CA2422424C - Pharmaceutical compositions for rectal and vaginal administration - Google Patents
Pharmaceutical compositions for rectal and vaginal administration Download PDFInfo
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- CA2422424C CA2422424C CA002422424A CA2422424A CA2422424C CA 2422424 C CA2422424 C CA 2422424C CA 002422424 A CA002422424 A CA 002422424A CA 2422424 A CA2422424 A CA 2422424A CA 2422424 C CA2422424 C CA 2422424C
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- active ingredient
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- 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
Abstract
The pharmaceutical compositions of the present invention comprise rectally and vaginally administerable dosage forms that contain effervescent agents as penetration enhancers for drugs. Effervescence occurs in the rectum or vagina, once the dosage form is administered or at a predetermined time following administration. The effervescent agents can be used alone or in combination with pH adjusting substance, which further promote dissolution and absorption of the active ingredient.
Description
PHARMACEUTICAL COMPOSITIONS
FOR RECTAL AND VAGINAL ADMINISTRATION
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Although generally not well accepted, various proposals have been advanced for rectal and vaginal administration of drugs. Because some veins in the rectum and vagina lead directly to the general circulation, when drugs are administered through the rectum or vagina, they have the advantage of bypassing the gastrointestinal and heptic metabolism process (i.e., reducing the first-pass effect). This can lead to faster onset of action and/or improved bioavailability of a drug. In addition, delivery of a drug through the rectum and vagina can be useful for patients unable or unwilling to take drugs orally or intravenously.
To improve the bioavailability of poorly absorbed drugs across the rectal and vaginal mucosa, penetration enhancers have been employed. Penetration enhancers are typically low molecular weight compounds, which enhance drug absorption across the mucosal membrane.
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 eiihancers are thought to increase drug permeability by affecting the membrane transport pathways and/or reducing the barrier effect of the mucosal lining.
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.
FOR RECTAL AND VAGINAL ADMINISTRATION
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Although generally not well accepted, various proposals have been advanced for rectal and vaginal administration of drugs. Because some veins in the rectum and vagina lead directly to the general circulation, when drugs are administered through the rectum or vagina, they have the advantage of bypassing the gastrointestinal and heptic metabolism process (i.e., reducing the first-pass effect). This can lead to faster onset of action and/or improved bioavailability of a drug. In addition, delivery of a drug through the rectum and vagina can be useful for patients unable or unwilling to take drugs orally or intravenously.
To improve the bioavailability of poorly absorbed drugs across the rectal and vaginal mucosa, penetration enhancers have been employed. Penetration enhancers are typically low molecular weight compounds, which enhance drug absorption across the mucosal membrane.
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 eiihancers are thought to increase drug permeability by affecting the membrane transport pathways and/or reducing the barrier effect of the mucosal lining.
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.
SUMMARY OF THE INVENTION
The pharmaceutical 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.
According to the present invention then, there is provided a dosage form adapted for rectal administration of a therapeutically effective amount of an active ingredient to a target area in the rectum of a mammal; comprising a therapeutically effective amount of an active ingredient; and at least one effervescent penetration enhancer; wherein said at least one effervescent penetration enhancer is present in an amount sufficient to increase the penetration of said active ingredient across said target area of said rectum, and to permit delivery of a therapeutically effective amount of said active ingredient.
According to a further aspect of the present invention, there is also provided the use of an effervescent penetration enhancer for delivering an active ingredient to a target area in the rectum of a mammal; comprising the steps of providing in the rectum of a mammal a dosage form comprising a therapeutically effective amount of an active ingredient and at least one effervescent penetration enhancer present in an amount sufficient to increase absorption of said active ingredient across a mucosa layer of said target area, causing said active ingredient and said effervescent penetration enhancer to release from said dosage form at said target area in said rectum and to provide effervescent action at said target area; so that said effervescent action promotes the absorption of a therapeutically effective amount of said active ingredient across said target area.
According to yet another aspect of the present invention, there is provided a dosage form adapted for vaginal administration of a therapeutically effective amount of an active ingredient to a target area in the vagina of a mammal; comprising a therapeutically effective 2a amount of an active ingredient; and at least one effervescent penetration enhancer; wherein said at least one effervescent penetration enhancer is present in an amount sufficient to increases the penetration of said active ingredient across said target area of said vagina.
According to yet a further aspect of the present invention, there is also provided the use of an effervescent penetration enhancer for delivering an active ingredient to a target area in the vagina of a mammal; comprising the steps of providing in the vagina of a mammal a dosage form comprising a therapeutically effective amount of an active ingredient and at least one effervescent penetration enhancer present in an amount sufficient to increase absorption of said active ingredient across a mucosa layer of said target area, causing said active ingredient and said effervescent penetration enhancer to release from said dosage form at said target area in said vagina and to provide effervescent action at said target area; so that said effervescent action promotes the absorption of a therapeutically effective amount of said active ingredient across said target area.
According to the present invention then, there is provided a dosage form adapted for rectal administration of a therapeutically effective amount of an active ingredient to a target area in the rectum of a mammal, said target area comprising rectal mucosa;
comprising a therapeutically effective amount of an active ingredient; and at least one effervescent penetration enhancer; wherein said at least one effervescent penetration enhancer comprises a pharmaceutically acceptable effervescent couple, said effervescent couple comprising an acid or equivalent thereof and a base or equivalent thereof and said base is present in an amount that is at least about twice the amount of said active ingredient (on a weight basis) and said effervescent couple is present in an amount sufficient to increase the penetration of said active ingredient across said rectal mucosa; and further comprising a pH adjusting substance; wherein said dosage form permits systemic delivery of a therapeutically effective amount of said active ingredient.
According to another aspect of the present invention then, there is also provided a method for delivering an active ingredient to a target area in the rectum of a mammal, said target area comprising rectal mucosa; comprising the steps of administering to the rectum of said mammal a dosage form comprising a therapeutically effective amount of an active ingredient; and at least one effervescent penetration enhancer comprising a pharmaceutically acceptable effervescent couple, said effervescent couple comprising an acid or equivalent thereof and a base or equivalent thereof and said base is present in an amount that is at least = CA 02422424 2007-06-11 2b about twice the amount of said active ingredient (on a weight basis) and said effervescent couple present in an amount sufficient to increase penetration of said active ingredient across said rectal mucosa; and a pH adjusting substance; causing said active ingredient and said effervescent penetration enhancer to release from said dosage form at said target area in said rectum and providing effervescent action at said target area thereby promoting penetration of a therapeutically effective amount of said active ingredient across said target area for systemic delivery to said mammal.
According to a further aspect of the present invention then, there is also provided a dosage form adapted for vaginal administration of a therapeutically effective amount of an active ingredient to a target area in the vagina of a mammal, said target area comprising vaginal mucosa; comprising a therapeutically effective amount of an active ingredient; and at least one effervescent penetration enhancer; wherein said at least one effervescent penetration enhancer comprises a pharmaceutically acceptable effervescent couple, said effervescent couple comprising an acid or equivalent thereof and a base or equivalent thereof and said base is present in an amount that is at least about twice the amount of said active ingredient (on a weight basis) and said effervescent couple is present in an amount sufficient to increases the penetration of said active ingredient across said vaginal mucosa; and further comprising a Ph adjusting substance; wherein said dosage form permits systemic delivery of a therapeutically effective amount of said active ingredient.
According to yet a further aspect of the present invention then, there is also provided a method for delivering an active ingredient to a target area in the vagina of a mammal, said target area comprising vaginal mucosa; comprising the steps of administering in the vagina of said mammal a dosage form comprising; a therapeutically effective amount of an active ingredient; and at least one effervescent penetration enhancer comprising a pharmaceutically acceptable effervescent couple, said effervescent couple comprising an acid or equivalent thereof and a base or equivalent thereof and said base is present in an amount that is at lest about twice the amount of said active ingredient (on a weight basis) and said effervescent couple present in an amount sufficient to increase penetration of said active ingredient across said vaginal mucosa; and a pH adjusting substance; causing said active ingredient and said effervescent penetration enhancer to release from said dosage form at said target area in said vagina and providing effervescent action at said target area thereby promoting penetration of 2c a therapeutically effective amount of said active ingredient across said target area for systemic delivery to said mammal.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The pharmaceutical 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, drugs 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.
In this regard, 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 recturn 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 llydrite 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. 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 maminalian 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 cm3, 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. For active ingredients that are weakly acidic or weakly basic, 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 COz. Thus, 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) 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.
The compositions may be administered in any dosage form suitable for delivery of an active ingredient to the rectum or vagina, respectively. For rectal administration, 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. For vaginal, administration, 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. In general, 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.
In a preferred embodiment, the composition is administered in the form of a tablet.
The tablets may, optionally, have special shapes to assist insertion of the compressed dosage form. These shapes include oval, capsule-shaped, and diamond-shaped tablets.
An applicator device may also be supplied with the tablets to make insertion easier and to facilitate insertion deep into the rectal or vaginal cavity. Such applicators are commonly used in the pharmaceutical industry for this purpose.
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, eg., U. S. Patents Nos. 5,178,878 and 5,223,264. Excipient fillers can be used to facilitate tableting. A filler desirably will also assist in the rapid dissolution of the dosage form. Nonlimiting examples of 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 5 soft gelatin capsules, hard gelatin capsules and the like made according to methods well known in the art.
In another preferred embodiment, the composition is administered in the form of a suppository. These are solid, molded units that are formed by pouring into suitable molds a molten wax or fatty material or other suitable substance as the base, into which is dissolved or dispersed the active ingredient and the effervescent penetration agent, and optionally, the pH adjusting substance, noneffervescent penetration enhancers and other excipients. Upon cooling, the base forms a solid containing the active ingredient and other ingredients dispersed in it and takes the shape of the mold. Examples of bases that could be used are cocoa butter, polyethylene glycols, polyvinyl pyrrolidone, 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 C 12) 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 ImhausenTM, WitepsolTM
and GelucireTM. Various grades of each of these are available for specific applications. Mixtures of various bases may also be utilized in order to obtain a suppository with the required properties. Other shaping methods for forming the suppositories including cold molding and compression may also be used.
In a more preferred embodiment, 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. Preferably, 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.
The compositions may be formulated for rapid, immediate, delayed or sustained release or a combination of these release forms. For delayed or sustained release, for example, 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 ofbiological origin, and combinations thereof.
Also encompassed by the term"active ingredient"are vitamins, minerals and dietary supplements as the same are defined, for example, in U. S. Patent No.
5,178,878.
More preferably, the active ingredients are drugs that display poor bioavailability, slow absorption or long tmaX. These active ingredients include small molecule drugs, nutritional supplements (such as vitamins and minerals), proteins and peptides and other substances of biological origin. Examples of such drugs include, but are not limited to, the following:
Drug Bioavailability (%) Acyclovir 15-30 Auranofin 15-25 Bretylium 23+9 Cyclosporine 23zL7 Cytarabine 20 Doxepin 27=L10 Doxorubicin 5 Hydralazine 16-35 Ketamine 20 7 Labetalol 1815 Mercaptopurine 12~:7 Methyldopa 25 16 Nalbuphine 25:L16 Naloxone 2 Pentoxifylline 19 13 Pyridostigmine 1 4:0 Terbutaline 14J:2 Verapamil 22 8 Riboflavin 11 Atenolol 50 Other 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. These include, but are not limited to, the use of additional chemical penetration enhancers and materials that aid in release and/or penetration of the drug in the rectum or vagina, respectively. There are various mechanisms by which such materials promote release and penetration of the active ingredient, and this invention is not limited to any one mechanism.
SUMMARY OF THE INVENTION
The pharmaceutical 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.
According to the present invention then, there is provided a dosage form adapted for rectal administration of a therapeutically effective amount of an active ingredient to a target area in the rectum of a mammal; comprising a therapeutically effective amount of an active ingredient; and at least one effervescent penetration enhancer; wherein said at least one effervescent penetration enhancer is present in an amount sufficient to increase the penetration of said active ingredient across said target area of said rectum, and to permit delivery of a therapeutically effective amount of said active ingredient.
According to a further aspect of the present invention, there is also provided the use of an effervescent penetration enhancer for delivering an active ingredient to a target area in the rectum of a mammal; comprising the steps of providing in the rectum of a mammal a dosage form comprising a therapeutically effective amount of an active ingredient and at least one effervescent penetration enhancer present in an amount sufficient to increase absorption of said active ingredient across a mucosa layer of said target area, causing said active ingredient and said effervescent penetration enhancer to release from said dosage form at said target area in said rectum and to provide effervescent action at said target area; so that said effervescent action promotes the absorption of a therapeutically effective amount of said active ingredient across said target area.
According to yet another aspect of the present invention, there is provided a dosage form adapted for vaginal administration of a therapeutically effective amount of an active ingredient to a target area in the vagina of a mammal; comprising a therapeutically effective 2a amount of an active ingredient; and at least one effervescent penetration enhancer; wherein said at least one effervescent penetration enhancer is present in an amount sufficient to increases the penetration of said active ingredient across said target area of said vagina.
According to yet a further aspect of the present invention, there is also provided the use of an effervescent penetration enhancer for delivering an active ingredient to a target area in the vagina of a mammal; comprising the steps of providing in the vagina of a mammal a dosage form comprising a therapeutically effective amount of an active ingredient and at least one effervescent penetration enhancer present in an amount sufficient to increase absorption of said active ingredient across a mucosa layer of said target area, causing said active ingredient and said effervescent penetration enhancer to release from said dosage form at said target area in said vagina and to provide effervescent action at said target area; so that said effervescent action promotes the absorption of a therapeutically effective amount of said active ingredient across said target area.
According to the present invention then, there is provided a dosage form adapted for rectal administration of a therapeutically effective amount of an active ingredient to a target area in the rectum of a mammal, said target area comprising rectal mucosa;
comprising a therapeutically effective amount of an active ingredient; and at least one effervescent penetration enhancer; wherein said at least one effervescent penetration enhancer comprises a pharmaceutically acceptable effervescent couple, said effervescent couple comprising an acid or equivalent thereof and a base or equivalent thereof and said base is present in an amount that is at least about twice the amount of said active ingredient (on a weight basis) and said effervescent couple is present in an amount sufficient to increase the penetration of said active ingredient across said rectal mucosa; and further comprising a pH adjusting substance; wherein said dosage form permits systemic delivery of a therapeutically effective amount of said active ingredient.
According to another aspect of the present invention then, there is also provided a method for delivering an active ingredient to a target area in the rectum of a mammal, said target area comprising rectal mucosa; comprising the steps of administering to the rectum of said mammal a dosage form comprising a therapeutically effective amount of an active ingredient; and at least one effervescent penetration enhancer comprising a pharmaceutically acceptable effervescent couple, said effervescent couple comprising an acid or equivalent thereof and a base or equivalent thereof and said base is present in an amount that is at least = CA 02422424 2007-06-11 2b about twice the amount of said active ingredient (on a weight basis) and said effervescent couple present in an amount sufficient to increase penetration of said active ingredient across said rectal mucosa; and a pH adjusting substance; causing said active ingredient and said effervescent penetration enhancer to release from said dosage form at said target area in said rectum and providing effervescent action at said target area thereby promoting penetration of a therapeutically effective amount of said active ingredient across said target area for systemic delivery to said mammal.
According to a further aspect of the present invention then, there is also provided a dosage form adapted for vaginal administration of a therapeutically effective amount of an active ingredient to a target area in the vagina of a mammal, said target area comprising vaginal mucosa; comprising a therapeutically effective amount of an active ingredient; and at least one effervescent penetration enhancer; wherein said at least one effervescent penetration enhancer comprises a pharmaceutically acceptable effervescent couple, said effervescent couple comprising an acid or equivalent thereof and a base or equivalent thereof and said base is present in an amount that is at least about twice the amount of said active ingredient (on a weight basis) and said effervescent couple is present in an amount sufficient to increases the penetration of said active ingredient across said vaginal mucosa; and further comprising a Ph adjusting substance; wherein said dosage form permits systemic delivery of a therapeutically effective amount of said active ingredient.
According to yet a further aspect of the present invention then, there is also provided a method for delivering an active ingredient to a target area in the vagina of a mammal, said target area comprising vaginal mucosa; comprising the steps of administering in the vagina of said mammal a dosage form comprising; a therapeutically effective amount of an active ingredient; and at least one effervescent penetration enhancer comprising a pharmaceutically acceptable effervescent couple, said effervescent couple comprising an acid or equivalent thereof and a base or equivalent thereof and said base is present in an amount that is at lest about twice the amount of said active ingredient (on a weight basis) and said effervescent couple present in an amount sufficient to increase penetration of said active ingredient across said vaginal mucosa; and a pH adjusting substance; causing said active ingredient and said effervescent penetration enhancer to release from said dosage form at said target area in said vagina and providing effervescent action at said target area thereby promoting penetration of 2c a therapeutically effective amount of said active ingredient across said target area for systemic delivery to said mammal.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The pharmaceutical 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, drugs 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.
In this regard, 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 recturn 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 llydrite 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. 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 maminalian 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 cm3, 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. For active ingredients that are weakly acidic or weakly basic, 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 COz. Thus, 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) 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.
The compositions may be administered in any dosage form suitable for delivery of an active ingredient to the rectum or vagina, respectively. For rectal administration, 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. For vaginal, administration, 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. In general, 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.
In a preferred embodiment, the composition is administered in the form of a tablet.
The tablets may, optionally, have special shapes to assist insertion of the compressed dosage form. These shapes include oval, capsule-shaped, and diamond-shaped tablets.
An applicator device may also be supplied with the tablets to make insertion easier and to facilitate insertion deep into the rectal or vaginal cavity. Such applicators are commonly used in the pharmaceutical industry for this purpose.
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, eg., U. S. Patents Nos. 5,178,878 and 5,223,264. Excipient fillers can be used to facilitate tableting. A filler desirably will also assist in the rapid dissolution of the dosage form. Nonlimiting examples of 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 5 soft gelatin capsules, hard gelatin capsules and the like made according to methods well known in the art.
In another preferred embodiment, the composition is administered in the form of a suppository. These are solid, molded units that are formed by pouring into suitable molds a molten wax or fatty material or other suitable substance as the base, into which is dissolved or dispersed the active ingredient and the effervescent penetration agent, and optionally, the pH adjusting substance, noneffervescent penetration enhancers and other excipients. Upon cooling, the base forms a solid containing the active ingredient and other ingredients dispersed in it and takes the shape of the mold. Examples of bases that could be used are cocoa butter, polyethylene glycols, polyvinyl pyrrolidone, 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 C 12) 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 ImhausenTM, WitepsolTM
and GelucireTM. Various grades of each of these are available for specific applications. Mixtures of various bases may also be utilized in order to obtain a suppository with the required properties. Other shaping methods for forming the suppositories including cold molding and compression may also be used.
In a more preferred embodiment, 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. Preferably, 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.
The compositions may be formulated for rapid, immediate, delayed or sustained release or a combination of these release forms. For delayed or sustained release, for example, 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 ofbiological origin, and combinations thereof.
Also encompassed by the term"active ingredient"are vitamins, minerals and dietary supplements as the same are defined, for example, in U. S. Patent No.
5,178,878.
More preferably, the active ingredients are drugs that display poor bioavailability, slow absorption or long tmaX. These active ingredients include small molecule drugs, nutritional supplements (such as vitamins and minerals), proteins and peptides and other substances of biological origin. Examples of such drugs include, but are not limited to, the following:
Drug Bioavailability (%) Acyclovir 15-30 Auranofin 15-25 Bretylium 23+9 Cyclosporine 23zL7 Cytarabine 20 Doxepin 27=L10 Doxorubicin 5 Hydralazine 16-35 Ketamine 20 7 Labetalol 1815 Mercaptopurine 12~:7 Methyldopa 25 16 Nalbuphine 25:L16 Naloxone 2 Pentoxifylline 19 13 Pyridostigmine 1 4:0 Terbutaline 14J:2 Verapamil 22 8 Riboflavin 11 Atenolol 50 Other 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. These include, but are not limited to, the use of additional chemical penetration enhancers and materials that aid in release and/or penetration of the drug in the rectum or vagina, respectively. There are various mechanisms by which such materials promote release and penetration of the active ingredient, and this invention is not limited to any one mechanism.
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 (NoveonTM
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. In addition to the effervescence-producing disintegration agents, 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.
Other excipients may be employed, 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.
Various modifications of the invention described herein will become apparent to those skilled in the art. Such modifications are intended to fall within the scope of the appending claims.
INDUSTRIAL APPLICABILITY
The invention relates to the pharmaceutical and medical industries and to the production of dosage forms.
Nonlimiting examples of known bioadhesives used in the present invention include: carbopol (various grades), sodium carboxy methylcellulose, methylcellulose, polycarbophil (NoveonTM
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. In addition to the effervescence-producing disintegration agents, 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.
Other excipients may be employed, 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.
Various modifications of the invention described herein will become apparent to those skilled in the art. Such modifications are intended to fall within the scope of the appending claims.
INDUSTRIAL APPLICABILITY
The invention relates to the pharmaceutical and medical industries and to the production of dosage forms.
Claims (15)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A dosage form adapted for rectal or vaginal administration of a therapeutically effective amount of an active ingredient to a target area in the rectum or in the vagina of a mammal, comprising:
(a) a therapeutically effective amount of an active ingredient; and (b) at least one effervescent penetration enhancer comprising a pharmaceutically acceptable effervescent couple comprising an acid and a base; and (c) a pH adjusting substance selected from the group consisting of sodium carbonate, potassium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and the equivalent potassium salts;
wherein said base is present in an amount at least two times the amount of said active ingredient on a weight basis and being sufficient to increase the penetration of said active ingredient across the mucosa layer of said target area of said rectum or said vagina, and to permit delivery of a therapeutically effective amount of said active ingredient across the mucosa layer of said target area, and wherein the pH adjusting substance 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.
(a) a therapeutically effective amount of an active ingredient; and (b) at least one effervescent penetration enhancer comprising a pharmaceutically acceptable effervescent couple comprising an acid and a base; and (c) a pH adjusting substance selected from the group consisting of sodium carbonate, potassium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and the equivalent potassium salts;
wherein said base is present in an amount at least two times the amount of said active ingredient on a weight basis and being sufficient to increase the penetration of said active ingredient across the mucosa layer of said target area of said rectum or said vagina, and to permit delivery of a therapeutically effective amount of said active ingredient across the mucosa layer of said target area, and wherein the pH adjusting substance 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.
2. The dosage form of claim 1, wherein said amount of said base is at least three times the amount of said active ingredient on a weight basis.
3. The dosage form of claim 1, wherein said amount of said base is equal to two times to three times the amount of said drug on a weight basis.
4. The dosage form of claims 1, 2 or 3, further comprising a bioadhesive, wherein said bioadhesive increases contact time between said active ingredient and a mucosa layer of said target area.
5. The dosage form of claim 4, wherein said bioadhesive is contained in a portion of said dosage form external to said active ingredient.
6. The dosage form of any one of claims 1 to 5, further comprising at least one noneffervescent penetration enhancer.
7. The dosage form of any one of claims 1 to 6, further comprising at least one noneffervescent disintegration agent.
8. The dosage form of any one of claims 1 to 7, wherein said dosage form is a suppository.
9. The dosage form of any one of claims 1 to 8 wherein said base is present in an amount equal to two times to three times the amount of said active ingredient on a weight basis; and said acid is present in an amount approximately equimolar to said base.
10. Use of a therapeutically effective amount of an active ingredient and at least one effervescent penetration enhancer comprising a pharmaceutically acceptable effervescent couple comprising an acid and a base, and a pH adjusting substance selected from the group consisting of sodium carbonate, potassium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and the equivalent potassium salts, for the manufacture of a medicament in a dosage form containing an amount of said base sufficient to increase absorption of said active ingredient across a mucosa layer of a target area in the rectum of a mammal, wherein said amount of base is at least two times the amount of active ingredient on a weight basis, for causing effervescent action at aid target area in order to promote the absorption of a therapeutically active amount of said active ingredient across said target area and wherein the pH adjusting substance alters the pH of the localized environment of the site of dissolution and absorption in the rectum to further improve dissolution and absorption.
11. The use of claim 10, wherein said amount of said base is two times to three times the amount of said active ingredient on a weight basis.
12. The dosage form of any one of claims 1 to 7 or 9, wherein said dosage form is a tablet.
13. The dosage form of any one of claims 1 to 7 or 9, wherein said dosage form is a capsule.
14. Use of a therapeutically effective amount of an active ingredient and at least one effervescent penetration enhancer comprising a pharmaceutically acceptable effervescent couple comprising an acid and a base, and a pH adjusting substance selected from the group consisting of sodium carbonate, potassium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and the equivalent potassium salts, for the manufacture of a medicament in a dosage form containing an amount of said base sufficient to increase absorption of said active ingredient across a mucosa layer of a target area in the vagina of a mammal, wherein said amount of base is at least two times the amount of active ingredient on a weight basis, for causing effervescent action at said target area in order to promote the absorption of a therapeutically active amount of said active ingredient across aid target area, and wherein the pH adjusting substance alters the pH of the localized environment of the site of dissolution and absorption in the vagina to further improve dissolution and absorption.
15. The use of claim 14, wherein said amount of said base is two times to three times the amount of said active ingredient on a weight basis.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2000/025634 WO2002024170A1 (en) | 2000-09-19 | 2000-09-19 | Pharmaceutical compositions for rectal and vaginal administration |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2422424A1 CA2422424A1 (en) | 2002-03-28 |
| CA2422424C true CA2422424C (en) | 2009-12-01 |
Family
ID=21741785
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002422424A Expired - Fee Related CA2422424C (en) | 2000-09-19 | 2000-09-19 | Pharmaceutical compositions for rectal and vaginal administration |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1318790A4 (en) |
| JP (1) | JP2004509142A (en) |
| AU (1) | AU7384700A (en) |
| CA (1) | CA2422424C (en) |
| WO (1) | WO2002024170A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1872775A1 (en) | 2006-06-29 | 2008-01-02 | Polichem S.A. | Use of a hydrophilic matrix comprising a polyacrylic acid derivative, a cellulose ether and a disintegrant for the manufacture of a medicament for treating female genital disorders |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1212704A (en) * | 1967-11-21 | 1970-11-18 | Prodotti Antibiotici Spa | Vaginal suppositories |
| US3888976A (en) * | 1972-09-21 | 1975-06-10 | William P Mlkvy | Zinc and strontium ion containing effervescent mouthwash tablet |
| NL7302521A (en) * | 1973-02-23 | 1974-08-27 | Foaming, effervescent capsules - contg. therapeutic agents for rectal and vaginal use | |
| JPS58152809A (en) * | 1982-03-05 | 1983-09-10 | Eisai Co Ltd | Stable foaming vaginal suppository |
| IT1251114B (en) * | 1991-07-26 | 1995-05-04 | Farcon Ag | ANTIVIRAL PHARMACEUTICAL FORMS FOR VAGINAL APPLICATION |
| DE4139883A1 (en) * | 1991-11-29 | 1993-06-03 | Michael Prof Dr Dittgen | Prodn. of bio-adhesive medicament, e.g. oral or vaginal tablet - comprises mixing drug with swellable, bio-adhesive polymer, dispersant and opt. binder |
| GB9523136D0 (en) * | 1995-11-11 | 1996-01-10 | Procter & Gamble | Silicone-containing powders |
| US5646151A (en) * | 1996-03-08 | 1997-07-08 | Adolor Corporation | Kappa agonist compounds and pharmaceutical formulations thereof |
| US6071539A (en) * | 1996-09-20 | 2000-06-06 | Ethypharm, Sa | Effervescent granules and methods for their preparation |
| EP2127642A3 (en) * | 1998-08-13 | 2010-02-24 | Cima Labs, Inc. | Microemulsions as solid dosage forms for oral administration |
-
2000
- 2000-09-19 EP EP00961968A patent/EP1318790A4/en not_active Ceased
- 2000-09-19 AU AU7384700A patent/AU7384700A/en active Pending
- 2000-09-19 CA CA002422424A patent/CA2422424C/en not_active Expired - Fee Related
- 2000-09-19 WO PCT/US2000/025634 patent/WO2002024170A1/en active Application Filing
- 2000-09-19 JP JP2002528206A patent/JP2004509142A/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU2000273847B2 (en) | 2006-09-14 |
| EP1318790A1 (en) | 2003-06-18 |
| JP2004509142A (en) | 2004-03-25 |
| AU7384700A (en) | 2002-04-02 |
| WO2002024170A1 (en) | 2002-03-28 |
| EP1318790A4 (en) | 2006-02-01 |
| CA2422424A1 (en) | 2002-03-28 |
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