JPH04502913A - Mucoadhesive carriers for therapeutic drug delivery - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Mucoadhesive carrier technology for therapeutic drug delivery This invention relates to carrier systems for administering therapeutic agents via mucosal membranes. especially, This carrier system exhibits enhanced adhesion to mucosal membranes and provides biological protection of therapeutic agents. Further improve scientific utilization.

Background technology Transport of drugs via buccal route and therapeutic use The composition and method have already been described by Warshaw et al. National Patent No. 3.133.862, Apple zwei g) U.S. Pat. No. 3,536,809, Zaffaroni U.S. Patent No. 3.598.122 to Zaffaroni, U.S. Patent No. 3.598.12 to Zaffaroni No. 3, U.S. Patent No. 3.972.995 to Tsuk et al. , U.S. Pat. No. 4.226.848 to Nagai et al., U.S. Pat. No. 4.25 to Nagai et al. No. 0.163, U.S. Patent No. 4.292.299 to Hicks et al. and Robinson, US Pat. No. 4,615,697. Robinso provides an overview of drug transport via mucous membranes and skin. dosage Afterwards, bioadhesion as a platform to hold the system in position within the oral cavity A buccal drug transport system with a reactive polymer has been proposed by Tsuta et al., Nagai et al., and Hicks. et al. and Robinson U.S. Pat. Most of these patents smell The drug promotes dissolution of the drug, thereby increasing its thermal power in the matrix. adhesive layer storage without the use of any special reagents that enhance the chemical activity. or embedded in a controlled release matrix. Ru.

In U.S. Pat. No. 3,598,123 to Zafaguchi Microcapsules serve as additional storage areas for drug transport in the adhesive layer. surrounding.

Until now, one way to make transport systems sticky has been to use water in a bioadhesive polymer matrix. It was based on harmony. Adhesion occurs when hydrated polymer buttons on the surface of the substrate bind to mucosal glycoproteins. This is caused by being entangled in the problem.

Under mild pressure, these entanglements form hydrophobic bonds that contribute to the strength of the adhesive. London dispersion force (London dispersion force) force) (e.g. van der Waals forces) This results in reinforcement of force.

Encapsulating the drug as a dispersion in polyethylene glycol improves solubility and dissolution rate. and thereby improve the bioavailability of poorly water-soluble drugs. let Improves solubility, improves solvent polarity and aqueous media ) in reducing the dielectric constant of arm Sci, 58.1505 (1969), Ingham , Arch, Biochem, Biophys.

Biochem, Biophy, Acta 815.515 (out of 1,985 It is described in. More specifically, the membrane and external phase (external phas e) Partitioning of hydrophobic and polar molecules between molecules directly affects macromolecules and other membrane components. Proven to be modified by polyethylene glycol without giving There is.

The carboxyl-functional polymers disclosed in Robinson It is a hydratable poly-7- useful for cal transport.

After adhesion, these poly7- molecules absorb saliva and its aqueous components within a hydrophilic polymer matrix. It depends solely on the adhesion of the transport system by which body fluids the drug dissolves and the drug is released. It is based on In these systems, the chemical potential and thermal power of the drug The biological activity is determined by the micro-fluid environment of the polymer matrix. ironment) to bring the drug to a state of saturation solubility. Ru. Therefore, the drug is transferred from the matrix into the oral cavity by the body that permeates the matrix. It is released at a rate that depends on the saturation solubility of the drug in the fluid.

Therefore, there is little control over the release rate. In addition, oral Polar drugs, including zwitterionic therapeutic compounds such as biosynthetic peptides with low bioavailability For example, the drug-diffusing interface between the polymer matrix and the oral mucosa is relatively non-polar. The biological microfluidic environment is lacking. Therefore, the solubility of these drugs is low.

Therefore, the systems currently available are limited to the expansion of drug Fickic through the polymer matrix. It simply depends on the Fickian diffusion.

Diffusion rates are affected by low chemical or thermodynamic activity and a highly polar aqueous environment. It is limited. These limiting factors improve drug distribution and penetration into the oral mucosa. It is disadvantageous for the purpose of

Many drugs are relatively poorly soluble and more lipophilic in their physical-chemical characteristics. It is recognized that Examples of drugs belonging to different therapeutic categories Drugs include estrogens, contraceptives, steroids, androgens, nifedipine, Contains flufenamic acid and its derivatives, spironolactone and griseofulvin. Ru. Therefore, in a controlled release matrix coupled to a suitable drug distribution environment, , improving the thermodynamic activity of such drugs may improve drug transport in the mucosa. would encourage.

The present invention provides a controlled viscous release carrier system that is highly effective for a wide variety of therapeutic agents. provides high bioavailability, thereby overcoming the shortcomings of the prior art and currently Discloses methods and compositions capable of meeting the needs of society.

Disclosure of invention The present invention is present in an amount sufficient to promote adhesion of the polymer matrix to mucosal tissue. Contains amorphous fumed silica, which is anhydrous but A hydratable mucoadhesive monolithic polymer matrix is contemplated. This substrate is Optionally, plasticized film-forming cellulose esters can be included.

The polymeric matrix is mucoadhesive and can be passed through the patient's mucous membranes, i.e., oral cavity, vagina, or It is highly suitable for the systemic delivery of a wide variety of therapeutic drugs via the rectum. . solubility limit, pH or enzymatic degr. adduction) and/or extensive metabolism by the liver. In particular, therapeutic drugs that have difficulty in absorption via the gastrointestinal route due to Suitable for use in combination with carriers. These drugs are hydrophilic in nature, It may be hydrophobic or amphiphilic, and may be classified into certain therapeutic categories, or Cardiovascular agents, bronchodilators, growth stimulants, enzymes, estrogens and androgens agents, anxiolytics, antidepressants, anti-Parkinson's agents, memory maintenance agents, memory preservation and enhancement drugs, contraceptives, antibiotics, antiviral agents, antiprotozoal agents, vitamins drugs, antidiabetic agents, gastrointestinal agents, anticonvulsants, anti-epidemic regulators, nutritional supplements, and appetite regulators may belong to the area of

Brief description of the drawing FIG. 1 illustrates a bilayer lacinate structure of a mucoadhesive therapeutic agent according to an embodiment of the present invention. This is a partial fragmentary view.

FIG. 2 is a cross-sectional view showing the dosage form of FIG. 1 surrounded by a protective film.

FIG. 3 has a retrieving element inside. FIG. 2 is a cross-sectional view of one embodiment of the therapeutic dosage form.

FIG. 4 is a plan view of one embodiment of the therapeutic dosage form, also having a retrieval element.

FIG. 5 is a section of another embodiment of the therapeutic dosage form showing another perforated retrieval element. This is a diagram.

Detailed disclosure of preferred embodiments The term "mucoadhesive" used here refers to in vivo and/or in vitro refers to substances that adhere to the surface of mucosal tissues. Such adhesion may cause In order to adhesively fix the drug type on the mucous membrane and to separate this mucosal adhesive substance from the mucous membrane. requires using a force of at least about 50 dynes/cat.

All mesh sizes are American sieve series (U, S, 5ieueSer, 1e s).

The mucoadhesive carrier of the present invention does not cause discomfort to the mucous membranes of the oral cavity, vagina, or rectum. A variety of therapeutic dosage forms suitable for convenient administration and application. Can be prepared into any freestanding size, shape, or type. This mucoadhesive carrier is For example, discs of suitable size and shape, hard or soft films, or can be prepared into a shape that can be inserted into the body. on a mucoadhesive carrier , optionally with a water-insoluble barrier film on one side or so that one side is non-stick. You can set up seven items.

The mucoadhesive carrier comprises a polymer matrix, as described in more detail below. Anhydrous but hydrated, present in sufficient quantity to further promote adhesion to mucosal tissues. 1, which is an amorphous fumed silica that can be combined with containing a polymeric matrix. The therapeutic agent may be distributed as a solution or dispersion within the carrier. It is.

Therapeutic agents that can be transported by the aforementioned carriers include I7β-estradiol. dehydroepiandrosterone, nifedibine, diltiazem (diI tiezem>, haloperidol, bubrenorphine hine), meperidine, 7=79:--, testosterone, progesterone Ron, norethhindrone (noreth 1ndrone), ethinyl est Radiol, mestranol, oxandrolone It is a drug such as. A relatively water-insoluble therapeutic agent is polyethylene glycol (PEG). ) can be combined with a polyol such as , can mix amorphous Huyu Mudoshiri power. Amphipathic and water-soluble therapeutics also It can be combined with a hydrophilic polyol to form a dispersion, and then the Bonded to silica.

Poly"7-, which is preferable as a polymer substrate, has an average molecular weight of about 1500, for example. to about 8,500, preferably from about 4,000 to about 8,000.

Polyols such as polyethylene glycol (PEG). These polio This promotes a decrease in the dielectric constant of the aqueous environment to which the carrier is exposed, making it relatively Increases the solubility of insoluble drugs, resulting in their therapeutic properties in the integrated polymeric matrix increases the thermodynamic activity of Through the stroma, capillaries under the mucosa and mucosal tissues ( This increases the diffusion of the therapeutic agent into the capillary bed. This is achieved in this way. Moreover, these polyols contain pharmaceutically acceptable inert It also has the distinct advantage of being a sexual adjuvant.

Furthermore, this mucoadhesive carrier composition may contain larger or larger Additional amounts of the same type of polyol or its derivatives with lower average molecular weight can be added. can be included in the meaning. This additional polyol is a plasticizer and diffusion aid. It seems to function as

Hydrophilic polyols are soluble in water and achieve highly favorable dissolution of therapeutic agents. Ru. These hydrophilic polyols reduce the dielectric properties of aqueous solutions in mucosal environments This creates a more polar, less aqueous environment. Therefore, here The hydrophilic polyols described in as a facilitator of therapeutic drug transport through polymeric matrices, as well as interfacial transport through physical membranes. It is believed that it works.

The mucoadhesive carrier composition has a melting temperature of at least about 50°C (about 120°F). Stable, melt-processable forms of polyethylene glycol, such as dotted polyethylene glycol, It is associated with a therapeutic agent that is either dispersed or in solution in a polymer. This composition consists of melting, It can be produced by solvent precipitation or a physical mixing process.

Amorphous fumed silica is added to the polymer matrix in the form of a processable dry powder. . The amount of fumed silica present will depend on the nature of any polymeric matrix utilized. change. However, the amount of fumed silica added is such that the polymer matrix becomes viscous. The amount is sufficient to enhance adhesion to the membrane tissue. If this polymer matrix is Fumed silica is preferably present if constituted by a polyol as The amount of is at least about 10 percent by weight of the substrate. On the other hand, also This polymeric matrix is compatible with other known bioviscous materials such as carboxyl-functional polymers. If the kimono is also included, the amount of fumed silica present is approximately 2 percent of the weight of the substrate. The concentration is preferably at least as low as about 3 percent of the weight of the substrate. . Examples of suitable silica include Carbosil (Cab-0-sil) ( Degassa Corp., Titilboro, New Jersey), Aerosil@ (Aer -0-sil■) (Degassa Koho,) Cadioxide, or shyloid (S), which is commercially available in the food and drug categories ylroid@) (Divis Division, W, R, Brace Co., [1avison mouth 1 vision.

11, microporous precipitated silicon dioxide such as R. Grace Company). It's on the side. The silica is located within and/or within the integral polymeric matrix of the carrier. or providing a large number of discrete particles distributed over a surface.

Additionally, the silica also acts as a reservoir for therapeutic agents.

Although not intended to be limited to one specific function, mucosal adhesion is currently limited to aqueous viscous Massive convective capillarity of the liquid on the membrane into the microembedding of microporous silica particles It is believed that this occurs due to These discrete particles absorb hydrated The polymeric matrix functions as a component of the mucosal membrane and, in some cases, from the mucus of the mucosal wall. The constituent elements of the glycoprotein are deposited on the surface of the silica and/or into the microporous silica particles inside. It is believed that it brings out the essence or a part of it. These water-insoluble microporous silica particles While the membrane is hydrated, some of the mucosal proteins from the mucosal wall become tangled, and the mucosal membrane The natural pressure exerted on the wall causes a strengthening of the adhesion and localizes the drug transport system. Hold.

Water-swellable but water-insoluble, fibrous, cross-linked carboxyl-functional polymer may contain any bioadhesive material such as

The polymer is based on the weight of unpolymerized repeating units and crosslinking reagent, respectively. approximately 80% of the repeating units have at least one carboxylic acid. sil functional group and a crosslinking reagent in the range of about 0.05 to about 1.5 percent. Contains many repeating units such as In a more preferred embodiment, at least Also, about 90% of the repeating units contain at least one carboxyl functional group; In an even more preferred embodiment, at least 95% of the repeating units are Contains at least one carboxyl functional group. In the most preferred embodiment, This bioadhesive material is a polymerization of only a single carboxyl functional group and a crosslinking reagent for it. It is a product of chemical reaction. In a further preferred embodiment, the bioadhesive substance contains a crosslinking reagent in the range of about 0.1 to about 1% by weight. such biostick substances It is called Carbopol■, (B, F, Gutdrich, Cincinnati, Ohio). trademark and is commercially available.

Other options for bioadhesives include those that are hydrophilic, water-dispersible, and contain free carboxyls. Includes polymers with relatively high base binding ability. Preferred polymers include Water-dispersible polycarboxylated vinyl polymers are included. polyacrylic Acid polymers are particularly preferred. The average molecular weight of this polymer is approximately 1.250.00 A range of 0 to about 3,000.000 is preferred. Suitable polyacrylic acid polymers includes, but is not limited to, Carbopol Ex55 resin, 43 4.934P, 940 and 941 (Carbopol@E x55 Re5 Commercially available from B.F. Gutdrich Co., Cincinnati, Ohio, under the trademark ``in''. lightly cross-linked polyalkenyl polyethers, such as those available in Contains acrylic acid polymer.

The cumulative mucoadhesive effect of these microporous silica particles on a carrier commonly known organisms such as mol, carbophil, and combinations thereof. To the best of the inventor's knowledge, whether or not it contains an adhesive substance, Not reported yet.

In addition to acting as a mucoadhesive, the silica may also be used to modulate the release of therapeutic agents. It also acts as a storage area. A therapeutic drug placed on a portion of silica powder. The presence of physical properties such as melting point, distribution coefficient, crystal form, and inherent solubility Each acts as a reservoir for a variety of different therapeutic agents or derivatives thereof.

This mucoadhesive composition contains polyvinyl alcohol, polyvinylpyrrolidone (polyvinylpyrrolidone) Don), sodium alginate, methylcellulose, hydroxypropyl cellulose base, hydroxypropyl methylcellulose, polyethylene glycol, carbo Pole, polycarbophil, carboxyvinyl, copolymer, propylene alginate glycol, alginic acid, methyl methacrylate copolymer, (needragit) Type, Rohm Pharma, New York, New York 1+l)) Raga Kantoko Guar Coum, Karaya Coum, Ethylene Vinyl Acetate, Di Methylpolysiloxane, polyoxyT-rukylenebucock copolymer (polokuzama) - Cosmetics, Toiletries, & Fragrances, Association , Ink: Commercially available polyoxyethylene-polyoxybrobylene Common polymers such as hydroxyethyl methacrylate copolymer (lock copolymer name), hydroxyethyl methacrylate copolymer, etc. Natural or synthetic hydratable adjuvants or mixtures thereof known to Can be attached to increase the tortuosity of monolithic polymeric matrices containing drugs .

Dissolution of a therapeutic agent within an integrated polymeric matrix increases the level of thermodynamic activity of that therapeutic agent. Facilitated by keeping it high. This activity, for example, and glyceryl behenate (glyc-eryl behenate), By using a combination of hydrophilic and hydrophobic excipients within the polymer matrix, The release of the therapeutic agent is regulated for superior bioavailability.

The resulting monolithic polymeric matrix is water-insoluble but water-permeable or substantially water-insoluble. It can also optionally be laminated to a water-impermeable, therapeutic agent-free barrier film.

This barrier film prevents or minimizes the backside diffusion of therapeutic agents and A backing that prevents attached tissues such as gums and teeth from being directly exposed to the substrate. ). The composition of this water-insoluble barrier film is compatible with the polymeric matrix. It is chosen to be stable and non-irritating to the patient. Preferably, this The barrier film components are compatible with the substrate, processable and extend the shelf life of the product. The constituent elements of the polymeric matrix ensure that this carrier system is physically stable. Contains elements.

The barrier film can include pharmaceutically orally administrable adjuvants. Illustration Adjuvants include hydrogenated vegetable oil, fine cellulose, and methyl cellulose. , calcium phosphate dihydrate, talc, kaolin, bentonite, hydroxyl High melting point glycerin esters such as lopyl cellulose and glycerin behenate , methylcellulose, cellulose acetate butyrate, polyvinylpyrrolidone, polyvinyl Alcohol, magnesium stearate, silicon dioxide, and stearic acid Contains phosphoric acid.

Preferably, the main component of this barrier layer or film is dicalcium phosphate. Munihydrate (Bncompress@), New York , Carmel, Nidoward, Mendel Corporation) and glyceryl behenate (Compli Cosprjtol@, Elmsford, New York, Ga. direct pressure, such as Gattefosse Corporation. It is a water-insoluble substance that can be compressed, and small amounts of cellulose derivatives are also present. this By incorporating these elements, blister bags and foil packs can be created that are convenient for patients to take medication. Inexpensive factory for double-laminated tablets or disc-shaped dosage forms that can be Improve productivity. In addition, hydrophilic compounds such as dicalcium phosphate dihydrate When an insoluble inorganic excipient is used in combination with a hydrophilic drug tether, a two-layered laminated film can be applied to mucous membranes. The nate carrier is provided with sufficient drug permeation barrier.

A preferred embodiment of the carrier comprises a water-swellable, hydratable, monolithic polymeric matrix; mucoadhesive disc consisting of a two-layer laminate containing a water-insoluble barrier film and It is. This mucoadhesive polymeric matrix delivers sufficient amounts of the therapeutic agent needed for treatment. Including variance.

The composition of the present invention and its manufacturing method are illustrated below.

The polymeric matrix has amorphous fumed silica and the necessary drug dispersed within it. Prepared by polyol. This hydrophilic polyol is preferably polyethylene lene glycol (PEG), in a more preferred embodiment at least about 5 Powdered polyethylene glycol that is melt processable with a melting point of 0°C (approximately 120'F) It is le. The average molecular weight of this polyethylene glycol is from about 1500 to about 85 00, preferably from about 4000 to about 8000. treatment The weight ratio of drug to hydrophilic polyol is about 500:1 to about 0.1:5, respectively. 00, preferably from about 1:2 to about 1:5.

microporous structure and from about 300 square meters/gram to about 700 square meters/gram Silica with a surface area in the range of from about 0.1 to about 40, preferably from about 10 to about 2 percent by weight, based on the amount Exist within a range.

Silica used in such mucoadhesive compositions may be used alone or in known hydratable biosticks, such as polycarbophil, and polyvinyl alcohol. Diffusion-inhibiting polymers such as Kohl or high tack, hydroxypropyl cells Loin (Klucel■) HXF1 Hercules, Inwa 1. Huyu used in any combination with components such as Stone, Texas).

These optional components may account for up to 50 percent by weight of the total weight of the polymer matrix. may exist within the range of

Present in an integrated polymeric matrix to maintain high levels of thermodynamic activity of therapeutic agents Preferred combinations of hydrophobic excipients and hydrophilic excipients include Acid glycerin (Compritol), Gattefosse Corpo, Elmsford, New York) and Polycarbophile. Sparse The weight ratio of aqueous excipient to woody excipient ranges from about 1=20 to about 3:1; Preferably it ranges from about 1:IO to about 1:1. relative to the total weight of the polymer matrix , this combination is possible up to a range of 50 weight percent.

Other relatively water-insoluble but hydratable adjuvants that increase the tortuosity of the polymer matrix are , dicalcium phosphate dihydrate (Encompress ). Completely hydrolyzed polyvinyl alcohol (vinol) ■) 125, Air Products and Chemicals, Ahrentown Pencil Luvenia) and dry, microporous, fine-grained silicon dioxide. Supplementary The preferred range for the total amount of these polymeric substrates forming the auxiliary agent is the total weight of the polymeric substrate. from about 0.5 to about 2 weight percent.

The components of the polymeric matrix, if necessary, are added in an amount of about 0.5% based on the total weight of the polymeric matrix. magnesium stearate, optionally present in a range of about 2 weight percent from Miscible with known lubricants such as sodium fumarate stearic acid or talc. It can be made smooth.

Barrier films, as an optional but preferred element of the invention, can be used on polymeric substrates. Excipients on the formulation that are similar to those used and, more importantly, comparable In laminate formulations, the therapeutic agent is transferred from the polymer matrix to the back side. non-degradable and impermeable barrier membranes to inhibit dispersion into It consists of a combination of pharmaceutical excipients that provide a film or barrier layer.

Preferred but non-limiting ingredients for barrier film compositions include: dicalcium phosphate dihydrate in the range of about 10 to about 25 weight percent as minutes. Things (Encom-press ■) and about 1 weight from about 061 Preferably FD&C Red #40 Lake (Kararon, Ind.) It is an aluminum rake like Cdoron, Inc. There is a coloring agent.

Approximately 1.0, which acts as a humidifier or binder to hold the laminate in perfect shape. fully hydrolyzed polyvinyl alcohol in the range of about 50.0 weight percent from Coal (Vinol ■ (Vir + ol) 125) fine grains (a fine gr ade) (U.S. sieve series, 40 mesh), or 3 to about 20 weight percent of highly adhesive hydroxypropyl cellulose ( Klucel HXF) is also suitable for use in barrier films. are doing. All weight percentages are relative to the total weight of this barrier film. It is.

The polymer matrix and barrier film are usually prepared side by side. How to prepare polymeric substrates An example of the law is given below.

An illustrative dissolution process internally dissolves the therapeutic agent in polyethylene glycol. A composition for mucous membranes was prepared. In this process, polyethylene glycol is It is typically melted at a temperature of 70°C (approximately 160°F). And while stirring constantly , slowly add the powdered therapeutic agent into the dissolved polyethylene glycol. Ru. Continue stirring until all of the therapeutic agent powder is dissolved. Next, test like this. Place the prepared liquid mucosal composition onto a surface, i.e. a flat aluminum foil. pour over the glass and let it solidify. Airtightness if necessary for relatively quick solidification Place this composition into a container at a temperature of about 4°C (40°F). It may be further cooled by placing it in a bath.

Alternatively, powdered polyethylene glycol can be used in the dry blending process. and the therapeutic agent to form the desired physical mixture.

The composition or physical mixture for mucous membranes has a dosage of about 60 to about 80 mesh. Glycerin behenate (Compr.i. toI■)), polyvinyl alcohol, dicalcium phosphate dihydrate (enco Empress@), hydroxypropyl cellulose ( Klvcel HXF) and microporous silicon dioxide Sid (Sylroid) 224 FP, Divis Division (mouth avison division), W, R, Fleis and Ka be mixed with hydrophilic or hydrophobic matrix-forming excipients for polymeric matrices such as . Optionally, further polyethylene glycol can be added. organic solvent or water The granulation process, which utilizes It can also be used for preparing and drying.

The resulting dry composition of polymeric matrix is optionally miscible with the aforementioned lubricants. can be lubricated.

Except that the barrier film or barrier layer does not contain therapeutic agents or adhesive substances. For example, some of the components of the polymer matrix can be prepared separately in a similar manner. .

The desired portions of the polymeric matrix and barrier layer are comprised of two-layer laminates of suitable size and shape. To obtain a mucoadhesive carrier, for example a carver press can be used. Press) are pressed together by a hydraulic press.

The preferred thickness of the mucosal composition comprising the integrated polymeric matrix is about 0.5 millimeters. It is approximately 10 mm from The preferred thickness of the barrier layer is approximately 0.5 mm. The range is approximately 20 mm from Torr. These dimensions are based on application amount, application area or for effective treatment by applying aqueous systems at mucosal sites for specific periods of time. It depends on requirements such as the rate of therapeutic drug delivery.

The preferred form of this delivery system depends on the site of application. flat disc, rectangle, circle It can take on shapes such as oval, oval, frame, biconvex, and hemisphere. Preferred character The rear shape is a disc type with a diameter of 5 mm to 50 mm.

In some cases, a retrieval element that is an appendage extending from the carrier is removed. may exist to facilitate.

The carrier of the present invention can take various forms. An example of the form is shown in Figures 1-5. is shown.

Figure 1 includes any barrier film or film that contains a dissolved therapeutic agent and provides a non-stick surface. comprises a mucoadhesive polymeric matrix to which a barrier layer is attached. A therapeutic dosage form 10 is shown.

In FIG. 2, the dosage form 10 is removed from the external environment prior to use. Encased within a protective protective envelope 16. This protective envelope 16 prevents the penetration of water vapor. It is sufficiently insulated and consists of a suitable packaging material such as aluminum foil or the like.

FIG. 3 shows another embodiment of the treatment surrounded by a protective envelope 116. 110 is shown. Another aspect of this technique is the shape of the string-like section. There are collection elements 118.

The functionality of the retrieval element assists in removing the dosage form 110 from the user. . FIG. 3 shows a string-like section 118 embedded within a polymer matrix 112. However, the position of this section 118 is such that it is easy to grasp and manipulate this section 118, and to It is not definitive as long as it achieves the functionality shown.

FIG. 4 is a top view of a spherical mucoadhesive dosage form 111 within a polymeric matrix 115. The retrieval element 119 is shown firmly fixed.

Another embodiment of a mucoadhesive dosage form is shown in FIG.

In this embodiment, the dosage form 210 includes a collection element within the polymeric matrix 212. Ribbon-like planar retrieval element provided with holes 214 to facilitate fixing 218 218 is embedded.

Various tests were conducted to demonstrate the effectiveness of the present invention.

These tests are described below.

Example 1: Preparation of a bioadhesive disc not including the invention For each layer, Accurately weigh all individual ingredients disclosed in Table I and place in an opaque bottle. for about 2 minutes. Then apply each mixture to a 45 mesh screen. I passed it three times. Collect the mixture that passed through the screen into a bottle and let it cool for an additional 2 minutes. Mixed. The composition of the barrier layer is about 130mm! Weighed J grams and calculated this as 12.5 millimeter diameter with a flat stainless steel holder plug at the bottom. It was placed inside a circular stainless steel mold. Let the powder cover the holes in the mold. I pounded the mold quietly. Next, 150 milligrams of the bioadhesive layer composition was added to Added on top of the barrier layer in the mold. After tapping gently again, this mold and flat part are It was placed on a manual press with a suitable push-in plug. Oraso 280 milligrams Laminated with two layers of ram with a thickness of 12.5 mm and 2.0 mm. Compression molded circular discs were used to test the in vivo bioviscosity of the three women shown in Example 2. It was collected for a wear test.

Table 1 Composition of bioadhesive discs Bioadhesive layer barrier layer Weight Weight Weight Weight dihydrate 1 Glycerin behenate’ 0.22 3.64 2.00 36.10 Colorant 3 ...0.04 0.72 Magnesium stearate... 0.04 0.72 Polyvinyl alcohol'0.28 4.63...・ ・Hydroxypropyl Cellulose '2.80 46.28 0.46 8.30 Polycarbophil' 1.65 27.27...Total 6.05 100.00 5.5 4 99,99 links 9. Karnoll, New York, commercially available phosphoric acid Dicalcium trihydrate.

2 Completetor■885 Gutfoose Corporation, Elmsfoose Glycerin behenate, commercially available from New York, New York.

3. FD&C Red #40 Lake, Coloron, Ink 9. commercially available Luminium Lake Colorant 4 Bynol @ 125 Air Products &ke Michals, Inc. 9. Allentown, Pennsylvania, commercially available polyvinyl alcohol.

5 Crucel ■HXF Hercules Ink 9. hyuston, texas, Commercially available hydroxypropyl cellulose.

6 Carbopol ■Ex-55 resin, B, F, Gutdrich Coho 9. commerce Polycarbophil is available locally.

Example 2: In vivo bioadhesion test Perform in vivo bioadhesion test using the disc prepared in Example 1 did. Three women were selected. Each patient places the disc on the oral cavity wall. It was attached to the upper right or upper left lip side. Attach the colorless side to the oral cavity wall. Special instructions were given to ensure that Subjects wore the disc after dinner; Continued normal activities such as brushing teeth and eating breakfast. After 12 hours, the subjects The disk was removed and the condition of the disk after removal was observed. In two subjects, the wearing The disc was very sticky the entire time. One subject was equipped with a disc. There was some difficulty in keeping it adhered to the application site. Disk its application Although it had softened at the site, it remained intact throughout the entire time of wear. about the beginning After 172 hours, all subjects showed strong tolerance to the product. two layers There was no evidence of separation.

Example 3: Preparation of a mucoadhesive carrier of the invention and the same carrier with a bioadhesive disc. Rear hydration comparison The process of disc preparation is the same as in Example 1. The composition of this carrier is shown in the table below. has been disclosed. To prepare this disc, a polymer matrix and a barrier film were used. 1.50 milligrams of each composition was used. Furthermore, silicone Bioadhesive disks without oxide were also prepared. of bioadhesive discs For the composition, the polymer matrix silica is placed on hydroxypropyl cellulose. I changed it. Both the composition (I) containing silica and the composition ([) without silica Using a press (Carver Press), 1000 psi and 10.000 psi It was compressed at a compression pressure of psi. of mucoadhesive carriers and bioadhesive discs. The hydration rate and water A sum range test was conducted.

Weigh three samples and add each to 0.1 molar pH 7.0 phosphate buffer. was placed in a Petri dish containing At different times, drain this buffer solution and To remove any remaining buffer solution without touching the sample, place the Petri dish on a microplate. I quietly and carefully sucked it up with Claw Wipe Baber. Weigh the sample and Determined weight increase.

The rate and extent of hydration of this sample was studied up to the 24 hour time point. The table below is The results of the study on the hydration of These results were demonstrated through polymeric matrices. Water penetration is rapid and statistics on the rate and extent of hydration for the compositions tested. There is no significant compaction pressure effect. It clearly proves that.

Table■ Mucoadhesive carrier composition Polymer matrix barrier film Weight Weight Weight Weight Constituent elements (grams) Percent (grams) (percent) Phosphoric acid dicalcium Dihydrate’ 1.10 18.33 3.62 60.33 Glycerin behenate '0.22 3.67 2.00 33.33 Colorant 3...0 ．． 04 0.67 Magnesium stearate L...0.04 0.67 Poly Vinyl alcohol'0.30 5.00...Hydroxypropyl Cellulose' 2.38 39.67 0.30 5.00 Polycarbophil' 1.80 30.00・-・・・・Hyumned silica’ 0.20 3 ．． 33... Total 6.00 100.00 6.00 100.00 1 Encompress Nidward Mendel Coop. Ink 1. Carme Le, New York, commercially available dicalcium phosphate trihydrate.

2 Completetor @ 885 Gatfuose Corporation, Elmsfo Commercially available glyceryl behenate, New York 3 FD&C Red #40 Lake, Coloron, Ink 1. commercially available Luminium Lake Colorant 4 Binol ■ 125 Air Products Andke Michals, Inc. 1. Allentown, Pennsylvania, commercially available polyvinyl alcohol 5 Crucel ■HXF Hercules Ink 9. hyuston, texas, Commercially available hydroxypropyl cellulose 6 Carbopol ■Ex-55 resin, B, F, Gutdrich Koho, commercial Polycarbophil 7 Thyroid 0244FP, available from Divis Business Dept., W.R., Brace & Co., Commercially Available Hyumd silicon dioxide Table■ Average (±S, D) weight of buffer uptake by mucoadhesive disc compositions percent 0, 75 98.71 ± 4.49 105-43 ± 15.282, 00 159 ．． 52±7.55 170.80±6.594, 00 233.70±15.2 0 244.70 ± 17.1620, 00 524.78 + 53.47 5 22.21±68.8524, 00 594.38±23.91 569.77 ±49.010, 75 114.87± 9.55 109.70±14.89 2,00 193.5g±24.44 177.79±32.374.00 2 90.92 + 41.49 265.68 ± 39.332 (L 00 62g , 00±108.63 628-84±129.6524, 00 738.1 4±151.25 692.60±92.261 Microporous silicon dioxide Mucoadhesive carrier containing 2rj & mucoadhesive without porous silicon dioxide The fine and microporous silicone as a mucoadhesive substance disclosed in Table ■ below A disc-type mucoadhesive carrier composition was prepared using a mosquito, and three women On the other hand, an in vivo adhesion test was conducted.

Table■ Composition of mucoadhesive carrier Polymer matrix barrier film Structure a Elements Weight (milligrams) Weight (milligrams) dicalcium phosphate Umu Dihydrate’ 27.5 90.5 Glycerin behenate’ 5.5 50.0 Colorant 31.0 Magnesium stearate...1.0 Polyvinyl alcohol 4 7.0 ...Hydroxypropyl Cell a-S60. OO,75 Hyumd Silica' 50.0...1 Encompress■ Nidward Me Ndel Corporation, Inc. 1. Carmel, New York, commercially available resources dicalcium phosphate trihydrate.

2 Compritor 0885 Gattefosse Corporation, Elmsfoss Commercially available glyceryl behenate, New York 3 FD&C Red #40 Lake, Coloron, Ink 1. commercially available Luminium Lake Colorant 4 Binol ■ 125 Air Products Andke Michals, Inc., Allentown, Pennsylvania, commercially available libinyl alcohol 5 Crucel @HXF Hercules Ink 1. hyuston, texas, Commercially available hydroxypropyl cellulose 6 Carbopol ■Ex-55 resin, B, F, Gutdrich Coho 1. commerce The preparation process for polycarbophil sample disks, which can be obtained commercially, is described in Example 1. It is similar to that. To perform in vivo evaluations as described in Example 2, each subject was In contrast, two discs were administered. Disc integrity after adhesive removal, discomfort during installation and how acceptable the product was to the subject. Conclusion The results are shown in Table V below.

Table V Evaluation of mucoadhesive substances in vivo 1. Very good, stable, comfortable, expensive unharmed 2 Good, no scratches, good firmness, low (disc is too big) 3. Very good, undamaged, comfortable, expensive The above test results show that the dry Ability of microporous silicon dioxide to mechanically adhere to mucin on the inner wall of the oral cavity It explains that it has. While performing normal morning activities such as brushing teeth and having breakfast. No patients had any problems. This disc will remain in place until the 12 hour point. It was observed that there was some residual accumulation.

Example 5: Preparation of mucosal composition Therapeutic drugs for the following: nifedipine; estradiol: piroxicam; arbutino or dehydroepiandrosterone (DHEA) in polyethylene. An anhydrous mucosal composition was prepared containing one dissolved in lene glycol. That's it This mucosal composition contains 0.5 grams of therapeutic agent and approximately 3350 (PEG3350) (7) Contains 2.0 grams of polyethylene glycol 4000 with an average molecular weight . Therefore, the weight ratio of therapeutic agent to PEG3350 is 1:4, respectively. child The composition for mucous membranes is prepared by placing a measured amount of PEG 3350 in a suitable container and heating it with hot water. Prepared by melting on plates at about 70°C (about 160°F). extinct Slowly add the powdered therapeutic agent into the liquid PEG3350 while stirring. I got it. Stir each dissolved mucosal composition until all therapeutic powder is dissolved. Ta.

This mucosal composition was then poured onto a flat aluminum foil and allowed to solidify. . Place the mucosal composition in an airtight container at approximately 40°F. The therapeutic agent and PEG3350 are combined by placing them in the freezer at a temperature of about 1 hour. The mucosal composition containing was further cooled. This hard flake is prepared using a mortar and pestle. The powder was powdered and passed through a 60 mesh screen. And this powdery mucous membrane The composition was used to prepare a mucoadhesive carrier in the form of a disc.

In vitro treatment by comparing physical mixtures of steamed leaves and PEG. Consideration was given to drug release. Approximately 90.0 milligrams of piroxicam, etc. Approximately 450 milligrams of a mucosal composition (according to Example 5) (prepared) and 450 milligrams of lactose (USP), stir thoroughly, It was compressed on a manual press into three circular discs for dissolution testing. each circle Each disc weighs 300 milligrams and measures 12.5 mm x It was 2 mm.

A physical mixture was also prepared. 60 mesh powder of piroxicam and PEG3350 They were mixed at a weight ratio of 1:4. Approximately 450 milligrams of this mixture gram of lactose (USP) to obtain a physical dispersion. For dissolution test Then, by manual pressing, three circular discs, each having the above weight and size, were produced. I got it.

United States Pharmacopoeia, 24th Edition (U.S. Pharmacopoeia, 24th Edition) For therapeutic drug release according to dissolution test method H described in SP XXIV) We conducted a study on the following. 500ml of 0.1M phosphate buffer solution Maintain a temperature of approximately 37°C (approximately 100°F) and rotate the basket at 50 revolutions per minute (rpm). I let it happen. Approximately 3 milliliter samples of this test medium at predetermined times. The pull was collected and quickly replaced with the same volume of blank buffer. This sump The analysis of the samples was carried out by ultraviolet spectrophotometry.

The table below specifically shows the dissolution ability of the mucosal composition and physical mixture of piroxicam. It shows.

The time required for 20 wt%, 50 wt% and 80 wt% of piroxicam to dissolve is calculated. Estimated from a linear plot of percent versus time.

Table■ Piroxicam in mucosal compositions versus physical mixtures in the unsubmerged state Dissolution test parameters for piroxicam one hour piroxicam Release parameters (T1) Type 20% 50% 80% Composition for mucous membranes 7 21 30 Physical mixture 18 44 60 ■ Below is the time taken for the release of piroxicam to reach the stated percentage. Refers to the interval (minutes).

As shown in Table ■, compared to the physical mixture, the equivalent amount of Piroxica from the mucosal composition is The time required for the gum to release is reduced by a factor of two. 0.1 molar phosphate buffer The saturation solubility of piroxicam in - is approximately 7.7 mg/ml. It has been determined. During the dissolution test, the sink condition is maintained. Although not followed, this data indicates that the initial dissolution rate of piroxicam is It clearly explains how things are much better than physical mixtures.

Therefore, it is expected that a higher concentration gradient will be achieved after mounting the mucosal carrier of the present invention. It is thought of. In this way controlled transport of piroxicam is obtained.

Example 7: Release of therapeutic agent in vitro To prepare the carrier, the compositions in Table 1 below were used.

Each carrier contains the therapeutic agent versus polyethylene glycol 8000 (PEG). 8,000) in a weight ratio of 1:2, respectively, the therapeutic agent, albuminal 2 doses of one of tinol or norephedrine (phenylpropanolamine) Contains an amount equivalent to 0 milligrams. This composition for mucous membranes is similar to the general composition described in Example 5. It was prepared according to the following steps. 150% of each of the polymer matrix and barrier film compositions. Weigh the disc-type mucoadhesive carrier in micro-IJ grams as described in Example 1. Using a Carver Press, following the general process It was compressed at 1000psi.

Table■ Test Composition Polymer Substrate Disorders for Arbutinol and Phenylpropanolamine wall film Components Weight (milligrams) Weight (milligrams) Dicalcium phosphate Trihydrate’ 27.5 90.50 Glycerin behenate 25.5 50.00 Colorant 31. OO Magnesium stearate 1.00 Polyvinyl alcohol'7.0...Hydroxypropyl Cellulose 50.75 Polycarbophil' 45.0... Humid Silica 7 5.0... Composition for mucous membranes' 60.0... 1 Encompress [Co., Ltd.] Nidward Mendel Coho. Ink 1. Carme Le, New York, commercially available dicalcium phosphate dihydrate.

2 Completetor @ 885 Gattefosse Corporation, Elmsfosse Glycerin behenate, commercially available from New York.

3 FD&C Red #40 Lake, Coloron, Ink 1. commercially available Luminium lake colorant.

4 Bynol @ 125 Air Products & Chemicals, Inc. - Rentown, PA, commercially available polyvinyl alcohol.

5 Crucel @HXF Hercules Ink 8. hyuston, texas, Commercially available hydroxypropyl cellulose 6 Carbopol Ex-55 Jin, B,, F, Gutdrich Coho 1. Commercially available polycarbophy Le.

7 Thyroid 0244FP, Divis Division, W, R, Brace and Company, commercially available evaporative silicone 8 arbutinol vs. PEG 3000 or phenylpropanolamine to PEG3000 weight ratio 1:2 Therapeutic drug release testing was performed according to the USP dissolution test method ■.

The dissolution medium included 0.0 with 30 weight percent PEG400 at a pH of 6.0. A 5 molar isotonic phosphate buffer of 500 microliters was selected. this method is described in Example 6.

Table 3 shows the results of examining the release of therapeutic agents for each composition.

Table■ Therapeutic drug release parameters Treatment drug 20% 50% 75% 90% Arbutinol 0.58 3.16 5.67 6.83 Phenylbrobanolamine 0.58 2.83 6.04 g, 421 T describes the release of therapeutic agents from mucoadhesive carriers. It refers to the time it takes to reach a certain percentage.

The results shown in Table ■ show that the release of therapeutic agents from these compositions Both sets of hydrophilic and hydrophobic compositions form a bilayer laminate structure of the carrier. It explains that it is controlled by a matrix consisting of a combination of

Significant hydrophilicity of the integrated polymeric matrix for the release of arbutinol from the polymeric matrix Mucoadhesive compounds containing arbutinol were used to determine the effect of hydrophobic and hydrophobic components. Several carrier compositions were prepared. The composition of these substrates is shown in the table below. It is shown.

Similar to the preparation of carriers for disc dosage forms, the preparation of compositions for mucous membranes is Preparations as described in Examples 5 and 6, except that they also included fumed silica. is essentially the same.

The composition of this mucoadhesive therapeutic agent carrier barrier film is similar to that of the barrier film of Example 4. The composition is the same as that of

Table■ Composition of polymer matrix dicalcium phosphate Dihydrate’ 0.01 122.50 27.50 27.50 27.50 Glycerin henate 25.50 5.50 0.01 144.50 5.50 points Rivinyl Alcohol’7.00 7.00 7.00? ,00 7.00h roxypropyl Cellulose 4... o, oi polycarbophil '45.00 45.00 45.00 45.00 45.00 Evaporated silica '5.00 5.00 5.00 5.00 5.00 Mucous membrane a' 60 ．． 00 60.00 60.00 60.00 60.00 Component fg h i j dicalcium phosphate Dihydrate’ 27,50 27.50 27-50 27.50 27.50 Glycerin henate 25.50 5,50 5.50 5,50 5.50 Polyvinyl Nil alcohol 37.70? , 70 7.70 0.01 143.00 Hido roxypropyl Cellulose' 150.00 ... ... ... ... Polycarbophy 545.00 0.01105.00 45.00 45.00 Evaporated Silica’ 5.00 5.00 5.00 5.00 5.00 Composition for mucous membranes” 60. 00 60.00 60.00 60.00 60.001 Encompress ■ Nidward Mendel Corp., Inc., Karnoll, New York, Commercial Dicalcium phosphate dihydrate available in

2 Compritor 0885 Gattefosse Corporation, Elmsfoss Glycerin behenate, commercially available from New York.

3 Bynol■125 Air Products and Chemicals, Inc. 1. Allentown, Pennsylvania Commercially Available Polyvinyl Alcohol .

4 Crucel @HXF Hercules Ink 9. hyuston, texas, Commercially available hydroxypropyl cellulose.

5 Carbo Ball @Ex-55 Resin, B, F, Gutudrich Coho 9. commerce Polycarbophil is available locally.

6 Thyroid 0244FF, Divis Division, W, R, Brace and Company, commercially available humid silicon dioxide 7 The ratio of arbutinol to PEG3000 is 1:2 (W/W) for each key. The carrier contains arbutinol and PEG3000 in a weight ratio of 1:2, respectively. The mucosal composition contained the equivalent of 20 milligrams of arbutinol. In example 7 Construct a plot of percent weight versus time, as detailed, for a given weight and , calculate the drug release parameter T (time) for the released drug of Ta. Table X below shows the results of these studies. From these results, polyvinyl Hydrophilic excipients such as alcohol and polycarbophil and glyceryl behenate Both hydrophobic excipients, such as It can be concluded that it is harmful.

In order to provide suitable therapeutic agent release characteristics, the amount of these excipients may range from, e.g. ．． 01 weight percent to approximately 50 weight percent. can be made into

Table X Therapeutic drug release parameters, TI a 1.25 4.33 8.58 13.60b 1.25 5.42 10 ．． 75...c 1.08 4.50 10.42...d 2.67 1 1.67...e 1.33 5.42 -=--f 2.25 11.67...g 1.50 6.25...IT is the percent release of the therapeutic agent from the mucoadhesive carrier. Refers to the time it takes to reach the destination.

Example 9: Release of piroxicam in vitro Double-layer laminate adhesive carrier for mucosal membranes in the form of a disc containing piroxicam of the therapeutic agent in vitro by the method already described in Example 7. A method test was conducted.

Table XI Mucoadhesive carrier composition Weight of each carrier (milligrams) dicalcium phosphate Dihydrate’ 27.50 90.50 Glycerin behenate’ 0.01 50.00 Coloring agent” 1. OO Magnesium stearate 1.00 Polyvinyl alcohol'7.00...Hydroxypropyl Cellulose 0.01 0.75 Polycarbophile'0.0]...-Hyumned Silica'5.00... ・PEG3000 19.53... Composition for mucous membranes" 60.00... ■ Encompress @ Nidward Mendel Koho, Inc. 1. Power・-Mel , New York, commercially available dicalcium phosphate trihydrate.

2 Completetor 0885 Katfo 7 Corporation, Elmsuf Ford, New York, commercially available glycerin behenate.

3. FD&C Red #4o Lake, Coloron, Ink 9. commercially available Luminium lake colorant.

4 Bynol @ 125 Air Products & Chemicals, Inc. - Rentown, PA, commercially available polyvinyl alcohol.

5 Crew Seven ■HXF Hercules Ink 9. hyuston, texas, Commercially available hydroxypropylcellulose.

6 Carbopol ■Ex-55 resin, B, F, Gutdrich Coho 9. commerce Polycarbophil is available locally.

7 Thyroid 0244FP, Divis Division, W, R, Brace and Company, Commercially Available Humid Silica Dioxide.

8 The weight ratio of piroxicam to PEG3000 is 1:2, 9 weight percent in 2 hours. cents, 13 weight percent at 3 hours, and 24.1 weight percent at 6 hours. , and 56 weight percent at 23 hours. The release rate of this therapeutic agent is According to the apparent zero order rate Ta. After 23 hours, approximately 36-47 percent by weight of the therapeutic agent is in the conocarrier. The therapeutic agent remains, indicating that this matrix composition has good controlled release. It suggests that.

Example 10: Release of β-estradiol in vitro Double-layer laminate mucoadhesive carrier in disc form containing 7β-estradiol A composition was prepared and the release properties of the therapeutic agent were tested in vitro. Preparation and The test procedure is similar to that described in Example 7.

Table Xff Mucoadhesive carrier composition Weight of each carrier (milligrams) Component Polymer matrix Barrier film dicalcium phosphate Trihydrate’ 27.50 90.50 Glycerin behenate: /' 5.50 50.00 Coloring agent' 1. OO Magnesium stearate 1.00 Polyvinyl alcohol'7.00...Hydroxypropyl Cellulose' 45.00 0.75 Polycarbophile' 45.00... Humid Silica' 5.00 ・ ・・Composition for mucous membranes” 15.00 ・・ ■ Encompress [Co., Ltd.] Nidward Mendel Koho, Inc. 1. Carme Le, New York, commercially available dicalcium phosphate trihydrate.

2 Completetor @ 885 Gattefosse Corporation, Elmsfosse Glycerin behenate, commercially available from New York.

3 FD&C Red #40 Lake, Coloron, Ink 1. commercially available Luminium lake 8 colors IFJ.

4 Bynol @ I25 Air Products and Chemicals, Inc. 1. Allentown, Pennsylvania Commercially Available Polyvinyl Alcohol .

5 Crucel @HXF Hercules Ink 1. hyuston, texas, Commercially available hydroxypropylcellulose.

6 Carbo Ball ■Ex-55 Resin, B, F, Gutudrich Coho 9. commerce Polycarbophil is available locally.

7 Thyroid 0244FF, Divis Division, W, R, Brace and Company, Commercially Available Humid Silicon Dioxide.

The weight ratio of 817β-estradiol to PEG3000 is 1:2° The release rate of the therapeutic agent in vitro was 2.5% by weight in 1 hour and 2.5% by weight in 2 hours. 4 weight percent, 9.5 weight percent at 5 hours, and 46.3 weight percent at 24 hours. It was a percentage of the amount. Therefore, the release of this therapeutic agent was a spurious zero-order response.

The carrier remains intact, indicating that the two-layer laminate transport system remains intact. This indicates that

Example I! As shown in Table X■ below the release of nifedipine in vitro, Mucoadhesive carrier in double-layer laminate disc formulation containing J-gram nifedipine An air composition was prepared. Disc preparation and in vitro release testing were performed in Example 7. It is similar to that of .

Table X■ Mucoadhesive carrier composition Weight of each carrier (milligrams) Component Polymer matrix Barrier film dicalcium phosphate Dihydrate’ 27.50 90.50 Glycerin behenate” 5.50 50.00 Coloring agent’ 1. OO Magnesium stearate 1.00 Polyvinyl alcohol'0.01...Hydroxypropyl Cellulose'0.01... Polycarbophil' o, oi...humid silica' 5. OO... ・Mucosal composition 8 30.00... PEG3000 35.00... 1 Encompress ■ Nidward Mendel Corp., Inc. 1. carmel, New York, commercially available dicalcium phosphate dihydrate.

2 Completetor■885 Gatfo Seven Corporation, Elmsfo Glycerin behenate, commercially available from New York.

3 FD&C Red #40 Lake, Coloron, Ink 1. commercially available Luminium lake colorant.

4 Bynol 0125 Air Products and Chemicals, Inc. 9. Allentown, Pennsylvania Commercially Available Polyvinyl Alcohol .

5 Crucel Texas, commercially available hydroxypropyl cellulose.

6 Carbopol ■Ex-55 resin, B. F. Gutdrich Koho, Commercial Polycarbophil is available locally.

7 Thyroid 9244FP, Davis Division, W. R, brace and Company, commercially available humid silicon dioxide.

8 The weight ratio of nifedipine to PEG800Q is 1:2.

The release rate of nifedipine in vitro is 4% by weight in 1 hour and 2 hours. 6.5 weight percent at 4 hours, 10.7 hours at 4 hours, 18.7 weight percent at 6 hours. and 21.0% by weight at 8 hours, the first treatment from the integrated matrix. The drug-releasing carrier composition may be used as a therapeutic agent for androgen stimulation. Prepared using 5 milligrams of dehydroepiandrosterone (DHEA), which is a Manufactured. The preparation method and in vitro release test are similar to that of Example 7.

Table XrV Mucoadhesive carrier composition Weight of each carrier (milligrams) Component Polymer matrix Barrier film dicalcium phosphate Dihydrate’ 27.50 90.50 Glycerin behenate” 5.50 50.00 Coloring agent’ 1. O O Magnesium stearate 1. OO Polyvinyl alcohol'7.00...Hydroxypropyl Cellulose' 0.01 0.75 Polycarbophile'0.01...Hymed Silica'5.　O　O　・ ・・Composition for mucous membranes” 15.00 ・・ PEG8000 3t53... 1 Encompress Co., Ltd. Nidward Mendel Corp. ink, carme Le, New York, commercially available dicalcium phosphate dihydrate.

2 Completetor @ 885 Gattefosse Corporation, Elmsfosse Glycerin behenate, commercially available from New York.

3 FD&C Red #40 Rake, Coloron, Ink, Commercially Available Aluminum lake colorant.

4 Binol■125 Air Products and Chemicals, Inc. Allentown, Pennsylvania Commercially Available Polyvinyl Alcohol .

5 Crucel @ HXF Hercules Inc., Hyuston, Texas. Commercially available hydroxypropylcellulose.

6 Carbopol@Ex-55 resin, B. F. Gutdrich Koho, Commercial Commercially available polycarbophil.

7 Thyroid■244FF, Davius Division, W, R- Brace Ann Company, commercially available humid silicon dioxide.

8 The weight ratio of DHEA to PEG8000 is 1:2.

The release rate of dehydroepiandrosterone in a test tube is 20% by weight in 6 hours. Basen), 1 (30% by weight at 15 hours, 40% by weight at 13 hours) and 50 weight percent at 23 hours. Therefore, this carrier Controlled release of the therapeutic agent was obtained.

A bilayer laminate mucoadhesive carrier was prepared using the compositions in Table XV below. Ta.

Table XV Mucoadhesive carrier composition Polymer matrix barrier film Weight Weight Weight Weight Components (milligrams) Percent (milligrams) Percent diphosphoric acid calcium Trihydrate' 85.0 42.5 ... Glycerin behenate 210. 0 5.0... Colorant 30.05 0.0? Humid Silica' 50.0 25.0...PEG3000 5 0.0 25.0...--Arbutinol 5.0 2.5... ... me cellulose butyrate ... 9.0 12.49 distilled acetylated mono Glyceride' 3.0 4.16 Solvent solution' 60.0 83.28 Total 200.0 100.0 72.05 100.001 Encompress■ Nidward Mendelian Coating, 5 Carmel, New York, Commercial Dicalcium phosphate dihydrate available in

2 Compritor 0885 Gattefosse Corporation, Elmsfoss Glycerin behenate, commercially available from New York.

3 FD&C Red #40 Lake, Coloron, Ink 1. commercially available Luminium lake colorant.

4 Thyroid 0244FP, Divis Division, W, R, Brace and Company, Commercially Available Humid Silicon Dioxide.

5 Mybaset @945, Eastman Chemical Products, Inc. 1. Kickston, TN, commercially available distilled acetylated monoglycerides .

6 Weight ratio of ethyl acetate to acetone distilled off during drying of the applied film: 1 One against one.

All ingredients for a polymeric matrix equivalent to 10 carriers in a disc dosage form, Weighed and blended through a 40 mesh stainless steel screen. this Compress 200 milligrams of the mixture into an approximately 13 mm x 3 mm Made into a circular disc. The mold surface, which is a part of this disk prepared in this way, is soaked in water. a suspension of a homogeneous barrier film composition that acts as an insoluble barrier film; Manually coated. The coating suspension for this barrier film consists of a polymer and a Dissolve the plasticizer in an organic solvent and finally add FD&C Red #40 lake powder to this suspension. It was prepared by adding it to the liquid.

Controlled drug release properties as described above in Example 7 for these carriers In order to determine this, an in vitro study was conducted. 2 by weight from the polymer matrix The time it takes for 0%, 50%, 75%, and 90% arbutinol to be released is approximately 0.8 hours, 2.6 hours, 6 hours, and 10.5 hours, respectively, and mainly Treatment from this polymeric matrix containing dry particulate silicon dioxide and PEG3000 This suggests that drug release is controlled.

Example 14: Mucoadhesive carrier with barrier film applied as coating suspension Lear's in vitro therapeutic drug release experiment For a two-layer laminate mucoadhesive carrier, the compositions of Table XVI below were prepared. did.

Table XVI Polymeric matrix composition Components Weight (milligrams) Weight percent dicalcium phosphate Dihydrate’ 85.0 42.5 Glycerin behenate 210.0 5.0 Evaporated silica” 50.0 25.0 polyoxyalkylene Block polymer' 50.0 25.0 Arbutinol 5.0 2.5 Total 200.0 100.0 1 Encompress■ Nidward Mendel Coop. Ink9. carmel, New York, commercially available dicalcium phosphate dihydrate.

2 Completetor■885 Gatfoose Corporation, Elmsfo Glycerin behenate, commercially available from New York.

3 Thyroid 0244FP, Divis Division, W, R, Brace and Company, Commercially Available Humid Silicon Dioxide.

4 Bullronic @F-68, BASF Wayand Corporation, Versi Bunny, New Chassis, commercially available polyoxyalkylene The process for preparing this polymer matrix is as follows.

All ingredients were passed through a 40 mesh stainless steel screen. 10 pieces An amount of each component equivalent to a disk was weighed. Then mix them completely. The final mixture was obtained.

A polymeric matrix in the form of a disc weighing approximately 200 milligrams was compressed, followed by Example 13. coated with a barrier film coating suspension. Dry these and Real kylene block copolymers and pluronic acid as an inert gel-forming reagent. Humid silicon dioxide as a mucoadhesive substance in combination with F68 A disc-type two-layer laminate carrier containing the following was obtained.

When examining the release rate of therapeutic drugs in vitro as described in Example 7, This carrier composition contains 20%, 50%, 75% and 90% by weight of arbutinol. It is known that the water is released in approximately 1 hour, 3.5 hours, 8 hours, and 15 hours, respectively. won. This carrier composition is therefore suitable for the common It functions as a substrate to control the release of therapeutic drugs.

For the polymeric substrate of the mucoadhesive carrier, the compositions in Table X■ below were prepared.

Table X■ Polymeric matrix composition Components Weight (milligrams) Weight percent dicalcium phosphate Dihydrate’ 37.0 18.5 Glycerin behenate 5.0 2.5 Polyvinyl alcohol 10.0 5 ．． 0 hydroxypropyl Cellulose 40.0 20.0 Humid silica' 35.0 17.5 Acrylic acid polymer' 35.0 1 ? , 5PEG3350 23.0 11.5 Composition for mucous membranes' 15.0 7.5 Total 200.0 100. O ■　Encompress■　Nidward Mendel Coho, Ink, Carmel, Ni New York, commercially available dicalcium phosphate trihydrate.

2 Completetor■885 Gattefosse Corporation, Elmsfosse Glycerin behenate, commercially available from New York.

3 Bynol ■ 125 Air Products and Chemicals, Inc. 9. Allentown, Pennsylvania Commercially Available Polyvinyl Alcohol .

4 Crucel ■HXF Hercules Ink 2. hyuston, texas, Commercially available hydroxypropyl cellulose.

5 Thyroid 0244FF, Divis Division, W, R, Brace and Company, Commercially Available Humid Silicon Dioxide.

6 Carbo Ball 0934P, B, F: Gutdrich Company, commercially Available acrylic acid polymers.

8. Preparation of this carrier with a weight ratio of arbutinol to PEG3000 of 1:2° The method is similar to that described in Example 6, except that this carrier also contains a This is substantially the same as the method for preparing solids. One side of this polymer matrix was as described in Example 13. manual coating using a barrier film coating suspension prepared and applied as described above. I clicked.

In order to determine the release characteristics of arbutinol from this carrier, the We investigated the release rate of therapeutic drugs in vitro. This carrier Ar uses fine dry silicon dioxide-polyethylene glycerin as a hydrophilic aid. Contains it in combination with Carbobol 0934P as an agent to control dispersion and improve the Adhesion can be strengthened by combining recon dioxide and PEG3350/8000 make it possible. The release of arbutinol in vitro was 22% by weight in 3 hours. 50% by weight at 7.5 hours, 75% by weight at 12 hours, and 1% by weight at 7.5 hours. 90% by weight in 8 hours and therefore this carrier controls the release. It has been shown once again that

The compositions in Table X■ below were used to prepare the polymeric matrix of the mucoadhesive carrier.

Table X■ Polymeric matrix composition Components Weight (milligrams) Weight percent dicalcium phosphate Dihydrate’ 37.0 18.50 Glycerin behenate 2.5 1.25 Polyvinyl alcohol 15.0 7.50 Hydroxypropyl Cellulose 37.5 18.75 Polycarbophile 25.0 12. 50 humid silica' 35.0 17.50 PEG3350 33.0 1 6.50 Composition for mucous membranes' 15.0? , 50 total 200.00 100.0 0 1 Encompress■ Nidward Mendel Koho. Ink9. carmel, New York, commercially available dicalcium phosphate trihydrate.

2 Completetor■885 Gatfoose Corporation, Elmsfo Glycerin behenate, commercially available from New York.

3 By No J ■ 125 Air Products and Chemicals, Inc. Allentown, Pennsylvania Commercially Available Polyvinyl Alcohol .

4 Crucel @HXF Hercules Ink 9. hyuston, texas, Commercially available hydroxypropyl cellulose.

5 Carbopol@Ex-55 resin, B, F, Gutdrich Coho, commercial Polycarbophil available in.

6 Thyroid @244FP, Davies Division, W, R, Brace and Company, commercially available humid silicon dioxide 7 The ratio of arbutinol to PEG3000 is 1:2 (W/W).

The method for preparing the polymer matrix of this carrier is similar to that described in Example 7. example The water-insoluble barrier film shown in step 13 was applied manually and the solvent was removed by air drying. I left.

According to the process disclosed in Example 7, the in vivo therapeutic agent release rate of this carrier is We have considered this. The release of arbutinol in vitro was 27% by weight in 2 hours. 50% by weight at 5 hours, 73% by weight at 10 hours, and and 90% by weight at 19 hours, thus controlling the release of this carrier. Demonstrates the ability to

Using the composition shown in Table X■ below, containing 17β-estradiol (micronized) inside A mucoadhesive sugar alcohol carrier matrix was prepared.

Table XIX carrier matrix composition Components Weight (milligrams) Weight percent dicalcium phosphate Dihydrate’ 65.0 32.5 Glycerin behenate 210.0 5.0 Humid silica 350.0 25.0 Mannitol 50, O25.0 17β-estradiol 5.0 2.5 Lactose 20.0 10.0 Total 200.00 100.00 1 Encompress 0 Nidward Mendel Coop. ink, carnol, ni New York, commercially available dicalcium phosphate dihydrate.

2 Completetor■885 Gattefosse Corporation, Elmsfosse Glycerin behenate, commercially available from New York.

3 Thyroid 0244FP, Divis Division, W, R, Brace and Company, commercially available humid silicon dioxide All components of this substrate were sieved through a 60 mesh stainless steel screen. did. Weigh, mix, and compress all ingredients equivalent to 10 substrates to form 10 substrates. It was made into a substrate disk. One side of this substrate disk was covered with a barrier film as disclosed in Example 13. Film coating was done manually with a coating suspension. This film code The coated surface was allowed to air dry and then subjected to the same test process as described in Example 7. An estradiol release test of this mucoadhesive carrier was then conducted.

The release rate of 17β-estradiol in vitro was 9.5% by weight in 5 hours. percent, 15 weight percent at 10 hours, 17 weight percent at 15 hours, and 19,5% by weight at 20 hours, thus the release of this carrier Describes controllability.

In the above example, the mucoadhesive matrix was prepared using a sugar alcohol such as mannitol. It is also shown that it can be prepared using combinations with silica. suitable for this purpose Other sugar alcohols include inositol, xylitol, sorbitol and similar It is a compound. Lubricants such as glyceryl behenate are amenable to production by direct compression techniques. included in this matrix composition for ease of use. dicalcium phosphate diwater An absorbable filler such as is mixed with.

Example 18: Mucoadhesive odor remover Containing fragrance within the barrier film as a mucoadhesive controlled release breath freshener or deodorant. Several mucoadhesive carriers were prepared.

These compositions are shown in Table XX below. The composition of the polymer matrix was kept constant.

Bi, Bii and B111 were obtained by varying the aroma composition of the barrier layer. use The fragrances used are peppermint oil USP1 Cinnamic Aldehyde FCC and Spearmint oil NF.

By the same process as described in Example 6, individual fragrances and polyethylene glycol ( A physical mixture of PEG) 8000 was prepared.

The components were then treated in the same manner as in Example 7 to obtain a carrier.

Table xX Carrier for mucoadhesive breath odor remover Polymer Substrate Barrier Film, Weight (milligrams) Component Weight It (milligrams) Lamb) Bi Bii B111 dicalcium phosphate Dihydrate’ 30.0 45.0 45.0 45.0 Glycerin behenate 27 ．． 5 45-0 45.0 45.0 Colorant 31.0 1.0 1.0 Magnesium stearate...1.0 1.0 1.0 Holihinylalco '7.5...Hydroxypropyl Cellulose 30.0 ... Humid silica 37 ．． 5... PEG3000 37.5 43.0 43.0 43.0 Peppermint Oil USP...15.0...Cina Mic aldehyde FCC... 15.0... Spearmint oil NF　・・・　・・・　・・・　15.01 Encompress ■ Nidoward Mendel Cope. Ink9. Carmel, New York, commercially available Dicalcium phosphate dihydrate.

2 Completetor @ 885 Gattefosse Corporation, Elmsfosse Glycerin behenate, commercially available from New York.

3 FD&C Red #40 Lake, Coloron, Ink 1. commercially available Luminium lake colorant.

4 Binol■125 Air Products & Kamicals, Inc. 1. Allentown, Pennsylvania Commercially Available Polyvinyl Alcohol .

5 Crucel ■HXF Hercules Ink 9. hyuston, texas, Commercially available hydroxypropylcellulose.

6 Thyroid 0244FF, Divis Division, W, R, Brace and Company, commercially available humid silicon dioxide.

Prepared with oxide, polyethylene glycol and other polymeric components. Mucosal adhesion Adhesion of sexual carrier was carried out.

Male alpino rats were sacrificed by stratification, their backs removed, and aerated water-cooled normal saline (n (ormal 5aline). This tissue should be removed so that the mucous membrane remains intact. Wash thoroughly to remove all partially digested food. part of the organization Cut it, hang it on a weight stand, fix it firmly, and keep it at the specified room temperature (normal 5). aline) placed in saline. In addition, another piece of tissue excluding the internal tissue was placed in a rubber stock. I placed it on the par. The mucoadhesive film is applied onto the mucin on the surface of the tissue on this stopper. A sample of the carrier was placed and arranged evenly. Then use this stopper as a tension meter. I placed it on the machine and adjusted the scale to O using a counterweight.

Using an experimental jack, the tissue on the slide/par was brought into contact with the tissue on the weight platform. . The full weight of the stopper was placed on the weight platform and held there for 60 seconds. . The interaction between these two films is then observed until the adhesive surfaces are separated. balance It was measured by the increase in number of people. Measured in milligrams. (Note: The maximum weight is 6 It was 500 milligrams. Beyond that point, all of the above adhesives are accurate. I couldn't measure it. ) The mucoadhesive strength of the three carriers used was This tension meter was too strong to measure in air without using liquid. This means that the test tube The set of Table XXI below suggests excellent adhesion of this disc to mucous membranes within Vitamin B12 mucoadhesive for vitamin absorption through mucous membranes using a composition A carrier was prepared.

Table XXI mucoadhesive vitamin carrier Components Polymer matrix, weight (milligrams) dicalcium phosphate Dihydrate’ 85.0 Glycerin behenate” io.

Humid Silica' 50.0 PEG8000 45.0 Vitamin B, 2 10.0 1 Encompress [Phase] Nidward Mendel Corp., Inc. 9. Carme Le, New York, commercially available dicalcium phosphate dihydrate.

2 Completetor @ 885 Gattefosse Corporation, Elmsfosse Glycerin behenate, commercially available from New York.

3 Thyroid 0244FF, Divis Division, W, R, Brace and Company, Commercially Available Humid Silicon Dioxide.

All ingredients were sieved through a 60 mesh stainless steel screen. polymerization Weigh the amount of ingredients equivalent to 10 polymer substrates, mix and compress them, and make 10 polymer substrates. Got the disc. One side of this polymer matrix disk is coated with a barrier film coating. coating suspension. The composition of this suspension and the application process are described in Example 13. It is stated.

Although the invention has been described with respect to specific embodiments set forth in detail, these include: This is for illustrative purposes only, and the present invention is not necessarily limited thereto. should be understood. As will be readily understood by those skilled in the art, modifications and variations may be made to this disclosure. It is obvious from the illustrations, drawings, and appended claims that it departs from the art of the invention. It can be reconfigured without needing to be reconfigured. Therefore, such a product of the present invention disclosed herein is Modifications and variations are intended to be within the scope of the invention and the claims that follow.

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Claims (32)

[Claims] 1. an anhydrous but hydratable monolithic polymeric matrix and its viscosity to mucosal tissues; suitable for therapeutic agents containing amorphous fumed silica present in sufficient amounts to promote deposition. mucosal carrier. 2. A mucoadhesive carrier according to claim 1, wherein the polymer matrix A mucoadhesive carrier composed of liol. 3. The mucoadhesive carrier according to claim 2, wherein the polyol is a polymer. Mucoadhesive carrier that is lyethylene glycol. 4. The mucoadhesive carrier according to claim 3, wherein the polyethylene Mucoadhesive glycols having an average molecular weight ranging from about 1,500 to about 8,500 sexual carrier. 5. The mucoadhesive carrier according to claim 3, wherein the polyethylene Mucoadhesive glycol with an average molecular weight ranging from about 4,000 to about 8,000 sexual carrier. 6. The mucoadhesive carrier according to claim 2, further comprising the above-mentioned polyester. A mucoadhesive carrier containing a therapeutic agent dissolved in an odor. 7. The mucoadhesive carrier according to claim 6, wherein the polyol is a polymer. A mucoadhesive carrier that is lyethylene glycol. 8. The mucoadhesive carrier according to claim 7, wherein the therapeutic agent is dipine, the average molecular weight of the polyethylene glycol is about 4000, and the weight ratio of nifedipine to polyethylene glycol is about 1:4, respectively. mucoadhesive carrier. 9. The mucoadhesive carrier according to claim 7, wherein the therapeutic agent is radiol, and the average molecular weight of the polyethylene glycol is about 4000. and the weight ratio of estradiol to polyethylene glycol is about 1, respectively. Pair 4 mucoadhesive carrier. 10. The mucoadhesive carrier according to claim 7, wherein the therapeutic agent is oxicam, and the average molecular weight of the above-mentioned polyethylene glycol is about 4000. and the weight ratio of piroxicam to polyethylene glycol is about 1:1, respectively. 4, a mucoadhesive carrier. 11. The mucoadhesive carrier according to claim 7, wherein the therapeutic agent is buterol, and the average molecular weight of the polyethylene glycol is about 4000. and the weight ratio of albuterol to polyethylene glycol is about 1:1, respectively. 4, a mucoadhesive carrier. 12. The mucoadhesive carrier according to claim 7, wherein the therapeutic agent is a dehydrogenase. Droepiandrosterone, the average molecular weight of the polyethylene glycol is approximately 4000 and dehydroepiandro for polyethylene glycol A mucoadhesive carrier in which the weight ratio of sterones is approximately 1 to 4, respectively. 13. The mucoadhesive carrier according to claim 7, wherein the therapeutic agent is edipine, the average molecular weight of the polyethylene glycol is about 8000, , and the weight ratio of nifedipine to polyethylene glycol is about 1:2, respectively. A mucoadhesive carrier. 14. The mucoadhesive carrier according to claim 7, wherein the therapeutic agent is oxicam, and the average molecular weight of the polyethylene glycol is about 8000, , and the weight ratio of piroxicam to the aforementioned polyethylene glycol is about 1, respectively. Pair 2 mucoadhesive carrier. 15. The mucoadhesive carrier according to claim 7, wherein the therapeutic agent is buterol, and the average molecular weight of the polyethylene glycol is about 8,000. and the weight ratio of albuterol to polyethylene glycol is about 1:1, respectively. 2, a mucoadhesive carrier. 16. The mucoadhesive carrier according to claim 7, wherein the therapeutic agent is a dehydrogenase. Droepiandrosterone, the average molecular weight of the polyethylene glycol is approximately 8000 and dehydroepiandro to polyethylene glycol A mucoadhesive carrier in which the weight ratio of sterones is about 1 to 2, respectively. 17. The mucoadhesive carrier according to claim 7, wherein the therapeutic agent is Nylpropanolamine, and the average molecular weight of the polyethylene glycol is about 800. 0, and the weight of phenylpropanolamine relative to polyethylene glycol is Mucoadhesive carriers in a quantitative ratio of about 1:2, respectively. 18. The mucoadhesive carrier according to claim 7, wherein the therapeutic agent is 17 β-estradiol, and the average molecular weight of the polyethylene glycol is approximately 80. 00 and 17β-estradiol to polyethylene glycol mucoadhesive carriers, each in a weight ratio of about 1:2. 19. The mucoadhesive carrier according to claim 2, wherein the polymer matrix A mucoadhesive carrier composed of a polyol mixture. 20. In the mucoadhesive carrier according to claim 1, further hydration is possible. mucoadhesive carrier containing adjuvants. 21. The mucoadhesive carrier according to claim 1, which is water-swellable. is a water-insoluble fibrous cross-linked carboxy-functional polymer. A mucoadhesive carrier containing. 22. A mucoadhesive carrier according to claim 1, wherein the mucoadhesive carrier is dispersed within the matrix. A mucoadhesive carrier containing a therapeutic agent. 23. A mucoadhesive carrier according to claim 1, wherein the polymer matrix A mucoadhesive carrier composed of acrylic acid polymer. 24. A mucoadhesive carrier according to claim 1, wherein the polymer matrix A mucoadhesive carrier composed of polyol and acrylic acid polymer. 25. The mucoadhesive carrier according to claim 1, further comprising: mucoadhesive carrier containing cellulose ester. 26. It is an anhydrous material containing a therapeutic agent and amorphous fumed silica that forms a mucosal adhesive surface. an integral polymer matrix that is hydrated and a non-adhesive surface that is affixed to the polymer matrix. A therapeutic dosage form comprising a water-insoluble barrier layer forming a water-insoluble barrier layer. 27. 27. The therapeutic dosage form of claim 26, wherein the polymeric matrix contains: A therapeutic dosage form that is provided with an embedded collection element. 28. 28. The therapeutic dosage form of claim 27, wherein the retrieval element is string-like. A therapeutic dosage form that is a section. 29. 28. The therapeutic dosage form of claim 27, wherein the collection element is planar. A therapeutic dosage form that is a shaped member. 30. The therapeutic dosage form according to claim 29, wherein the planar member is perforated. therapeutic dosage form. 31. A mucoadhesive carrier suitable for therapeutic agents, which is anhydrous but hydrated. an integrated sugar alcohol matrix and sufficient to promote adhesion of the matrix to mucosal tissue. a mucoadhesive carrier comprising amorphous fumed silica present in an amount of 32. The mucoadhesive carrier according to claim 31, wherein the sugar alcohol A mucoadhesive carrier in which the alcohol is mannitol.