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WO1991006289A1 - Support muco-adhesif servant a liberer un agent therapeutique - Google Patents

Support muco-adhesif servant a liberer un agent therapeutique Download PDF

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Publication number
WO1991006289A1
WO1991006289A1 PCT/US1989/004882 US8904882W WO9106289A1 WO 1991006289 A1 WO1991006289 A1 WO 1991006289A1 US 8904882 W US8904882 W US 8904882W WO 9106289 A1 WO9106289 A1 WO 9106289A1
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WO
WIPO (PCT)
Prior art keywords
accordance
polyethylene glycol
therapeutic agent
mucoadhesive
carrier
Prior art date
Application number
PCT/US1989/004882
Other languages
English (en)
Inventor
Dilip R. Sanvordeker
Sau-Hung Spence Leung
Original Assignee
Watson Laboratories, 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 Watson Laboratories, Inc. filed Critical Watson Laboratories, Inc.
Priority to EP19890912797 priority Critical patent/EP0452334A4/en
Priority to PCT/US1989/004882 priority patent/WO1991006289A1/fr
Priority to JP2500642A priority patent/JPH04502913A/ja
Publication of WO1991006289A1 publication Critical patent/WO1991006289A1/fr
Priority to FI913127A priority patent/FI913127A0/fi
Priority to DK911276A priority patent/DK127691D0/da
Priority to NO91912558A priority patent/NO912558L/no

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays

Definitions

  • This invention relates to a carrier system for administration of a therapeutic agent via a mucosal membrane.
  • the carrier system exhibits enhanced adhesion to the mucosal membrane and provides improved bioavailability of the therapeutic agent.
  • Buccal drug delivery systems with bioadhesive polymers as a platform for holding the system in place in the oral cavity after application have been described in the aforementioned U.S. Patents to Tsuk et al., to Nagai et al., to Hicks et al. and to Robinson.
  • the drug is incorporated in a reservoir in the adhesive layer or embedded in the controlled release matrix without the use of any specific agent to promote drug dissolution and thereby enhance the thermodynamic activity of the drug in the matrix.
  • a microcapsule encloses the drug as an added reservoir embedded in the adhesive layer of the bi-laminate drug delivery system.
  • a method of adhering a delivery system was by hydration of a bioadhesive polymer matrix. Adhesion results from the entanglement of the hydrated polymer chains on the surface of the matrix with the glycoproteins of the mucosa. Under mild pressure such entanglement leads to a reinforcement of adhesion due to London dispersion forces (e.g. van der Waal's forces), as well as hydrophobic, ionic and hydrogen bonding forces that contribute to the adhesion strength.
  • London dispersion forces e.g. van der Waal's forces
  • the carboxy-functional polymers disclosed in Robinson are hydratable polymers which are useful for buccal delivery of drugs. These polymers rely solely on the adhesion of the delivery system followed by drug dissolution in the hydrophilic polymer matrix due to a body fluid such as saliva or its aqueous component to effect release of the drug.
  • a body fluid such as saliva or its aqueous component to effect release of the drug.
  • the chemical potential or the thermodynamic activity of the drug is built up to the point of saturation solubility of the drug in the micro-fluid environment of the polymer matrix. Consequently, the drug is released out of the matrix into the buccal interfacial environment at a rate dependent on the saturation solubility of the drug in the body fluid which permeates the matrix. Thus there is little control over the rate of release.
  • polar drugs including zwitter-ionic therapeutic compounds such as bio-synthetic peptides which are subject to poor oral bioavailability
  • zwitter-ionic therapeutic compounds such as bio-synthetic peptides which are subject to poor oral bioavailability
  • solubility of these drugs is poor.
  • the present invention contemplates an anhydrous but hydratable mucoadhesive monolithic polymeric matrix which includes amorphous fumed silica present in an amount sufficient to enhance adhesion of the polymeric matrix to mucosal tissue.
  • the matrix may include a plasticized, film-forming cellulose ester.
  • This present polymeric matrix is mucoadhesive, and is eminently well suited for systemic delivery of a wide variety of therapeutic agents via the mucous membranes of a patient, i.e., by buccal, vaginal or rectal route.
  • Therapeutic agents which exhibit absorption problems by the gastro-intestinal route due to solubility limitations, pH or enzymatic degradation and/or extensive metabolism by the liver are particularly well suited for use in combination with the present carrier.
  • These agents can be hydrophilic, hydrophobic or amphiphilic in nature and can belong to a specific therapeutic class or within an area covering cardiovascular, bronchodilation, growth-stimulating supplements, enzyme supplements, estrogen and androgen supplements, anti-anxiety, antidepressant, anti-parkinsonism, memory maintenance, memory retention or enhancement, birth-control, antibiotic, antiviral, antiprotozoal, vitamin, antidiabetic, gastro-intestinal, anticonvulsant, immunomodulation, nutritional supplements and appetite modulating therapy.
  • FIGURE 1 is a fragmentary sectional view showing the bi-laminate structure of a mucoadhesive therapeutic dosage form embodying the present invention
  • FIGURE 2 is a sectional view showing the dosage form of FIGURE 1 enclosed within a protective envelope;
  • FIGURE 3 is a sectional view of an alternative embodiment of the present therapeutic dosage form having a retrieving element therein;
  • FIGURE 4 is a planar view of an alternative embodiment of the present therapeutic dosage form also provided with a retrieving element; and FIGURE 5 is a sectional view of yet another embodiment of the present therapeutic dosage form showing an alternative retrieving element provided with perforations.
  • mucoadhesive is a material that adheres to a mucosal tissue surface in-vivo and/or in-vitro. Such adhesion will adherently localize the dosage form onto the mucus membrane and requires the application of a force of at least about 50 dynes/cm to separate the mucoadhesive material from the mucus membrane. All mesh sizes are U.S. Sieve Series.
  • the mucoadhesive carrier of the present invention can be fabricated in a wide variety of self-supporting sizes, shapes or forms that provide a therapeutic dosage form suitable for comfortable and convenient application and adhesion to the buccal, vaginal or rectal mucosa.
  • the mucoadhesive carrier can be fabricated in the form of a disc of a suitable size and shape, a hard or soft film, or an implantable form, for example.
  • An optional water-insoluble barrier film can be provided on the mucoadhesive carrier so as to render a side or face thereof non-adhesive.
  • the present mucoadhesive carrier comprises a monolithic polymer matrix that is anhydrous but hydratable, and amorphous fumed silica present in an amount sufficient to enhance adhesion of the matrix to tissue as is more fully described hereinbelow.
  • a therapeutic agent is distributed within the carrier as a solution or a dispersion therein.
  • therapeutic agents capable of being delivered by the foregoing carrier are 17 ⁇ 5-estradiol, dehydroepiandrosterone, nifedipine, diltiezem, haloperidol, buprenorphine, meperidine, fentanyl, testosterone, progesterone, norethindrone, ethinyl estradiol, mestranol, oxandrolone, and the like.
  • Therapeutic agents which are relatively insoluble in water can be combined with a polyol such as a polyethylene glycol (PEG) which is then admixed with the amorphous fumed silica to form the matrix.
  • Therapeutic agents which are amphiphilic and water soluble also can be admixed with the hydrophilic polyol to form a dispersion which is then combined with the silica.
  • Preferred polymers for the polymeric matrix are polyols, e.g., polyethylene glycols (PEG) having a number average molecular weight in the range of about 1500 to about 8500, preferably in the range of about 4000 to about 8000.
  • PEG polyethylene glycols
  • These polyols promote lowering of the dielectric constant of the aqueous environment to which the carrier is exposed and solubilize relatively insoluble agents thereby increasing the thermodynamic activity of the therapeutic agent in the monolithic polymer matrix. Enhancement of the diffusion of the therapeutic agent across the matrix into the mucosa and the capillary bed of the mucosal tissue underneath is thus achieved. Additionally, these polyols have the distinct advantage of being inert, pharmaceutically acceptable adjuvants.
  • the mucoadhesive carrier composition can optionally include an additional amount of the same polyol or a derivative having a higher or lower number average molecular weight.
  • the additional polyol is believed to function as a plasticizer and diffusion aid.
  • Hydrophilic polyols which are water-soluble provide very favorable dissolution of the therapeutic agents. These hydrophilic polyols create a less polar aqueous environment by lowering the dielectric property of the aqueous solution of the mucosal environment. Thus, the hydrophilic polyols described herein are believed to function as a dissolution promoter and/or facilitator of therapeutic agent transport through the polymer matrix as well as interfacial transport across a biological membrane such as the mucosa.
  • the mucoadhesive carrier composition is combined with a therapeutic agent as a dispersion or solution of the therapeutic agent in a stable melt-processable form of the polymer, such as polyethylene glycol having a melting point of at least about about 50°C. (about 120°F.).
  • a therapeutic agent as a dispersion or solution of the therapeutic agent in a stable melt-processable form of the polymer, such as polyethylene glycol having a melting point of at least about about 50°C. (about 120°F.).
  • the composition is processable by melt, solvent deposition or physical blending processes.
  • Amorphous fumed silica is added to the polymeric matrix in a processable dry powder form.
  • the amount of fumed silica present varies, depending on the nature of the polymeric matrix utilized in any given instance; however, the amount of fumed silica added is sufficient to enhance the adhesion of the polymeric matrix to mucosal tissue. If the polymeric matrix is constituted primarily by a polyol, the amount of fumed silica present preferably is at least about 10 percent by weight of the matrix. On the other hand, if the polymeric matrix also includes other known bioadhesives such as a carboxy-functional polymer, the amount of fumed silica present can be as low as about 2 percent by weight of the matrix, and preferably is at least about 3 percent by weight of the matrix.
  • silica examples include fumed silicon dioxide such as Cab-o-sil (Degussa Corp., Teterboro, New Jersey), Aer-o-sil® (Degussa Corp.) or microporous precipitated silicon dioxide such as Sylloid ® (Davison Division, W. R. Grace Company) available commercially in food and pharmaceutical grades.
  • the silica serves to provide a plurality of discrete particles that are distributed within and/or on the surface of the monolithic polymeric matrix of the present carrier.
  • silica can serve as a reservoir for a therapeutic agent.
  • mucoadhesion occurs due to bulk convective capillary flow of the aqueous mucus-loaded fluid into the micro-environment of the microporous silica particles.
  • These discrete particles serve as hydrating absorbent components and are believed to draw components or portions of the glycoprotein from the mucous of the mucosal wall into the microporous silica particles at the surface and/or in the polymer matrix, as the case may be.
  • During hydration of these water-insoluble microporous silica particles the entanglement of portions of mucoproteins from the mucosal wall occurs leading to a reinforced adhesion brought about by the naturally applied pressure of the mucosal wall which holds the drug delivery system in place.
  • An optional bioadhesive such as a water-swellable, but water-insoluble, fibrous, cross-linked carboxy-functional polymer can also be present.
  • This polymer contains a plurality of repeating units of which at least about 80 percent contain at least one carboxyl functionality and about 0.05 to about 1.5 percent cross-linking agent substantially free from polyalkenyl polyether, with the percentages being based upon the weights of unpolymerized repeating unit and cross-linking agent, respectively.
  • at least about 90 percent of the repeating units contain at least one carboxyl functionality, and in still more preferred practice, at least 95 percent of those repeating units contain at least one carboxyl functionality.
  • the bioadhesive is a reaction product of the polymerization of only a carboxyl-functional monomer and a cross-linking agent therefor.
  • the bioadhesive contains about 0.1 to about 1 percent by weight of polymerized cross-linking agent.
  • Such a bioadhesive is commercially available under the trademark Carbophil® from B.F. Goodrich, Cincinnati, Ohio.
  • Other optional bioadhesives include polymers which are hydrophilic and water-dispersible, have free carboxylic groups and a relativey high base binding capacity.
  • Preferred polymers include water dispersible polycarboxylated vinyl polymers. Polyacrylic acid polymers are particularly preferred.
  • Suitable polyacrylic acid polymers include, but are not limited to, polyacrylic acid polymers lightly crosslinked with a polyalkenyl polyether such as those commercially available from B.F. Goodrich, Cincinnati, Ohio, under the trademarks Carbopol ® Ex 55 Resin, 434, 934P, 940 and 941.
  • a polyalkenyl polyether such as those commercially available from B.F. Goodrich, Cincinnati, Ohio, under the trademarks Carbopol ® Ex 55 Resin, 434, 934P, 940 and 941.
  • the cumulative mucoadhesive effect of these microporous silica particles on the carrier, with or without the inclusion of a known bioadhesive such as Carbopol ® , Carbophil and combinations thereof, has not been reported to the best of our knowledge.
  • silica serving as a mucoadhesive, it can also serve as a reservoir for the controlled release of the therapeutic agents.
  • Inclusion of a therapeutic agent loaded portion of silica powder serves as a reservoir for a variety of therapeutic agents or their derivatives with varying physical properties such as melting points, partition coefficient, crystal form and intrinsic dissolution rates.
  • the mucoadhesive carrier composition can also be combined with known natural or synthetic hydratable adjuvants or a mixture thereof, such as polyvinyl alcohol, polyvinyl pyrrolidone (povidone) , sodium alginate, methyl cellulose, hydroxyl propyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycols, carbopol, polycarbophil, carbox vinyl copolymers, propylene glycol alginate, alginic acid, methyl methacrylate copolymers, (Eudragit ® type, from Rohm Pharma, N.Y., NY), tragacanth gum, guar gum, karaya gum, ethylene vinyl acetate, dimethylpolysiloxanes, polyoxyalkylene block copolymers (Poloxamers, the Cosmetic, Toiletry and Fragrance Association, Inc. name for a commercially available polyoxyethylene-polyoxypropylene block copolymer) hydroxyethylmethacrylate
  • the dissolution of the therapeutic agent within the monolithic polymer matrix is enhanced by maintaining a high level of thermodynamic activity of the therapeutic agent. This activity is maintained by utilizing hydrophilic and hydrophobic excipients in combination, e.g., polycarbophil and glyceryl behenate, respectively, in the polymer matrix to control the release of the therapeutic agent for superior bioavailability.
  • the resulting monolithic polymer matrix can be optionally laminated to a water-insoluble, but water-permeable or substantially water-impermeable, barrier film which does not contain the therapeutic agent.
  • the barrier film serves as a backing to prevent or minimize back diffusion of the therapeutic agent and protect the extraneous tissues, such as gums and teeth, from direct exposure to the matrix.
  • the composition of the water-insoluble barrier film is chosen in such a manner as to be compatible with the polymer matrix and so that it is stable and non-irritating to the patient.
  • components of this barrier film include components of the polymer matrix to ensure compatibility, processability and physical stability of the carrier system during the shelf life of the product.
  • the barrier film may include pharmaceutically edible adjuvants.
  • Illustrative adjuvants include hydrogenated vegetable oil. microcrystalline cellulose, methylcellulose, calcium phosphate dihydrate, talc, kaolin, bentonite, hydroxypropyl cellulose, high melting glyceryl esters such as glyceryl behenate, methylcellulose, cellulose acetate butyrate, polyvinyl pyrrolidone, polyvinyl alcohol, magnesium stearate, silicon dioxide, and stearic acid.
  • barrier layer or film major components of the barrier layer or film are directly compressible, water- insoluble materials such as dicalcium phosphate dihydrate (Encompress ® , Edward Mendell Co. Inc., Carmel, NY) and glyceryl behenate (Compritol®, Gattefosse Corporation, Elmsford, NY) together with a minor amount of a cellulose derivative. Inclusion of these ingredients improves cost-effective manufacture of a bi-laminate tablet or disc type dosage form that can be blister packed or foil packed for convenient dispensing by the patient.
  • dicalcium phosphate dihydrate Engel ®
  • glyceryl behenate Compritol®, Gattefosse Corporation, Elmsford, NY
  • hydrophilic, water-insoluble inorganic excipient such as dicalcium phosphate dihydrate in combination with a hydrophilic agent provides a satisfactory drug permeation barrier, for bi-laminate carriers for mucosal applications.
  • a preferred embodiment of the present carrier is a mucoadhesive disc composed of a bi-laminate including a water-swellable, hydratable monolithic polymer matrix and a water-insoluble barrier film.
  • the mucoadhesive polymer matrix contains a dispersion of the therapeutic agent in an amount sufficient for the desired medical treatment.
  • the polymer matrix is provided by a polyol in which is dispersed amorphous fumed silica and the desired medicament.
  • the hydrophilic polyol is preferably, a polyethylene glycol (PEG) , more preferably a melt-processable powder form of PEG having a melting point of at least about 50°C. (about 120°F.).
  • the number average molecular weight of the PEG is in the range of about 1500 to about 8500, preferably about 4000 to about 8000.
  • the weight ratio of the therapeutic agent: hydrophilic polyol is in the range of about 500:1 to about 0.1:500, preferably about 1:2 to about 1:5, respectively.
  • Silica having a microporous structure and a
  • about 700 m /g is present in an amount of about 0.1 to about 40, preferably about 10 to about 35 weight percent, based on the total weight of the polymeric matrix including the weight of the silica.
  • the silica utilized in the resulting mucoadhesive composition can be utilized alone or in combination with optional components such as a known hydratable, bioadhesive polymer, e.g., polycarbophil, or a diffusion retarding polymer such as a polyvinyl alcohol or a high viscosity grade hydroxypropyl cellulose (Klucel ® HXF, Hercules, Inc., Houston, Texas) . These optional components can be present in the range of up to about 50 weight percent, based on the total weight of the polymer matrix.
  • a known hydratable, bioadhesive polymer e.g., polycarbophil
  • a diffusion retarding polymer such as a polyvinyl alcohol or a high viscosity grade hydroxypropyl cellulose (Klucel ® HXF, Hercules, Inc., Houston, Texas) .
  • These optional components can be present in the range of up to about 50 weight percent, based on the total weight
  • a preferred combination of a hydrophobic excipient with a hydrophilic excipient present in the monolithic polymer matrix is glyceryl behenate (Compritol® , Gattefosse' Corp., Elmsford, NY) and polycarbophil, respectively.
  • the weight ratio of hydrophobic to hydrophilic excipient is in the range of about 1:20 to about 3:1, preferably about 1:10 to about 1:1. Up to about 50 weight percent, based on the total weight of the polymer matrix, of this combination can be present.
  • Suitable adjuvants that increase the tortuosity of the polymer matrix are dicalcium phosphate dihydrate (Encompress®) , fully hydrolyzed polyvinyl alcohol (Vinol 125, Air Products and Chemicals Inc., Allentown, PA) and dry microporous and microfine silicon dioxide.
  • a preferred range of the total amount of these polymer matrix forming adjuvants is about 0.5 to about 50 weight percent based on the total weight of the polymer matrix.
  • the components of the polymer matrix can be blended and lubricated, if necessary, with known lubricants such as magnesium stearate, sodium fumarate, stearic acid or talc, optionally present in the range of about 0.5 to about 2 weight percent based on the total weight of the polymer matrix.
  • the barrier film as an optional but preferred element of this invention, is composed of a combination of pharmaceutical excipients similar to those that are used in the polymer matrix and more importantly, that are relatively water-insoluble and in a laminate form provide a non-disintegrating therapeutic agent-impervious barrier film or layer to inhibit back diffusion of the therapeutic agent from the polymer matrix.
  • Preferred ingredients useful but not exclusive to the compositions of the barrier film are dicalcium phosphate dihydrate (Encompress ® ) in the range of about 10 to about 25 weight percent and a colorant, preferably an aluminum lake, such as FD&C red #40 lake (from Coloron, Inc.) in the range of about 0.1 to about 1 weight percent.
  • Hydrophilic polymers such as fully hydrolyzed polyvinyl alcohol (Vinol® 125) of a fine grade (40 mesh, U.S.
  • the polymeric matrix and the barrier film usually are prepared separately.
  • An illustrative melt process produces a mucosal composition in which the therapeutic agent is dissolved in the polyethylene glycol.
  • the polyethylene glycol is melted, " usually at a temperature of about 70°C. (about 160°F.).
  • the powdered therapeutic agent is then slowly added to the molten polyethylene glycol under constant stirring. Stirring is continued until all the therapeutic agent particles present are dissolved.
  • the thus produced liquid mucosal composition is then poured onto a surface, i.e., flattened aluminum foil, and solidified. Additional cooling, if desired or necessary to provide a relatively rapid solidification, can be performed by placing the composition in an airtight container which is placed in a freezer at a temperature of about 4 °C. (about 40 °F.) .
  • the powdered polyethylene glycol and therapeutic agent are intimately admixed to produce the desired physical admixture.
  • the above mucosal composition or physical admixture is then finely ground to a powder of about 60 to about 80 mesh and blended with other matrix forming hydrophilic and hydrophobic excipients of the polymer matrix such as glyceryl behenate
  • Compritol ® polyvinyl alcohol, dicalcium phosphate dihydrate (Encompress ® ) , hydroxypropyl cellulose (Klucel ® HXF) and silica in the form of microporous, microfine silicon dioxide (Sylloid 224 FP, Davison Division, W. R. Grace & Company) .
  • additional polyethylene glycol can be added.
  • a granulation process utilizing an organic solvent or water may be used to prepare, dry and obtain granules in a range of about 40 to about 200 mesh. This resulting dried preparation of the polymer matrix can optionally be blended and lubricated with the aforementioned lubricants.
  • barrier film or layer is prepared separately utilizing some of the constituents of the polymer matrix with the exception that the barrier film or layer does not contain a therapeutic agent or an adhesive.
  • the components of the polymer matrix and the barrier film in their required portions are compressed together as by a hydraulic press, e.g., a Carver Press, to obtain a bi-laminate mucoadhesive carrier of a suitable size and shape.
  • a hydraulic press e.g., a Carver Press
  • a preferred range for the thickness of the mucosal composition containing monolithic polymer matrix is about 0.5 mm to about 10 mm.
  • a preferred range for the thickness of the barrier film is about 0.5 mm to about 20 mm. These sizes are dependent upon the requirements of the dose, site of application and delivery rate of the therapeutic agent for an effective therapy via application of the system on the mucosal site for a specified period.
  • a preferred shape for the delivery system depends on the site of application. It can be a flat disc, rectangular, circular, oval, oblong, rod, bi-convex or hemispheric shaped.
  • a preferable shape of the carrier is a disc shape 5 mm to 50 mm in diameter.
  • a retrieving element which is an appendage extending from the carrier is present to facilitate removal.
  • the carrier of the present invention may have various configurations. Illustrative configurations are shown in FIGURES 1-5.
  • FIGURE 1 shows therapeutic dosage form 10 of the present invention comprised of a mucoadhesive polymer matrix 12 containing a dissolved therapeutic agent and having attached thereto optional barrier film or layer 14 which provides a non-adhesive face.
  • the dosage form 10 is enclosed in a protective envelope 16 which protects the dosage form 10 from the external environment prior to use.
  • This protective envelope 16 is substantially water vapor impermeable and is composed of an appropriate packaging material such as aluminum foil or the like.
  • FIGURE 3 shows an alternative embodiment of therapeutic dosage form 110 enclosed in the protective envelope 116.
  • a retrieving element in the form of a string-like segment 118 is present. The function of the retrieving element is to assist in removal of the dosage form 110 from the user.
  • FIGURE 3 shows the string-like segment 118 embedded within the polymer matrix 112
  • the location of the segment 118 is not critical so long as the segment 118 can be conveniently grasped and manipulated to perform its intended function.
  • FIGURE 4 is a planar view of a mucoadhesive spherical dosage form 111 showing the retrieving element 119 anchored within the polymeric matrix 115.
  • dosage form 210 is provided with embedded planar retrieving element 218 in the form of a ribbon which is provided with perforations 214 that facilitate the anchoring of the retrieving element 218 within the polymeric matrix 212.
  • EXAMPLE 1 Preparation of bioadhesive discs which do not embody the present invention
  • all the individual ingredients, disclosed in TABLE I, below, were weighed accurately and mixed in an opaque bottle for about two minutes. Each mixture was then passed through a 45 mesh screen three times. The screened mixture was collected in a bottle and mixed for an additional 2 minutes.
  • Approximately 130 mg of the composition of the barrier layer was weighed and placed in a circular stainless steel die having a 12.5 mm diameter and a flat stainless steel holder plug at the bottom. The powder was gently tapped to cover the die hole. Then 150 mg of the composition of the bioadhesive layer was added on the top of the barrier layer in the die.
  • EXAMPLE 3 Preparation of the mucoadhesive carrier of the present invention and hydration comparison of same with a bioadhesive disc
  • the procedure for the preparation of discs was similar to that of EXAMPLE 1.
  • the composition of the carrier is disclosed in TABLE II, below.
  • 150 mg each of the compositions of the polymer matrix and the barrier film were utilized.
  • bioadhesive discs without silicon dioxide were prepared.
  • the silica of the polymer matrix was replaced with hydroxypropyl cellulose. Both compositions with (I) and without (II) silica were compressed at 1000 psi and 10,000 psi compression pressure using a Carver Press. Samples of the mucoadhesive carrier and the bioadhesive disc, with and without silica, respectively, were tested for the rate and extent of hydration.
  • Composition I 1 Composi.tion II2
  • composition of a mucoadhesive carrier in disc form using microfine and microporous silica as a mucoadhesive as disclosed in TABLE IV, below, was prepared and tested for jLn vivo adhesion in three female subjects.
  • Polymer matrix Barrier film Component Weight (mg) Weight, (mg)
  • Klucel ® HXF from Hercules, Inc., Houston, Texas, a commercially available hydroxypropyl cellulose.
  • EXAMPLE 5 Preparation of a mucosal composition Anhydrous mucosal compositions comprising one of the following therapeutic agents: nifedipine; estradiol; piroxicam; albuterol or dehydroepiandrosterone (DHEA) , dissolved in polyethylene glycol were prepared. Each mucosal composition contained 0.5 grams of a therapeutic agent and 2.0 grams of polyethylene glycol 4000 which has a number average molecular weight of about 3350 (PEG 3350) . Thus the weight ratio of therapeutic agent to PEG 3350 was 1:4, respectively. The mucosal composition was prepared by melting the weighed amount of PEG 3350 in a suitable vessel at about 70° C. (about 160 °F.) on a hot plate. The powdered therapeutic agent was added slowly to the liquid PEG 3350 under constant stirring. The stirring of each molten mucosal composition was continued until all the therapeutic agent particles present dissolved.
  • PEG 3350 polyethylene glycol 4000 which has a number average mole
  • the mucosal composition was then poured onto a flattened aluminum foil and allowed to solidify. Additional cooling of the mucosal composition containing the therapeutic agent and PEG 3350 was performed by placing the mucosal composition in an airtight container which was placed in a freezer at a temperature of about 4°C. (about 40 °F.) for about one hour. The produced hardened flakes were powdered with a mortar and pestle and passed through a 60 mesh screen. The mucosal composition in powder form was then used for preparation of mucoadhesive carriers in disc form.
  • a physical admixture was also prepared. 60 Mesh powders of piroxicam and PEG 3350 were intimately admixed in a 1:4 weight ratio.
  • T is the time (in minutes) to achieve the depicted percent release of piroxicam.
  • compositions of TABLE VII, below, were utilized to prepare carriers.
  • Each carrier contained 20 mg equivalent of one of the therapeutic agents, albuterol or norephedrine (phenylpropanolamine) , in a mucosal composition having a therapeutic agent:polyethylene glycol 8000 (PEG 8000) weight ratio of a 1:2, respectively.
  • the mucosal compositions were prepared in accordance with the general procedure described in EXAMPLE 5.
  • 150 Mg each of the compositions of the polymer matrix and the barrier film were weighed and the mucoadhesive carriers in disc form were compressed at 1000 psi using a Carver Press following the general procedure described in EXAMPLE 1.
  • FD & C red #40 lake from Coloron, Inc. a commercially available aluminum lake colorant.
  • Vinol ® 125 from Air Products and Chemicals, Inc., Allentown, PA, a commercially available polyvinyl alcohol.
  • Klucel ® HXF from Hercules, Inc., Houston, Texas, a commercially available hydroxypropyl cellulose.
  • Therapeutic agent release testing was conducted by the USP Dissolution Test Method II.
  • the dissolution medium chosen was 500 ml of a 0.05M isotonic phosphate buffer having a 6.0 pH with 30 weight percent PEG 400. This method is described in EXAMPLE 6.
  • T is the time (in hours) to achieve the depicted percent release of the therapeutic agent from the mucoadhesive carrier.
  • the results illustrated in TABLE VIII demonstrate therapeutic agent release from these compositions is controlled by the matrix composed of a combination of both hydrophilic and hydrophobic components that form the bilaminate structure of the mucoadhesive carrier.
  • EXAMPLE 8 Determination of the effect of hydrophilic and hydrophobic components on the release of the therapeutic agent from the polymer matrix Several compositions of mucoadhesive carriers containing albuterol were prepared to determine the effect of key hydrophilic and hydrophobic components of the monolithic polymer matrix on the release of albuterol from the polymer matrix. The compositions of these matrices are illustrated in TABLE IX, below. The methods of preparation of the mucosal composition as well as preparation of the carrier in disc form are substantially the same as those described in EXAMPLE 5 and EXAMPLE 6, respectively, except that the carrier included fumed silica as well.
  • composition of the barrier film of this mucoadhesive therapeutic agent carrier was the same as that of the barrier film of EXAMPLE 4.
  • Encompress® from Edward Mendell Co. Inc., Carmel, NY, a commercially available dicalcium phosphate dihydrate.
  • Kluce® HXF from Hercules, Inc., Houston, Texas, a commarcially available hydroxypropyl cellulose.
  • Carbopol® Ex-55 Resin from B.F. Goodrich Corp. a commercially available polycarbophil.
  • Sylloid ®244 FP from the Davison Division of W. R. Grace and Company, a commerciall available fumed silicon dioxide.
  • T is the time (in hours) to achieve the depicted percent release of the therapeutic agent from the mucoadhesive carrier.
  • composition of TABLE XI, below, of a bi-laminate mucoadhesive carrier in disc form with 20 mg of piroxicam was prepared and tested for _in vitro therapeutic agent release by the methods described previously in EXAMPLE 7.
  • FD & C red #40 lake from Coloron, Inc. a commercially available aluminum lake colorant.
  • Vinol ® 125 from Air Products and Chemicals, Inc., Allentown, PA, a commercially available polyvinyl alcohol.
  • Klucel ® HXF from Hercules, Inc., Houston, Texas, a commercially available hydroxypropyl cellulose.
  • Carbopol® Ex-55 Resin from B.F. Goodrich Corp. a commercially available polycarbophil.
  • the rate of _in vitro release of therapeutic agent was 5 weight percent in one hour, 9 weight percent in two hours, 13 weight percent in three hours and 24.1 weight percent in 6 hours and 56 weight percent in 23 hours.
  • the therapeutic agent released followed an apparent zero order rate.
  • EXAMPLE 10 In vitro 17 ff-estradiol release The composition of TABLE XII, below, of a bi-laminate mucoadhesive carrier in disc form with 17 B -estradiol was prepared and tested in vitro for therapeutic agent release characteristics. The preparation and testing procedures were similar to those described in EXAMPLE 7. TABLE XI
  • Component Polymer matrix Barrier film Dicalcium phosphate dihydrate 1 27.50
  • Encompress® from Edward Mendell Co. Inc., Carmel, NY, a commercially available dicalcium phosphate dihydrate.
  • FD & C red #40 lake from Coloron, Inc. a commercially available aluminum lake colorant.
  • Vinol r®s 125 from Air Products and Chemicals, Inc., Allentown, PA, a commercially available polyvinyl alcohol.
  • Klucel ® HXF from Hercules, Inc., Houston, Texas, a commercially available hydroxypropyl cellulose.
  • Carbopol ® Ex-55 Resin from B.F. Goodrich Corp. a commercially available polycarbophil.
  • composition of TABLE XIII, below, of a mucoadhesive carrier in the form of a bi-laminate disc containing 10 mg of nifedipine was prepared.
  • the procedures for disc preparation and JLn vitro release testing were similar to those of EXAMPLE 7.
  • Mucosal composition 30.00 PEG 8000 35.00 Encompress ® from Edward Mendell Co. Inc., Carmel,
  • FD & C red #40 lake from Coloron, Inc. a commercially available aluminum lake colorant.
  • Vinol ® 125 from Air Products and Chemicals, Inc., Allentown, PA, a commercially available polyvinyl alcohol.
  • Carbopol ® Ex-55 Resin from B.F. Goodrich Corp. a commercially available polycarbophil.
  • Sylloid ® 244 FP from Davison Division of W. R.
  • the rate of _in vitro release of nifedipine was 4 weight percent in 1 hour, 6.5 weight percent in 2 hours, 10.7 weight percent in 4 hours, 18.7 weight percent hours and 21.0 weight percent in 8 hours suggesting a zero order therapeutic agent release from the monolithic matrix.
  • EXAMPLE 12 In vitro dehydroepiandrosterone release The composition of TABLE XIV, below, of a bi-laminate mucoadhesive carrier in the form of a disc was prepared with 5 mg of dehydroepiandrosterone (DHEA) , an androgen, as the therapeutic agent. The methods for preparation and _in vitro release testing were similar to those described in EXAMPLE 7. TABLE XIV Mucoadhesive carrier composition
  • Encompress® from Edward Mendell Co. Inc., Carmel, NY, a commercially available dicalcium phosphate dihydrate.
  • Allentown, PA a commercially available polyvinyl alcohol. 5 Klucel ® HXF from Hercules, Inc., Houston, Texas, a commercially available hydroxypropyl cellulose.
  • Carbopol ® Ex-55 Resin from B.F. Goodrich Corp. a commercially available polycarbophil.
  • EXAMPLE 13 Alternative method of applying the barrier film as a coating suspension and in vitro therapeutic agent release
  • TABLE XV The components of TABLE XV, below, were used to form a bi-laminate mucoadhesive carrier.
  • Encompress® from Edward Mendell Co. Inc., Carmel, NY, a commercially available dicalcium phosphate dihydrate.
  • Co ⁇ pritol 885 from Gattefosse Corporation, Elmsford, NY, a commercially available glyceryl behenate.
  • 3 FD&C red #40 lake from Coloron, Inc. a commercially available aluminum lake colorant.
  • Sylloid®244 FP from Davison Division of W. R. Grace and
  • Ethyl acetate:acetone in a 1:1 weight ratio evaporated during drying of the applied film. All components for the polymer matrix equivalent to 10 carriers in disc form were screened through a 40 mesh stainless steel screen, weighed and blended. 200 Mg of this blend were compressed into approximately 13 mm x 3 mm circular discs. A portion of the discs so prepared was coated manually on one side with a homogenous suspension of the compounds of the barrier film to serve as a water-insoluble barrier film.
  • the barrier film coating suspension was prepared by dissolving the polymer and the plasticizer in the organic solvent solution followed by the addition of the FD&C Red #40 lake powder to the suspension to obtain the final suspension.
  • EXAMPLE 14 In vitro therapeutic agent release experiment of a mucoadhesive carrier having a barrier film applied as a coating suspension
  • TABLE XVI Polymer matrix composition Component Weight, (mg) Weight percent
  • Rate of _ir ⁇ vitro release of therapeutic agent studies showed that this carrier composition released 20%, 50%, 75% and
  • This carrier composition thus provides a controlled release matrix for therapeutic agents as exemplified by albuterol.
  • EXAMPLE 15 In vitro therapeutic agent release experiment of a mucoadhesive carrier having a barrier film applied as a suspension The composition of TABLE XVII, below, for a polymer matrix of a mucoadhesive carrier was prepared.
  • Encompress ® from Edward Mendell Co. Inc., Carmel, NY, a commercially available dicalcium phosphate dihydrate.
  • Compritol ® 885 from Gattefosse Corporation,
  • Vinol ® 125 from Air Products and Chemicals, Inc., Allentown, PA, a commercially available polyvinyl alcohol.
  • Klucel ® HXF from Hercules, Inc., Houston, Texas, a commercially available hydroxypropyl cellulose.
  • Sylloid ® 244 FP from Davison Division of W. R. Grace and Company, a commercially available fumed silicon dioxide.
  • Carbopol ® 934P from B.F. Goodrich Company a commercially available acrylic acid polymer. 7 Albuterol:PEG 8000 weight ratio of 1:2.
  • Rate of jLn vitro release of therapeutic agent studies were performed to determine release characteristics of albuterol from this carrier.
  • This carrier includes microfine dry silicon dioxide-polyethylene glycol in combination with Carbopol 934P as an hydrophilic adjuvant to provide diffusional control and possible potentiation of mucoadhesion with the silicon dioxide and PEG 3350/8000 combination.
  • In vitro release of albuterol was 22 weight percent at 3 hours, 50 weight percent at 7.5 hours, 75 weight percent at 12 hours and 90 weight percent at 18 hours thus illustrating again a controlled release profile of this carrier.
  • EXAMPLE 16 In vitro therapeutic agent release experiment of a mucoadhesive carrier having a barrier film applied as a coating suspension The composition of TABLE XVIII, below, was utilized to prepare a polymer matrix of the mucoadhesive carrier.
  • Sylloid ® 244 FP from Davison Division of W. R. Grace and Company, a commercially available fumed silliiccoonn ddiiooxxiiddee.. 7 Albuterol:PEG 8000 weight ratio of 1:2.
  • a rate of _in vitro release of therapeutic agent study of this carrier was performed according to the procedure disclosed in EXAMPLE 7.
  • I_n vitro release of albuterol was 27 weight percent at 2 hours, 50 weight percent at 5 hours, 73 weight percent at 10 hours and 90 weight percent at 19 hours thus demonstrating the controlled release property of the carrier.
  • EXAMPLE 17 In vitro therapeutic agent release experiment of a mucoadhesive carrier having a barrier film applied as a coating suspension
  • TABLE XIX The composition of TABLE XIX, below, was utilized to prepare a mucoadhesive sugar alcohol carrier matrix having 17 ⁇ > -estradiol (micronized) distributed therein.
  • Encompress ® from Edward Mendell Co. Inc., Carmel, NY, a commercially available dicalcium phosphate dihydrate, a particulate controlled release modulating agent.
  • Sylloid ® 244 FP from Davison Division of W. R. Grace and Company, a commercially available fumed silicon dioxide.
  • a mucoadhesive matrix can be prepared utilizing a sugar alcohol, such as mannitol, in combination with fumed silica.
  • sugar alcohols suitable for this purpose are inositol, xylitol, sorbitol, and the like.
  • a lubricant such as glyceryl behenate is included in the matrix composition to facilitate manufacture by direct compression techniques.
  • An absorbent filler such as dicalcium phosphate dihydrate was incorporated into the matrix composition to modulate the medicament release rate.
  • EXAMPLE 18 Mucoadhesive breath fresheners Several mucoadhesive carriers containing flavoring in the barrier film were prepared as mucoadhesive controlled release breath fresheners or deodorants. These compositions are illustrated in TABLE XX hereinbelow. The composition of the polymer matrix was held constant. The flavoring of the composition of the barrier film was varied to obtain Bi, Bii and Biii. The flavorings utilized were peppermint oil USP, cinna icaldehyde FCC and spearmint oil NF. Physical mixtures of the individual flavorings and polyethylene glycol (PEG) 8000 were prepared by the same procedure described in EXAMPLE 6. Then, components were processed in a manner similar to EXAMPLE 7 to obtain carriers. TABLE XX Mucoadhesive breath freshener carriers Polymer matrix Barrier films, weight (mg)
  • Encompress ® from Edward Mendell Co. Inc., Carmel, NY, a commercially available dicalcium phosphate dihydrate.
  • FD & C red #40 lake from Coloron, Inc. a commercially available aluminum lake colorant.
  • Klucel ® HXF from Hercules, Inc., Houston, Texas, a commercially available hydroxypropyl cellulose.
  • EXAMPLE 19 Evaluation of the mucoadhesive properties of mucoadhesive carriers The adhesiveness of mucoadhesive carriers prepared with silicon dioxide, polyethylene glycol and other polymeric components was performed with compositions illustrated in EXAMPLE 13, EXAMPLE 14 and EXAMPLE 15.
  • composition of TABLE XXI was utilized to prepare a polymer matrix of a mucoadhesive carrier of a vitamin, B, 2 , for trans-mucosal absorption of the vitamin.
  • Sylloid ® 244 FP from Davison Division of W. R. Grace and Company, a commercially available fumed silicon dioxide.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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Abstract

On décrit un support muco-adhésif approprié pour un agent thérapeutique. Ce support permet une libération réglée de l'agent thérapeutique par l'intermédiaire de la muqueuse. Le support muco-adhésif comporte une matrice polymère monolithe (12) qui est anhydre mais hydratable, et de la silice fumée amorphe. La silice améliore les caractéristiques muco-adhésives du support. Un film ou une couche de séparation insoluble dans l'eau (14) peut éventuellement être fixé(e) à la matrice polymère afin d'y former une face non adhésive.
PCT/US1989/004882 1989-10-31 1989-10-31 Support muco-adhesif servant a liberer un agent therapeutique WO1991006289A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP19890912797 EP0452334A4 (en) 1989-10-31 1989-10-31 Mucoadhesive carrier for delivery of therapeutical agent
PCT/US1989/004882 WO1991006289A1 (fr) 1989-10-31 1989-10-31 Support muco-adhesif servant a liberer un agent therapeutique
JP2500642A JPH04502913A (ja) 1989-10-31 1989-10-31 治療薬輸送のための粘膜粘着性キャリアー
FI913127A FI913127A0 (fi) 1989-10-31 1991-06-27 Vid slemhinnan haeftade stoedsystem foer frigoerande av ett terapeutiskt aemne.
DK911276A DK127691D0 (da) 1989-10-31 1991-06-28 Mucoadhaesivt baerestof og farmaceutisk doseringsform indeholdende dette baerestof
NO91912558A NO912558L (no) 1989-10-31 1991-06-28 Mucoadhesiv baerer for avlevering av terapeutiske midler.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1989/004882 WO1991006289A1 (fr) 1989-10-31 1989-10-31 Support muco-adhesif servant a liberer un agent therapeutique

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JP (1) JPH04502913A (fr)
DK (1) DK127691D0 (fr)
FI (1) FI913127A0 (fr)
NO (1) NO912558L (fr)
WO (1) WO1991006289A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0601835A1 (fr) * 1992-12-04 1994-06-15 Susanna Elizabeth Chalmers Produit pharmaceutique
WO2000010528A1 (fr) * 1998-08-24 2000-03-02 The Procter & Gamble Company Compositions mucoadhesives orales liquides
DE19847252A1 (de) * 1998-10-02 2000-04-13 Jenapharm Gmbh Verwendung von Testosteronestern und/oder Testosteron zur Herstellung von bukkal applizierbaren bioadhäsiven Systemen mit zeitgesteuerter Arzneistoffwirkung
WO2000042992A3 (fr) * 1999-01-21 2000-10-19 Lavipharm Lab Inc Compositions pour administration par les muqueuses et procedes associes
WO2000062753A1 (fr) * 1999-04-16 2000-10-26 Jenapharm Gmbh & Co. Kg Preparations pharmaceutiques ou cosmetiques pour l'application locale intradermique d'hormones
US6319513B1 (en) 1998-08-24 2001-11-20 The Procter & Gamble Company Oral liquid mucoadhesive compounds
WO2005074883A1 (fr) * 2004-01-29 2005-08-18 Sinclair Pharmaceuticals Limited Compositions aqueuses contenant des melanges de polymeres synthetiques et de biopolymeres, utilisees pour traiter la secheresse de la peau et des muqueuses, et aptes a etre utilisees comme vehicules d'ingredients actifs
WO2007096906A2 (fr) * 2006-02-27 2007-08-30 Panacea Biotec Ltd. Nouvelles compositions bucco-adhésives et procédé d'élaboration desdites compositions
USRE42126E1 (en) 1999-07-02 2011-02-08 The Procter & Gamble Company Delivery system for oral care compositions comprising organosiloxane resins using a removable backing strip
US8835414B2 (en) 2008-12-19 2014-09-16 Itf Research Pharma S.L.U. Treatment of vaginal atrophy in women with cardiovascular pathology risk
US9114143B2 (en) 2008-08-07 2015-08-25 Itf Research Pharma, S.L.U. Treatment of vaginal atrophy in women with tumor pathology risk
US9554976B2 (en) 2002-09-11 2017-01-31 The Procter & Gamble Company Tooth whitening product
US10285915B2 (en) 2012-10-17 2019-05-14 The Procter & Gamble Company Strip for the delivery of an oral care active and methods for applying oral care actives
CZ308594B6 (cs) * 2014-09-29 2020-12-23 VÝZKUMNÝ ÚSTAV VETERINÁRNÍHO LÉKAŘSTVÍ, v.v.i. Mukoadhezivní nosiče částic, způsob přípravy a použití

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6248358B1 (en) * 1998-08-25 2001-06-19 Columbia Laboratories, Inc. Bioadhesive progressive hydration tablets and methods of making and using the same
JP4683168B2 (ja) * 2000-05-17 2011-05-11 ライオン株式会社 歯牙又は歯茎用貼付剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4740365A (en) * 1984-04-09 1988-04-26 Toyo Boseki Kabushiki Kaisha Sustained-release preparation applicable to mucous membrane in oral cavity

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1873783A (en) * 1982-10-08 1984-04-12 Verex Laboratories Inc. Constant release formulation
US4915948A (en) * 1987-08-31 1990-04-10 Warner-Lambert Company Tablets having improved bioadhesion to mucous membranes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4740365A (en) * 1984-04-09 1988-04-26 Toyo Boseki Kabushiki Kaisha Sustained-release preparation applicable to mucous membrane in oral cavity

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5643589A (en) * 1992-12-04 1997-07-01 Chalmers; Susanna Elizabeth Desiccant formulated for treating wounds or lesions
EP0601835A1 (fr) * 1992-12-04 1994-06-15 Susanna Elizabeth Chalmers Produit pharmaceutique
US6319513B1 (en) 1998-08-24 2001-11-20 The Procter & Gamble Company Oral liquid mucoadhesive compounds
WO2000010528A1 (fr) * 1998-08-24 2000-03-02 The Procter & Gamble Company Compositions mucoadhesives orales liquides
AU753251B2 (en) * 1998-08-24 2002-10-10 Procter & Gamble Company, The Oral liquid mucoadhesive compositions
DE19847252A1 (de) * 1998-10-02 2000-04-13 Jenapharm Gmbh Verwendung von Testosteronestern und/oder Testosteron zur Herstellung von bukkal applizierbaren bioadhäsiven Systemen mit zeitgesteuerter Arzneistoffwirkung
DE19847252B4 (de) * 1998-10-02 2004-02-12 Jenapharm Gmbh & Co. Kg Bukkal applizierbare bioadhäsive Systeme mit zeitlich gesteuerter Wirkstofffreisetzung enthaltend Testosteronester und fakultativ zusätzlich Testosteron
WO2000042992A3 (fr) * 1999-01-21 2000-10-19 Lavipharm Lab Inc Compositions pour administration par les muqueuses et procedes associes
AU776525B2 (en) * 1999-01-21 2004-09-16 Lavipharm Laboratories, Inc. Compositions and methods for mucosal delivery
WO2000062753A1 (fr) * 1999-04-16 2000-10-26 Jenapharm Gmbh & Co. Kg Preparations pharmaceutiques ou cosmetiques pour l'application locale intradermique d'hormones
USRE42126E1 (en) 1999-07-02 2011-02-08 The Procter & Gamble Company Delivery system for oral care compositions comprising organosiloxane resins using a removable backing strip
US10493016B2 (en) 2002-09-11 2019-12-03 The Procter & Gamble Company Tooth whitening product
US9554976B2 (en) 2002-09-11 2017-01-31 The Procter & Gamble Company Tooth whitening product
WO2005074883A1 (fr) * 2004-01-29 2005-08-18 Sinclair Pharmaceuticals Limited Compositions aqueuses contenant des melanges de polymeres synthetiques et de biopolymeres, utilisees pour traiter la secheresse de la peau et des muqueuses, et aptes a etre utilisees comme vehicules d'ingredients actifs
WO2007096906A3 (fr) * 2006-02-27 2007-10-18 Panacea Biotec Ltd Nouvelles compositions bucco-adhésives et procédé d'élaboration desdites compositions
WO2007096906A2 (fr) * 2006-02-27 2007-08-30 Panacea Biotec Ltd. Nouvelles compositions bucco-adhésives et procédé d'élaboration desdites compositions
US9114143B2 (en) 2008-08-07 2015-08-25 Itf Research Pharma, S.L.U. Treatment of vaginal atrophy in women with tumor pathology risk
US8835414B2 (en) 2008-12-19 2014-09-16 Itf Research Pharma S.L.U. Treatment of vaginal atrophy in women with cardiovascular pathology risk
US10285915B2 (en) 2012-10-17 2019-05-14 The Procter & Gamble Company Strip for the delivery of an oral care active and methods for applying oral care actives
US10285916B2 (en) 2012-10-17 2019-05-14 The Procter & Gamble Company Strip for the delivery of an oral care active and methods for applying oral care actives
CZ308594B6 (cs) * 2014-09-29 2020-12-23 VÝZKUMNÝ ÚSTAV VETERINÁRNÍHO LÉKAŘSTVÍ, v.v.i. Mukoadhezivní nosiče částic, způsob přípravy a použití

Also Published As

Publication number Publication date
DK127691A (da) 1991-06-28
EP0452334A4 (en) 1991-12-11
JPH04502913A (ja) 1992-05-28
FI913127A0 (fi) 1991-06-27
EP0452334A1 (fr) 1991-10-23
DK127691D0 (da) 1991-06-28
NO912558D0 (no) 1991-06-28
NO912558L (no) 1991-06-28

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