotics, antimicrobials, laxatives, anorexics, antihistamines, antiasthmatics, antidiuretics, antiflatuents, antimigraine agents, antispasmodics, sedatives, antihyperactives, antihypertensives, tranquilizers, decongestants, beta blockers; peptides, proteins, oligonucleotides and other substances of biological origin, and combinations thereof.
  • active ingredient are vitamins, minerals and dietary supplements as the same are defined, for example, in U.S. Patent No. 5,178,878, the disclosure of which is also incorporated by reference herein.
  • ingredients or techniques may preferably be used with the present compositions to enhance the dissolution and absorption of the pharmaceutical ingredient and/or to improve the disintegration profile.
  • ingredients or techniques include, but are not limited to, the use of additional chemical penefration enhancers and materials that aid in release and/or penefration of the drug in the rectum or vagina, respectively.
  • additional chemical penefration enhancers and materials that aid in release and/or penefration of the drug in the rectum or vagina, respectively.
  • a bioadhesive polymer may preferably be included in the drug delivery device to increase the contact time between the dosage form and the rectal or vaginal mucosa.
  • Nonlimiting examples of known bioadhesives used in the present invention include: carbopol (various grades), sodium carboxy methylcellulose, methylcellulose, polycarbophil (Noveon AA-1), hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate, and sodium hyaluronate.
  • Disintegration agents may also be employed to aid in dispersion of the drug in the rectum or vagina, respectively.
  • Disintegration agents include, for example, any pharmaceutically acceptable effervescent agent.
  • a dosage form according to the present invention may include suitable noneffervescent disintegration agents.
  • Nonlimiting examples of disintegration agents include, for example, microcrystalline cellulose, croscarmelose sodium, crospovidone, starches and modified starches.
  • excipients such as fillers, agents used to insure homogeneity of the composition and agents used to aid in preparation, as are well-known in the art.
  • the invention relates to the pharmaceutical and medical industries and to the production of dosage forms.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques comprenant des formes posologiques pouvant être administrées par voie rectale et vaginale, qui contiennent des agents effervescents comme activateurs de pénétration de médicaments. L'effervescence se produit dans le rectum ou le vagin après administration de la forme posologique ou au bout d'une durée prédéterminée consécutive à l'administration. Les agents effervescents peuvent être utilisés seuls ou en combinaison avec une matière de réglage de pH qui active davantage la dissolution et l'absorption de l'ingrédient actif.
PCT/US2000/025634 2000-09-19 2000-09-19 Compositions pharmaceutiques pour administration par voie rectale et vaginale WO2002024170A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP00961968A EP1318790A4 (fr) 2000-09-19 2000-09-19 Compositions pharmaceutiques pour administration par voie rectale et vaginale
CA002422424A CA2422424C (fr) 2000-09-19 2000-09-19 Compositions pharmaceutiques pour administration par voie rectale et vaginale
JP2002528206A JP2004509142A (ja) 2000-09-19 2000-09-19 直腸及び膣投与用医薬組成物
AU2000273847A AU2000273847C1 (en) 2000-09-19 Pharmaceutical compositions for rectal and vaginal administration
PCT/US2000/025634 WO2002024170A1 (fr) 2000-09-19 2000-09-19 Compositions pharmaceutiques pour administration par voie rectale et vaginale
AU7384700A AU7384700A (en) 2000-09-19 2000-09-19 Pharmaceutical compositions for rectal and vaginal administration

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2000/025634 WO2002024170A1 (fr) 2000-09-19 2000-09-19 Compositions pharmaceutiques pour administration par voie rectale et vaginale

Publications (1)

Publication Number Publication Date
WO2002024170A1 true WO2002024170A1 (fr) 2002-03-28

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/025634 WO2002024170A1 (fr) 2000-09-19 2000-09-19 Compositions pharmaceutiques pour administration par voie rectale et vaginale

Country Status (5)

Country Link
EP (1) EP1318790A4 (fr)
JP (1) JP2004509142A (fr)
AU (1) AU7384700A (fr)
CA (1) CA2422424C (fr)
WO (1) WO2002024170A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1872775A1 (fr) * 2006-06-29 2008-01-02 Polichem S.A. Emploi d'une matrice hydrophile contenant un dérivé polyacrylique, un éther de cellulose et un désintégrant, pour la production d'un médicament pour le traitement des troubles génitales d'une femme

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3888976A (en) * 1972-09-21 1975-06-10 William P Mlkvy Zinc and strontium ion containing effervescent mouthwash tablet
US5646151A (en) * 1996-03-08 1997-07-08 Adolor Corporation Kappa agonist compounds and pharmaceutical formulations thereof
US6129906A (en) * 1995-11-11 2000-10-10 The Procter & Gamble Company Silicone containing powders

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1212704A (en) * 1967-11-21 1970-11-18 Prodotti Antibiotici Spa Vaginal suppositories
NL7302521A (en) * 1973-02-23 1974-08-27 Foaming, effervescent capsules - contg. therapeutic agents for rectal and vaginal use
JPS58152809A (ja) * 1982-03-05 1983-09-10 Eisai Co Ltd 安定な発泡性「膣」坐剤
IT1251114B (it) * 1991-07-26 1995-05-04 Farcon Ag Forme farmaceutiche antivirali per applicazione vaginale
DE4139883A1 (de) * 1991-11-29 1993-06-03 Michael Prof Dr Dittgen Verfahren zur herstellung bioadhaesiver arzneimittel
US6071539A (en) * 1996-09-20 2000-06-06 Ethypharm, Sa Effervescent granules and methods for their preparation
US6280770B1 (en) * 1998-08-13 2001-08-28 Cima Labs Inc. Microemulsions as solid dosage forms for oral administration

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3888976A (en) * 1972-09-21 1975-06-10 William P Mlkvy Zinc and strontium ion containing effervescent mouthwash tablet
US6129906A (en) * 1995-11-11 2000-10-10 The Procter & Gamble Company Silicone containing powders
US5646151A (en) * 1996-03-08 1997-07-08 Adolor Corporation Kappa agonist compounds and pharmaceutical formulations thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1318790A4 *

Also Published As

Publication number Publication date
EP1318790A1 (fr) 2003-06-18
JP2004509142A (ja) 2004-03-25
CA2422424A1 (fr) 2002-03-28
CA2422424C (fr) 2009-12-01
AU7384700A (en) 2002-04-02
EP1318790A4 (fr) 2006-02-01
AU2000273847B2 (en) 2006-09-14

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