JP2001510788A - Tannic acid polymer compositions for pharmaceutically controlled release of pharmaceutical agents into the oral cavity - Google Patents

Abstract

  (57) [Summary] The present invention relates to controlled or sustained release compositions for the release of drugs or other agents. The essential components of the composition of the present invention include one or more polymers and tannic acid or tannin. The release of the drug or other agent is at a given time period and at a given concentration. The site of action of the drug is local, local or systemic. The polymer is cellulosic or proteinaceous.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION Field of the Invention The field of the invention is controlled or sustained release compositions for releasing one or more drugs or other drugs. The essential components of the composition of the present invention include one or more polymers and tannic acid or tannin. The release of the desired drug can be adjusted for a predetermined period of time and a predetermined concentration. The site of action of the drug is local, local or systemic. The polymer is cellulosic or proteinaceous.

Related Art Controlled release products are well known in the pharmaceutical arts and by maintaining a desired level of a pharmaceutical product for a desired period of time, while reducing the number of doses required to achieve the desired level. Used to increase patient compliance.

A composition comprising a polymer and tannic acid or tannin Calderon et al. Agr. Food Chem. 16: 479 (19
68) compared tannic acid and quebracho tannin co-precipitates with gelatin forming gelatin / tannin precipitates. Calderon disclosed that proteins as different as ovalbumin and gelatin readily combined with tannins to form a precipitate. Calderon presents the problem that precipitates form between proteins and tannins in natural beverages such as fruit juices, wines and beers, and furthermore, adding proteins such as gelatin to cloudy solutions Studied the possibility of capturing cloudy particles and reducing tannins in beverages. Calderon did not direct the use of the precipitate and further characterized it.

[0004] US Pat. No. 3,255,018 discloses an adhesive chewing gum comprising a complex of tannic acid and gelatin. This complex is added to make the gum base non-adhesive to the teeth.

[0005] US Pat. No. 3,679,792 discloses a chewing gum composition having anti-cariogenic activity. The chewing gum comprises a gelatin-tannic acid adduct which is used as an adhesive to counteract the tendency of the chewing gum composition to adhere to teeth, especially certain types of dentures and artificial teeth.

[0006] US Patent No. 4,274,410 discloses a vaginal contraceptive device and a drug release sponge. This document discloses a collagen slurry and a tanning agent for crosslinking collagen.

[0007] US Pat. No. 5,223,029 discloses hardened materials for medical and dental applications. The essential components include tricalcium phosphate or tetracalcium phosphate and a setting regulator, which may include tannin and collagen. This reference describes degraded gelatin (water-soluble gelatin or gelatin 21, Nita Ge
latin Inc. Product). Collagen can be used by preparing it as a separate solution from the tannin solution, by dissolving it in the tannin solution, or by using it in a powdered state. The use of the tannin-collagen combination other than the hardener, as well as its physical properties, is not shown. Furthermore, this document discloses the use of this complex to slowly release tannic acid for the formation of cement, but not its use as a flexible adhesive. Furthermore, there is no indication that the conjugate should be used for drug release or is suitable for this purpose.

[0008] Rodu et al. Oral Pathol. 17: 324 (1988) evaluated the in vitro virucidal activity of soluble components of the topical film-forming drug Zilactin ^™ . Zilactin ^™ is a hydroxypropylcellulose-based film-forming drug. Other active ingredients include tannic acid, salicylic acid and boric acid, which are disclosed as being necessary for the unique adhesive film forming properties of the drug.

[0009] Rodu et al. Oral Pathol. 17: 564 (1988) discloses a bioadhesive, Zilactin ^™, as a mucosal bioadhesive, which is based on hydroxypropylcellulose and complexed with three organic acids. Zilactin ^™ has been reported to form an adhesive and soluble film, resulting in significant relief of pain and protection of ulcers from irritation for several hours. This medicament was made by dissolving a combination of hydroxypropylcellulose and tannic acid, among other embodiments, in SD40 alcohol for comparative testing with the parent compound Zilactin ^™ . The physical properties of the binary conjugate have not been studied, and the use of this conjugate for drug release was not disclosed or suggested.

[0010] US Pat. No. 5,081,157 discloses a film-forming composition for topically applying a medicament to body tissue. Film-forming compositions include hydroxypropylcellulose for treating mucocutaneous tissue as well as other wet tissues by forming an adhesive film. An esterifying agent is an essential component of the film. Weak carboxylic acids such as tannic acid have been suggested as specific esterifying components. The cellulosic compound reacts with the weak carboxylic acid to form a film.

[0011] Gamiz Gracia et al. Pharm. Biomed. Anal. 1
5: 447 (1997) discloses a flow injection assay for determining albumin tannate in tablets. Tannic acid albumin is tannic acid (
Tannin) and albumin (50%) and are used in the treatment of diarrhea because of their astringent properties. This document discloses albumin tannate as a drug and not as a carrier for the drug. No physical properties of this compound have been reported.

US Pat. No. 4,524,824 discloses a dental cement in which tannic acid derivatives comprising a tannic acid-protein combination are reported. Suggested proteins include albumin and gelatin. A precipitate forms between the tannic acid and the protein. This precipitate is used to slowly release tannic acid for the formation of cement, not for the formation of a flexible adhesive. Further, there is no disclosure or suggestion of using such a conjugate for drug release.
No physical properties of the complex are provided.

WO 93/10827 discloses a coating guidewire using a protein-based coating, which has been pretreated by adding a weak organic acid such as tannic acid. Suggested proteins include gelatin, collagen and albumin. No physical properties are provided for this coating. Further, there is no disclosure or suggestion of releasing the drug from the coating.

Oral Delivery Systems Oral controlled release delivery systems should ideally be adapted so that the release rate and profile can meet physiological and chronotherapeutic needs. The art describes free forms, such as sublingual tablets, troches, and buccals. In addition to non-adhesive oral sustained release or controlled release forms, other forms for adhering to the oral mucosa have been designed to deliver active pharmaceutical agents directly into the oral mucosa or into saliva . Ointments and other viscous adhesive compositions have also been used. The active ingredients in all these forms can act locally or systemically.

US Pat. No. 4,829,056 discloses etorphine, at least one monosaccharide,
A buccal tablet consisting of a disaccharide or a mixture thereof and a mixture of xanthan gum and locust bean gum in a weight ratio of 3: 1 to 1: 1 is described. Here, the total weight of monosaccharide and / or disaccharide relative to the total weight of xanthan and locust bean gum is from 20: 1 to 3: 1. The buccal tablet is intended to be placed between the gingival surface of the jaw and the buccal mucosa, where the buccal tablet gels to produce a soft hydrated tablet, which provides release of etorphine up to 2 hours. Can be held in this position. Buccal tablets are stated to provide improved bioavailability.

US Pat. No. 4,948,580 describes a bioadhesive composition, which can be utilized as an oral drug delivery system, wherein the copolymer poly (methyl vinyl ether / anhydrous) is dispersed in an ointment base. Maleic acid) and gelatin. The composition is stated to be useful for delivering active ingredients such as steroids, antifungals, and antibacterials to the oral mucosa.

US Pat. No. 4,597,959 discloses a cosmetic breath freshener (cos) in wafer form.
A composition is described which has delayed release properties. The composition includes a plurality of microencapsulated droplets of a flavorant contained in an adhesive base.

US Pat. No. 5,077,051 describes bioadhesive microcapsules, which include xanthan gum, locust bean gum, bulking ag
ent) and the active agent. The microcapsules are stated to be useful for delivering buffers to the oral cavity for anti-caries purposes. The microcapsules prepare a hot aqueous solution or suspension of the active agent; add xanthan gum, locust bean gum and a bulking agent to form a viscous solution; and then (a) cool and then dry the viscous solution. To obtain a solid material, which is then formed into microcapsules or (b) prepared by spray drying the viscous solution to form microcapsules.

[0019] US Pat. No. 4,915,948 describes a tablet, which is stated to have improved mucosal adhesion. The tablets comprise a water-soluble biopolymer selected from xanthan gum, pectin and mixtures thereof, and a solid polyol having a solubility in water at room temperature of greater than about 20 g / 100 g solution.

US Pat. Nos. 4,994,276, 5,128,143, and 5,1
No. 35,757 describes controlled release excipients, which are synergistic heterodisperse polysaccharides (
For example, a polysaccharide gum that can crosslink a heteropolysaccharide such as xanthan gum with this heteropolysaccharide, for example, in combination with locust bean gum), which can be directly compressed after addition of drug and lubricant powder, conventional wet granulation Or a combination of the two can be processed into an oral solid dosage form. The release of the drug from this formulation has been reported to proceed according to a zero or first order mechanism.

US Pat. No. 4,059,686 describes a pharmaceutical formulation for buccal administration, which is a mixture of a pharmaceutically active agent, a pharmaceutical carrier, and sodium polyacrylate in conventional dosage form. It is characterized by: It adheres strongly to local sites and dissolves slowly over time, releasing a suitable amount of active agent. This formulation is designed to adhere to mucous membranes.

US Pat. No. 4,876,092 describes an adhesive formulation in sheet form, which comprises as essential ingredients a carboxyvinyl polymer, a poorly water-soluble methacrylic acid copolymer, a polyhydric alcohol and a pharmaceutically active agent. An adhesive layer and a poorly water-soluble carrier layer containing a pharmaceutically active poorly water-soluble film-forming high molecular weight compound and a plasticizer as essential components. It can adhere to the oral cavity for extended periods of time and release the active agent. This formulation is designed to adhere to mucous membranes.

US Pat. No. 3,972,995 describes a dosage form for buccal administration of a drug,
This is applied directly to the inner surface of the mouth. The dosage form comprises a poorly water-soluble, waterproof and flexible support member, a water-activated adhesive precursor applied to the surface of the support member, and a central portion of the support member directly or in a matrix. And an active ingredient dispersed and applied. This dosage form is applied directly to the inner surface of the mouth. Contact with saliva activates the adhesive, and causes the support member to adhere to the interior surface of the mouth, thereby exposing the active ingredient to a limited area of the oral mucosa, while at the same time, the active ingredient is transmitted from other parts of the oral environment Be isolated.

US Pat. No. 5,330,761 describes a controlled release bioadhesive tablet that includes a topically active agent, a heterodisperse gum matrix, and a pharmaceutically acceptable diluent. The final product adheres to the mucosa and releases the topically active agent over the desired period.

[0025] Nagai, T .; (J. Cont. Rel. 6: 353 (1987))
Described are sustained release tablets that can stick strongly to human gums but not to the buccal mucosa. In addition, self-administering plasters having a water-impermeable backing layer (film) are described.

US Pat. No. 4,772,470 discloses an oral plaster comprising a soft adhesive film comprising a compatible polycarboxylic acid and / or a mixture of polycarboxylic anhydride and a vinyl acetate polymer, and a topical agent comprising An oral formulation comprising such an oral bandage formulated therein is disclosed. This oral plaster or formulation has been reported to show strong adhesion for a long duration when applied to the oral mucosa or teeth. This patent is said to teach a composition for topical administration of a pharmaceutically active agent. This is primarily depicted for the use of an anesthetic composition, but may also include other agents. The composition comprises the active agent in a pharmaceutically acceptable solvent and also as a mixture with the bioadhesive.

US Pat. No. 4,900,554 describes an adhesive device for applying to body tissue. It has an adhesive layer and a backing layer located on one side of the adhesive layer. The adhesive layer comprises one or more acrylic polymers having adhesive properties when dissolved or swelled in water, and at least one poorly water-soluble cellulose derivative. The backing layer is poorly or slightly water-soluble. This patent discloses a composition comprising the active agent in a mixture, which also includes a bioadhesive. In addition, it includes a backing layer so that the adhesive does not adhere to adjacent areas.

US Pat. No. 5,446,070 relates to compositions and methods for topical administration of pharmaceutically active compounds, and particularly to anesthetic compounds for topical administration. The present invention is a flexible bioadhesive composition for topical administration. The present invention is a flexible bioadhesive composition comprising a pharmaceutically active agent, a solvent and a plasticizer as a mixture with a polysaccharide bioadhesive carrier, wherein the composition is substantially free of water, It is substantially poorly water soluble, and the pharmaceutically active agent is present in an amorphous form. This patent states that the anesthetic can be added to the carrier at very high loading without compromising the adhesive properties, so that faster delivery of the anesthetic to the tissue can occur without substantial crystallization of the drug Is disclosed. This document discloses that the composition is used for topical administration to hard tissues such as teeth.

European Patent Application 223 245 discloses a curable composition for dentistry applications, comprising a methacrylate monomer and a polymerization initiator, and having the property of polymerizing in situ to form a cured filler. This document discloses that such fillers are used in combination with an active agent, whereby the active agent is released from the cured filler.

Further, each of the above references further discusses sustained release compositions, many of which can be used to release pharmaceutically active agents into the oral cavity.

Some problems are associated with controlled or sustained release formulations in the oral cavity.

The main problem is to provide long-term release at effective concentrations. For example, the onset of a fungal infection in the oral cavity and subsequent entry into other parts of the body can be life threatening for a compromised patient. Therefore, it is desirable to release the antifungal agent progressively. However, this is very difficult to achieve.

Buccal tablets and sublingual tablets are pharmaceutical preparations intended primarily for systemic effect.
These tablets are placed between the cheeks and gums, or under the tongue, and dissolve slowly. The drug is absorbed through the oral mucosa and enters directly through the systemic circulation rather than through the portal circulation. The advantage of these tablets is the efficient absorption of the drug. This is because the drug is not broken down in the liver. However, if the tablet disintegrates and dissolves too quickly, the purpose of this method of administration will not be achieved.

A problem with these sustained release devices relates to the comfort area. Patients often reject these oral sustained release devices. This is because they have a "foreign matter" feeling. As a result, these devices are often removed by the patient.

In recent years, tablets for stomatitis have been developed, which are directly applicable to the affected area. However, this formulation is also hard and has a certain thickness, and the person using it is aware of its presence. Thus, the tablet can be removed with the tongue and swallowed during eating and drinking. Therefore, it is difficult to keep it in the oral cavity for a long time.

In addition, known formulations usually consist of ingredients that are soluble or disintegrable in the mouth.
Therefore, most of the pharmaceutically active agents contained in the formulation are swallowed without being absorbed through the oral mucosa. Therefore, these formulations are not entirely satisfactory as sustained or controlled release formulations for the oral cavity.

In order to delay the disintegration of the above formulations, the following trials have been attempted as formulations for buccal administration with no successful results.

1. 1. adding large amounts of binders, for example starch, without using disintegrants; 2. adding a large amount of a hydrophobic lubricant, such as magnesium stearate; Coating tablets with a water-repellent base, for example wax or paraffin.

Ointments are not satisfactory for buccal administration. This is because the adhesiveness is insufficient and the solubility is rather high.

[0040] Mucosal patches that exhibit good long-term adhesion cause side effects, such as itching and irritation of the mucosa at the patch site, or even necrosis in severe cases. (Con
tact-Dermatitis 25 (4): 230-6 (1991); Ma
turitas 13 (2): 151-4 (1991). ) In addition to health complications, the side effect profile of the product can lead to additional treatment costs by requiring treatment by a physician or visiting an emergency room.

Another problem is localized release to the teeth. That is, drugs designed to be delivered to the teeth, such as dental whiteners and desensitizers, are largely wasted. This is because the delivery is to the entire oral cavity and not locally to the teeth.

Another problem is that it is difficult to apply a sustained release device for the oral cavity.

A particular problem involves the difficulty of obtaining a prolonged release of a highly soluble drug when the delivery system is in an aqueous environment, such as the oral cavity. Hydrogel systems release drugs too quickly. Corrosive systems, such as those using the polymer Eudragit ^™ , also result in an undesirably rapid release.

Accordingly, there is a need for an oral controlled release pharmaceutical delivery device having the following properties:
Release can be sustained at the desired concentration for the desired period of time, and can be particularly for highly soluble drugs when the delivery system is in an aqueous environment such as the oral cavity. Necrosis is avoided. Release can be localized to the teeth. The application is easy and not complicated. Patient comfort is provided. This device does not give the oral cavity a foreign body sensation. This device promotes buccal absorption, resulting in rapid systemic delivery of the released drug. The device may also provide local treatment of the oral mucosa.

SUMMARY OF THE INVENTION The present invention broadly relates to a liquid composition comprising a polymer and tannic acid or tannin, which composition dries to form a solid composition that allows for controlled release of the drug. Alternatively, a precipitate is formed, which dries to form a solid composition that allows for controlled release of the drug.

In a highly preferred embodiment, the present invention relates to a liquid composition comprising a polymer and tannic acid or tannin, wherein the liquid composition is dried to provide an adhesive solid composition capable of controlled release of the drug Or may form a precipitate, which may dry to form an adherent solid composition that allows for controlled release of the drug.

The present invention further encompasses a liquid composition comprising a polymer and tannic acid or tannin and a drug, wherein the liquid composition dries to form a solid composition capable of controlled release of said drug. Alternatively, a precipitate is formed, which is dried to form a solid composition capable of controlled release of the drug.

In a highly preferred embodiment, the present invention relates to a liquid composition comprising a polymer and tannic acid or tannin and a drug, wherein the liquid composition is dried to provide an adhesive with a controlled release of said drug. Form a solid composition or form a precipitate,
The precipitate dries to form a solid composition to which the controlled release of the drug is adherent.

The present invention further includes a liquid composition comprising a polymer and tannic acid or tannin and a drug, wherein the drug is encapsulated in liposomes or microcapsules, microspheres, nanocapsules or nanospheres, and wherein Drying the liquid composition to form a solid composition capable of controlled release of the drug, or forming a precipitate, and drying the solid composition capable of controlled release of the drug To form

In a highly preferred embodiment, the invention relates to a liquid composition comprising a polymer and tannic acid or tannin and a drug, wherein said drug is encapsulated in liposomes or microcapsules, microspheres, nanocapsules or nanospheres And wherein the liquid composition dries to form an adherent solid composition capable of controlled release of the drug, or forms a precipitate, which precipitate dries to control the drug. It forms an adhesive solid composition that can be released.

The present invention naturally encompasses a solid composition comprising a polymer, tannic acid or tannin, and a drug, wherein the solid composition is capable of controlled release of the drug.

In a preferred embodiment, the present invention relates to an adhesive solid composition comprising a polymer, tannic acid or tannin, and a drug, wherein the solid composition is capable of controlled release of the drug.

[0053] In a preferred embodiment, the polymer is a protein. Preferred proteins include, but are not limited to, gelatin, hydrolyzed gelatin, albumin and collagen.

[0054] In another embodiment, the polymer is a cellulosic polymer. Preferred polymers include, but are not limited to, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

The present invention also relates to a method of making each of the compositions disclosed herein.

The present invention also relates to the use of the above solid compositions in the treatment of various conditions or in applications where controlled release of the drug is desired.

In a preferred embodiment, the present invention relates to a composition for sustained release of a drug in the oral cavity.

In a very preferred form, the present invention is in the form of a pharmaceutical oral patch, which may adhere to the surface of a tooth or other hard dental structure, where it may be used for topical, systemic or local treatment Of the drug.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention broadly relates to a liquid composition comprising a polymer and tannic acid or tannin, wherein the composition is a dry, solid composition capable of controlled release of the drug. Or form a precipitate that dries to form a solid composition that allows for controlled release of the drug.

[0060] In a preferred embodiment, the polymer is a protein. Preferred proteins include, but are not limited to, gelatin, hydrolyzed gelatin, albumin and collagen.

[0061] In another embodiment, the polymer is a cellulosic polymer. Preferred polymers include, but are not limited to, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

In a preferred embodiment of the present invention, the liquid composition comprises a polymer and tannic acid or a mixture of tannins.

[0063] The minimum essential components of the liquid composition can be a polymer and tannic acid or tannin. However, it is understood that the liquid composition can include more than one polymer. Thus, the composition may include more than one protein, more than one cellulosic polymer, and combinations of the two.

Thus, the composition may consist essentially of any protein or cellulosic polymer disclosed herein, as well as other suitable proteins and cellulosic polymers, and tannic acid or tannin.

Optional components include plasticizers such as glycerol, polyethylene glycol, and citrate, and glycerol is a particularly preferred plasticizer when the polymer is hydrolyzed gelatin.

However, glycerol can also be used as a plasticizer with other proteins described herein, or in common embodiments where the protein is used in combination with tannic acid or tannins.

An emulsifier can also optionally be added.

In a highly preferred embodiment, the present invention relates to a liquid composition comprising a polymer and tannic acid or tannin, wherein the liquid composition is dried to provide an adhesive solid composition capable of controlled release of the drug Or forms a precipitate which dries to form an adherent solid composition that allows for controlled release of the drug.

[0069] In a preferred embodiment, the polymer is a protein. Preferred proteins include, but are not limited to, gelatin, hydrolyzed gelatin, collagen and albumin.

In another embodiment, the polymer is a cellulosic polymer. Preferred cellulosic polymers include, but are not limited to, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

In a preferred embodiment, the liquid composition comprises a polymer and tannic acid or a mixture of tannins.

The minimum essential component of the liquid composition can be a polymer and tannic acid or tannin. However, it is understood that the liquid composition can include more than one polymer. Thus, the composition may include more than one protein, more than one cellulosic polymer, and combinations of the two.

Thus, the composition may consist essentially of any protein or cellulosic polymer disclosed herein, as well as other suitable proteins and cellulosic polymers, and tannic acid or tannin.

[0074] Other components are included as needed. These include plasticizers such as glycerol, polyethylene glycol and citrate, and when the polymer is hydrolyzed gelatin, glycerol is a particularly preferred plasticizer.

Emulsifiers can also be added as needed.

The present invention further encompasses a liquid composition comprising a polymer and tannic acid and tannin and a drug, wherein the liquid composition dries to form a solid composition capable of controlled release of the drug. Or it forms a precipitate that can be dried to form a solid composition that allows for controlled release of the drug.

[0077] In a preferred embodiment, the polymer is a protein. Preferred proteins include, but are not limited to, gelatin, hydrolyzed gelatin, collagen and albumin.

In an alternative embodiment, the polymer is a cellulosic polymer and tannic acid or tannin and drug. Preferred cellulosic polymers include
Examples include, but are not limited to, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

In a preferred embodiment, the liquid composition comprises a mixture of a polymer, tannic acid or tannin, and a drug.

Thus, the minimum essential components of the liquid composition can be a polymer, tannic acid or tannin, and a drug. However, it should be understood that one or more polymers or types of polymers may be included. That is, more than one protein, more than one cellulosic polymer, and combinations of the two are included.

Thus, the composition comprises essentially any of the proteins or cellulosic polymers disclosed herein, as well as other suitable proteins and cellulosic polymers, and tannic acid or tannin, and a drug. Can consist of

[0082] Optional agents include plasticizers such as glycerol, polyethylene glycol and citrate, and glycerol is a particularly preferred plasticizer when the polymer is a protein, especially hydrolyzed gelatin.

[0083] Emulsifiers may also be added as needed.

In a more preferred embodiment, the present invention relates to a liquid composition comprising a polymer and tannic acid or tannin and a drug, wherein the liquid composition is dried to provide an adhesive solid composition capable of controlled release of the drug. Or a precipitate that dries to form an adherent solid composition capable of controlled release of the drug.

[0085] In a preferred embodiment, the polymer is a protein. Preferred proteins include, but are not limited to, gelatin, hydrolyzed gelatin, collagen and albumin.

[0086] Alternatively, the polymer is a cellulosic polymer. Preferred cellulosic polymers include hydroxyethyl cellulose, hydropropyl cellulose,
And hydroxypropyl methylcellulose, but are not limited thereto.

In a preferred embodiment, the liquid composition comprises a polymer and a mixture of tannic acid or tannin and a drug.

The minimum essential ingredients for forming an adhesive solid composition can be a polymer, tannic acid or tannin, and a drug. However, the liquid composition may include more than one polymer or polymer type. Thus, the composition includes various proteins, cellulosic polymers, and mixtures of the two.

Thus, the composition comprises essentially any of the proteins or cellulosic polymers disclosed herein, as well as other suitable proteins and cellulosic polymers, and tannic acid or tannin, and a drug. Can consist of

Optional components include plasticizers such as glycerol, polyethylene glycol and citrate, with glycerol being a particularly preferred plasticizer when the polymer is hydrolyzed gelatin.

[0091] Emulsifiers may also be added, if desired.

The invention further encompasses a liquid composition comprising a polymer and a tannic acid or tannin and a drug, wherein the drug comprises a liposome or microcapsule,
The liquid composition is entrapped in microspheres, nanocapsules or nanospheres and the liquid composition is dried to form a solid composition capable of controlled release of the drug, or a solid composition capable of controlled release of the drug. Form a precipitate that can be dried to form an object.

[0093] Also, for this aspect of the invention, in which the drug is entrapped in liposomes or microcapsules, microspheres, nanocapsules or nanospheres, in a preferred embodiment, the polymer is a protein. Preferred proteins include, but are not limited to, gelatin, hydrolyzed gelatin, collagen, and albumin.

[0094] The liposomes can be multilamellar or unilamellar vesicles. Liposomes comprise phospholipids and / or sphingolipids and optionally lipids (eg, cholesterol and phosphatidylic acid) and antioxidants. Preferred phospholipids are soy lecithin, egg lecithin, soy phosphatidylcholine, egg phosphatidylcholine, synthetic phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidylethanolamine, alone or in mixtures thereof. A preferred sphingolipid is sphingomyelin. More preferred liposomes comprise phosphatidylcholine, phosphatidylethanolamine, cholesterol and antioxidants.

The microcapsules, microspheres, nanocapsules or nanospheres comprise a polymer and optionally a plasticizer and an emulsifier. Preferred polymers including these microcapsules, microspheres, nanocapsules or nanospheres include polyalkyl methacrylates (eg, polymethyl methacrylate), polyalkyl cyanoacrylates (eg, polymethyl cyano methacrylate), polyesters (eg, polylactic acid and Polylactic acid / glycolic acid copolymers), cellulose derivatives (eg, ethyl cellulose and cellulose acetate) and proteins (eg, albumin, gelatin, and hydrolyzed gelatin), and polysaccharides (eg, sodium alginate, pectin, chitosan, guar gum, And xanthan gum).

[0096] In an alternative embodiment of the liquid composition of the present invention, the polymer is a cellulosic polymer. Preferred cellulosic polymers include, but are not limited to, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

In a preferred such embodiment, the liquid composition comprises a polymer, tannic acid or a mixture of tannins and a drug, entrapped in liposomes or microcapsules, microspheres, nanocapsules or nanospheres.

Thus, the minimum essential components of a liquid composition can be a polymer, tannic acid or tannin and a drug entrapped in liposomes or microcapsules, microspheres, nanocapsules or nanospheres. However, it should be understood that it may include one or more polymers or types of polymers. That is, 1
One or more proteins, one or more cellulosic polymers, and combinations of the two are included. In addition, one or more liposomes or microcapsules, microspheres, nanocapsules or nanospheres, or any combination thereof, are also included.

[0099] Thus, the composition basically comprises any of the proteins or cellulosic polymers disclosed herein, as well as the liposomes or microcapsules, microspheres, nanocapsules disclosed herein. Or other suitable proteins and cellulosic polymers, and tannic acids or tannins, and drugs, either entrapped in the nanospheres, or liposomes or microcapsules, microspheres, nanocapsules or nanosphere combinations.

Optional agents include plasticizers such as glycerol, polyethylene glycol,
Glycerol is a particularly preferred plasticizer when the polymer is a protein (especially hydrolyzed gelatin).

[0101] Emulsifiers may also be added as needed.

In a highly preferred embodiment, in this further aspect of the invention, wherein the drug is entrapped in liposomes or microcapsules, microspheres, nanocapsules or nanospheres, the invention also comprises a polymer and a tannic acid. Or a liquid composition comprising a tannin and a drug, wherein the drug is entrapped in liposomes or microcapsules, microspheres, nanocapsules or nanospheres, and wherein the liquid composition is dried to control the drug. It forms a releaseable adhesive solid composition or forms a precipitate that can be dried to form an adhesive solid composition capable of controlled release of the drug.

[0103] In a preferred embodiment, the polymer is a protein. Preferred proteins include, but are not limited to, gelatin, hydrolyzed gelatin, collagen, and albumin.

[0104] Liposomes can be multilamellar or unilamellar vesicles. Liposomes contain phospholipids and / or sphingolipids and optionally lipids (eg, cholesterol and phosphatidic acid) and antioxidants. Preferred phospholipids are soy lecithin, egg lecithin, soy phosphatidylcholine, egg phosphatidylcholine, synthetic phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidylethanolamine, alone or in mixtures. A preferred sphingolipid is sphingomyelin. More preferred liposomes include phosphatidylcholine, phosphatidylethanolamine, cholesterol and antioxidants.

The microcapsules, microspheres, nanocapsules or nanospheres comprise a polymer and optionally a plasticizer and an emulsifier. Preferred polymers including these or microcapsules, microspheres, nanocapsules or nanospheres are polyalkyl methacrylates (eg, polymethyl methacrylate), polyalkyl cyanoacrylates (eg, polymethyl cyano methacrylate), polyesters (eg, polylactic acid and Polylactic / glycolic acid copolymers), cellulose derivatives (eg, ethyl cellulose and cellulose acetate) and proteins (eg, albumin, gelatin, and hydrolyzed gelatin), and polysaccharides (eg, sodium alginate, pectin, chitosan, guar gum, and Xanthan gum).

In an alternative composition of the liquid composition of the present invention, the polymer is a cellulosic polymer. Preferred cellulosic polymers include, but are not limited to, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

In such preferred embodiments, the liquid composition comprises a polymer, tannic acid or a mixture of tannins and a drug, entrapped in liposomes or microcapsules, microspheres, nanocapsules or nanospheres.

Thus, the minimum essential components of a liquid composition can be a polymer, tannic acid or tannin, and a drug, entrapped in liposomes or microcapsules, microspheres, nanocapsules or nanospheres. However, it should be understood that one or more polymers or types of polymers may be included. That is, it includes one or more proteins, one or more cellulosic polymers, and any combination thereof. It is further understood that one or more types of liposomes or microcapsules, microspheres, nanocapsules or nanospheres or a combination of the two are also encompassed.

Thus, the composition comprises essentially any of the proteins or cellulosic polymers disclosed herein, as well as any liposomes or microcapsules, microcapsules as disclosed herein. Other suitable proteins and cellulosic polymers, and tannic acids or tannins, and drugs, either entrapped in spheres, nanocapsules or nanospheres, or liposomes or microcapsules, microspheres, nanocapsules or nanosphere combinations Can consist of

Optional agents include plasticizers (eg, glycerol, polyethylene glycol, and citrate), and glycerol is a particularly preferred plasticizer when the polymer is a protein and especially hydrolyzed gelatin.

[0111] Emulsifiers may also be added as needed.

The invention naturally encompasses a solid composition comprising a polymer, tannic acid or tannin, and a drug, wherein the solid composition allows for controlled release of the drug.

[0113] In a preferred embodiment, the polymer is a protein. Preferred proteins include, but are not limited to, gelatin, hydrolyzed gelatin, albumin and collagen.

Alternatively, the polymer is a cellulosic polymer. Preferred polymers include, but are not limited to, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

Since the liquid composition may comprise a polymer, tannic acid or a mixture of tannin and a drug, the solid composition thus comprises a mixture of the polymer, tannic acid or tannin, and a drug.

Thus, the drug is dispersed or embedded in the polymer-tannic acid / tannin dried matrix.

[0117] The minimum essential ingredients in the solid composition may include a polymer, tannic acid or tannin, and a drug. However, it is understood that the solid composition may include one or more suitable polymers. Thus, the composition includes one or more proteins, one or more cellulosic polymers, and a combination of the two.

Thus, the solid composition basically consists of any of the proteins or cellulosic polymers disclosed herein, as well as other suitable proteins and cellulosic polymers, and tannic acids or tannins and drugs. Can consist of

When appropriate, the solid compositions of the present invention can be prepared using a suitable drug coating,
Can be coated.

In a preferred embodiment, the present invention relates to a solid adhesive composition comprising a polymer, tannic acid or tannin, and a drug, wherein the solid composition is capable of controlled release of the drug.

[0121] In a preferred embodiment, the polymer is a protein. Preferred proteins include, but are not limited to, gelatin, hydrolyzed gelatin, albumin and collagen.

Alternatively, the polymer is a cellulosic polymer. Preferred cellulosic polymers include, but are not limited to, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

The solid adhesive composition comprises a polymer, tannic acid or a mixture of tannin and a drug.

Thus, the drug is dispersed or embedded in the polymer-tannic acid / tannin dried adhesive matrix.

The minimum essential composition in the solid adhesive composition can be a polymer, tannic acid or tannin, and a drug. However, it is understood that the solid composition may include one or more polymers. Thus, the composition includes one or more proteins, one or more cellulosic polymers, and a combination of the two.

Accordingly, the composition is essentially composed of any of the proteins or cellulosic polymers disclosed herein, combinations thereof, and other suitable polymers, and tannic acids or tannins, and drugs. Can be.

[0127] The solid compositions described herein include biodegradable formulations.

Although the above description relates specifically to the release of drugs, it should be understood that other agents may be released from the solid compositions described herein. Examples of such agents include cosmetics, vitamins, minerals, flavorants, pigments,
Poisons (eg, insecticides, odorants, etc.) include, but are not limited to.

To control the release of a drug or other agent from the solid compositions disclosed herein, the agent can be entrapped in a polymer: tannic acid matrix. The degree of such capture, and thereby the sustained release, is controlled by the choice of polymer.

[0130] The solvents used to prepare the polymer-tannin conjugates can be useful as release-modifying agents. Since they can strongly influence the release rate, as shown in the examples herein.

The outer polymer matrix as shown in the examples herein is in the form of a release-modifying agent. Since it contributes to the control of the release of the drug. Delaying release from the inner matrix by changing the amount is
It may be formulated with or without its own release-modifying agent.

The release of the drug is also controlled by the addition of a pH-modifying agent, a release-modifying agent, a solubility-modifying agent, and combinations thereof to a solution or suspension of the polymer added to the dried precipitate. obtain.

The present invention also relates to a method of forming each of the compositions disclosed herein.

[0134] In its broadest embodiment, the polymer and tannic acid or tannin are mixed with a solvent, and the mixture is then dried to form a solid composition.
Alternatively, the polymer can be first dissolved in a solvent, and the tannic acid or tannin can be separately dissolved in the solvent before mixing.

The polymer may or may not form a precipitate when mixed with tannic acid or tannin. In embodiments where the tannic acid or tannin forms a precipitate with the polymer, the composition is formed as follows: (1) the polymer is dissolved in a solvent; and (2) the tannic acid or tannin is added to the solvent. (3) a precipitate is formed; and (4) the precipitate is dried to form a solid composition.

The drug (s) can be added to the polymer solution or tannic acid solution. When added to a polymer solution that forms a precipitate, the drug is then mixed with the precipitate that is formed, and therefore, when the precipitate is dried, the drug is embedded in a solid composition that is formed from the precipitate. Or dispersed.

However, in an alternative embodiment, a solid composition can be formed as in steps 1-4, and then one or more drugs are used for controlled release of the drug from the dried precipitate. Can be added to this precipitate for further processing. The drug can be added to the dried precipitate in solution and then subsequently dried or mixed with the precipitate in powdered form. It can then be pressed together or otherwise shaped according to methods well known in the art.

Preferred solvents for the polymer include water, ethanol and mixtures of water and ethanol, isopropanol, mixtures of water and isopropanol, n-
But not limited to propanol, and mixtures of water and n-propanol.

Preferred solvents for tannic acid or tannins include water, ethanol and mixtures of water and ethanol, isopropanol, mixtures of water and isopropanol, n-propanol, and mixtures of water and n-propanol. However, the present invention is not limited to these.

When the polymer is a protein, preferred solvents include water, ethanol and mixtures of water and ethanol, isopropanol, mixtures of water and isopropanol, n-propanol, and mixtures of water and n-propanol. However, the present invention is not limited to these.

When the polymer is a cellulosic polymer, preferred solvents include water,
Ethanol and mixtures of water and ethanol, isopropanol, mixtures of water and isopropanol, n-propanol, and mixtures of water and n-propanol.

When the polymer and tannic acid are dissolved in the same solvent, preferred solvents include
Water, ethanol, and mixtures of water and ethanol, isopropanol, mixtures of water and isopropanol, n-propanol, and mixtures of water and n-propanol.

[0143] In an alternative embodiment, the dried precipitate disclosed above is ground into a powder, which is then mixed with further polymer in a solvent, which mixture then forms the final solid composition Dried to make. Thus, this second polymer forms the outer matrix of the composite.

Polymers-Preferred polymers for mixing with the tannic acid / tannin precipitate include any polymer that physically binds the powder together, which makes it possible for the powder to adhere to the teeth as a mass. enable. The polymer needs to be flexible, and therefore requires a plasticizer. The polymer should be degradable and / or allow saliva to diffuse therethrough to allow release of the drug from the powder. The polymer should be either soluble or dispersible in the solvent in which the powder is insoluble, so that the powder does not redissolve when the polymer is added.

The second polymer may optionally contain a release-modifying agent, a pH-adjusting agent, an emulsifier,
And may be formulated with a solubility-modifying agent.

This preferred second polymer is a polyacrylate polymer, and especially Eud
RAGIT ^™ polymer.

When the first polymer is a protein or cellulosic polymer, preferred polymers that can be used as the second polymer include Eudragit ^™ L-100
, ^{Eudragit TM L30D-55, Eudragit TM} S-100, Eu dragit TM NE-100, Eudragit TM NE-30, Eudragi
t ^™ RL, Eudragit ^™ RS, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, pectin, calcium pectinate, alginic acid, calcium alginate, cellulose acetate phthalate, carbopol
), Guar gum, tragacanth gum, gum arabic, other vegetable gums, and chitosan.

The second polymer serves as a matrix for the tannic acid polymer composite powder (precipitate). It binds with the powder for ease of application and control of dosing. That is, a pre-measured amount of the pharmaceutical agent can be applied in one single application than in repeated applications (eg, as in a varnish coated tooth).

It may further help control the rate of drug release by controlling or attenuating the ability of saliva to interact with sediment. The degradation of the polymer and its permeability by saliva allow the release of the powder into saliva, thereby allowing the release of the drug.

In a preferred embodiment, the composition is made as follows: (1) Dissolve the protein and drug in a solvent comprising ethanol and water; (2) Dissolve tannic acid or tannin in ethanol and water (3) to form a precipitate; (4) drying the precipitate to form a solid composition.

In a very preferred embodiment, the first four steps above are performed, but
The following further steps then take place: (5) grinding the dried precipitate into a powder; (6) powdering the Eudragit ^{™ in} a solvent containing ethanol and water or as a latex suspension in water. Mixing with polymer and plasticizer; (7
) Dry the mixture.

In a highly preferred embodiment of the present invention, the protein is hydrolyzed gelatin and the second polymer is Eudragit ^™ L-100.

Suitable drugs include, but are not limited to: nicotine, nicotine salts,
Nicotine polymer conjugates, lidocaine, piroxicam, flurbiprofen, dihydroergotamine mesylate, ergotamine tartrate, sumatriptan succinate, isosorbide dinitrate, isosorbide mononitrate, nifedipine nitrate, ondansetron hydrochloride, and peptide drugs.
Very or significantly water soluble drugs are particularly suitable for release from embodiments where a protein-tannic acid / tannin precipitate has been formed. Embodiments comprising a second polymer are particularly suited for release of such drugs.

In certain embodiments of the invention, the same or a different drug may be added to the second polymer solution and released (if solidified) therefrom.

The present invention also relates to the use of the solid compositions in treating various conditions. The composition may also be used as a powder or microcapsule in a capsule for oral delivery to the gastrointestinal tract, or in a tablet for oral delivery to the gastrointestinal tract, alone or with typical excipients. Compressed or lozenges for local delivery to the oral cavity or for delivery to the gastrointestinal tract, suppositories for rectal delivery, vaginal tablets or vaginal suppositories, or as ointments for topical use Can be used.

Thus, depending on the use of the composition, the physical form of the composition may be adjusted. For example, the compositions can be used as films, nanoparticles, microparticles, or beads.
The composition may also be used as a lozenge, suppository, vaginal tablet or vaginal suppository, or as an ointment, as a powder or microcapsule in capsules, alone or compressed with typical excipients into tablets. . Where appropriate, the compositions of the present invention may be coated with a suitable pharmaceutical coating.

In a preferred embodiment, the present invention relates to a composition for sustained release of a drug in the oral cavity. In a very preferred form, the invention is in the form of a pharmaceutical oral patch, which can be attached to the surface of a tooth, denture, or other hard tooth structure.

The method provides for buccal absorption of the active agent, resulting in rapid systemic delivery of the desired amount of the agent for the desired amount of time.

The method also provides for delivery of the active agent confined to the tooth area, which avoids releasing the oral cavity elsewhere.

The method also allows for local treatment of the affected area of the oral or throat area.

The present invention also provides a composition described herein to a patient by adhesively attaching the solid, sustained release composition to a hard surface of the patient's mouth, such as a tooth or denture. I do.

As a pharmaceutical oral patch, the solid composition can be modified to any shape and size, depending on the purpose of the drug release. Thus, if a large amount of drug is to be released, in addition to increasing the concentration of the drug in the sustained release composition, the solid form may be larger in size and / or larger in thickness. possible.

An important consideration for shape and size is that the patch does not discomfort the patient when applied and effectively releases the desired pharmaceutically active agent at the desired level and for the desired duration. It is possible. For example, for rapid release of small amounts of drug, a thin layer in which the drug is dispersed may be required.

The following considerations are important when choosing the site of application: (1) saliva flow around the site; (2) ease of use for application; (3) patient comfort.

The patch component is suitable for remaining in the oral cavity for an extended period of time. In a preferred embodiment, the patch remains in the oral cavity for 6-8 hours. However, other embodiments may continue for various desired times.

The present invention also relates to a method of making a sustained release composition such that the release rate can be adjusted in the final solid form.

The present invention also relates to the use of a composition of the present invention for releasing a suitable pharmaceutical agent in the oral cavity. Potentially, any pharmaceutically active agent can be released, but as described, suitable agents are those that are soluble or very soluble in water.

In addition, potentially any condition can be treated by release of the drug from the patch. These are described in more detail below.

Preferred sites of application include, but are not limited to, upper teeth.

Sites of action for pharmaceutically active agents include systemic delivery through the oral mucosa of the mouth, throat, and esophagus itself, the oral mucosa, or topical delivery to one or more teeth.

The amount of active agent contained in the final controlled release product can be determined by one of ordinary skill in the art without undue experimentation and generally will range from about 0.1% to about 3% by weight of the final product.
5% by weight. The particular amount of active agent included will, of course, depend on the particular agent and its intended use.

The present invention may include other topically active agents such as flavorings and sweeteners. Flavoring agents can be natural or synthetic. Flavors are common flavors, including wintergreen, peppermint, spearmint, menthol, fruit flavors, vanilla, cinnamon, various spices, or others known in the art. In general, Chemical Used in Food Processing, Publication No. 1274, National Academy of Science.
Any flavoring or food additive may be used, such as those described in es, pages 63-258. The amount of flavoring used is usually a matter of taste for factors such as flavor type, individual flavor, and desired intensity. Generally, the final product will contain from about 0.1% to about 5% by weight of the flavor.

[0173] Sweeteners useful in the present invention include sucrose and aspartame. In general,
Sweeteners (if present) may comprise from about 0.001% to about 5.0% by weight of the final product.
Included in the amount.

An effective amount of a colorant (eg, titanium dioxide dye, FD & C. dye, and D
. & C. Dye: Kirk-Othmer Encyclopedia of C
Chemical Technology, Vol. 5, pages 857-884); softeners, stabilizers, binders, odor control agents, and preservatives also do not reduce their adhesion or their pharmacological effects As long as they do not interfere with

The term “therapeutically effective amount” means an amount of a pharmaceutically active agent that, when released from a dental patch described herein, is sufficient to produce a desired effect. Is intended. These amounts are known in the art or can be determined by methods known in the art. The amount depends on the drug chosen, and the site of action is the tooth itself, the oral mucosa (and the area of the oral mucosa), or systemic.

The upper limit for the amount of drug in the composition is determined by the nature of the polymer matrix and the chemical interaction of the drug with the polymer matrix.

The amount of active agent in the composition required to provide the desired amount and concentration in the oral cavity can be determined by known methods. Thus, the concentration and amount of drug per unit area of the patch (ie, per square or cubic millimeter) can be independently varied to achieve the desired effect. Higher concentrations of drug contained in thinner dosage forms result in drugs with a faster onset and shorter duration. High concentrations of drug (more milligrams of drug per square or cubic millimeter) contained in thicker dosage forms provide a powerful effect with a quick onset and a long duration. Low concentrations of drug in thinner dosage forms produce a milder effect with a slower onset and shorter duration. Lower concentrations of the drug contained in the thicker dosage form have a milder effect with a slower onset and a longer duration. As demonstrated in the above description, the ability to coat thin or thick is important to the practitioner practicing the invention, as required for a particular anatomical site of interest, and for particular anatomical sites. According to the medicine
Provides a means to change systemic medication. The term "onset" is intended to mean the time required to reach a desired concentration level of a pharmaceutical agent. It is used according to its ordinary meaning and its art-recognized meaning.

As used herein, the term “duration” refers to a period of time during which a desired concentration of a pharmaceutical agent is delivered. This term is used according to its ordinary and art-recognized meanings.

As used herein, the term “adhesive” refers to an adhesive that adheres, and preferably strongly adheres, a release layer to teeth or other hard structures in the mouth, such as dentures. means. To be considered as an adhesive, the material must be able to maintain adhesion in the moist or wet environment of the mouth. It can also be "self-adhesive" if it adheres to the site of interest without the need to enhance its adhesion with another adhesive. Thus, the term "adhesive" is used according to its ordinary and art-recognized meanings.

Adhesion may only be quantified for a particular type of test or use.
This is not essentially a fundamental physical property, such as surface free energy or film thickness, whose measurements can be accomplished by various methods. Therefore, "adhesion performance" must be defined and measured in the context of the intended application. Whether a given adhesive is effective on the oral cavity can be determined by a peel test in artificial saliva.

[0181] The strength of the bond was determined as disclosed in US Patent No. 4,615,697.
For example, dynes per square centimeter can be measured by standard tests for measuring force.

The term “subject” or “patient” is intended to include all mammals, preferably humans.

As used herein, the term “patch” is intended to mean a three-dimensional solid composition that can adhere to teeth or other hard structures in the mouth such as dentures, A pharmaceutically active agent may be included and the pharmaceutically active agent may be released in an effective amount from its adhesion site in the oral cavity for a desired period of time.

“Pharmaceutically active agents” allow the removal of undesirable physiological conditions (eg,
(See below.) Any chemical or biochemical that can be released to prevent, cure, or ameliorate is contemplated. The term "drug" is used interchangeably herein. These terms are used according to their ordinary and art-recognized meanings.

Although any drug may be used depending on the purpose of the treatment, the following are examples: 1. anti-inflammatory analgesic: content 0.1-5% 2. Steroidal anti-inflammatory: content 0.002 to 0.5% 3. Antihistamine: 0.1-2% 4. Local anesthetic: 0.05-2% Disinfectants and disinfectants: 0.01-10% 6. Vasoconstrictor: 0.01-1% 7. hemostatic: 0.05-1% 8. Chemotherapeutic drugs: 0.05-1% Antibiotics: 0.001-10% 10. Cosmetics 11. Tooth desensitizing agent:
0.1 to 10% Antifungal: 0.1 to 10% 13. Vasodilator: 0.1 to 10% 14. Antihypertensive: 0.1 to 10% Antiemetics: 0.1 to 10% 16. Antimigraine drug: 0.1 to 10% Antiarrhythmic drug: 0.1 to 10% 18. Asthma drug: 0.1 to 10% Antidepressant: 0.1 to 10% 20. Vaccine: 0.1-1% 21. Peptide: 0.1-1% 22. Hormones: 0.1-1% 23. Antiproton pump or H receptor blocker: 0.1-10% 24. Smoking cessation aids:
Examples of 1-5% anti-inflammatory analgesics include acetaminophen, methyl salicylate, monoglycol salicylate, aspirin, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen, flurbiprofen, Fentizac, bufexamac, piroxicam, phenylbutazone, oxyfenbutazone, clofezone, pentazocine, mepilizol, and tiaramid hydrochloride.

Examples of steroidal anti-inflammatory agents include hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, prednisolone acetate, methylprednisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flumethasone, fluoro Metron, beclomethasone dipropionate, and budesonide.

Examples of antihistamines include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate, isotipendyl hydrochloride, triperenamine hydrochloride, promethazine hydrochloride, and metzilazine hydrochloride.

Examples of local anesthetics include dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-butylaminobenzoic acid 2- (diethylamino) ethyl ester hydrochloride (p-butylaminominbenzoic acid)
d 2- (diethylamino) ethyl ester hydroc
chloride, procaine hydrochloride, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride
e), mepivacaine, cocaine hydrochloride, and piperokine hydrochloride.

Examples of disinfectants and disinfectants include trimerosol, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine, providone iodide, cetylpyridinium chloride, eugenol, and trimethyl bromide. Contains ammonium.

Examples of vasoconstrictors include naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, and tramazoline hydrochloride.

Examples of hemostatic agents include thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbazochrome sodium sulfonate, rutin, and hesperidin.

Examples of chemotherapeutic agents include vinblastine, cisplatin, 5-fluorouracil (5FU), methotrexate (MTX), 6 mercaptopurine (6MP), 1
-Β-D-arabinofuranosylcytosine (ara-C), mechlorethamine, chlorambucil, melphalan oxazaphosphorin (melphalan oxaz)
aphosporines), carboplatin, JM40, spiroplatin,
Tetraplatin, JM216, and Taxol (
taxol).

Examples of antibiotics include penicillin, methicillin, oxacillin, cephalotin, cephaloridin, erythromycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, metacycline, chloramphenicol. , Kanamycin, streptomycin, gentamicin, bacitracin, and cycloserine.

Examples of antifungals include amphotericin, clotrimazole, econazole nitrate,
Fluconazole, glisofluvin (grisofu)
lvin), itraconazole, ketoconazole, miconazole, nystatin, terbinafine hydrochloride, undecenoic acid, and zinc undecenoate.

Examples of vasodilators include buflomezil hydrochloride, buchenei hydrochloride (buchenei).
ne hydrochloride), naphthidrofurixarate (naft)
Idrofury oxalate, oxpentiphyllin (oxpenti)
fylline), trinitroglycerin, isosorbide dinitrate, isosorbide mononitrate, and pentaerythritol tetranitrate.

Examples of antihypertensives include amlodipine, benazepril hydrochloride
hydrochloride, captopril, clonidine hydrochloride, diazoxide, diltiazem hydrochloride, enalapril maleate, enalaprilat, felodipine, isradipine, nicardipine hydrochloride, nifedipine, atenolol, metenolol tartrate, oxpronolol hydrochloride
enol hydrochloride), propranolol hydrochloride, and verapamil hydrochloride.

Examples of antiarrhythmic agents include quinidine, quinidine salts, procainamide hydrochloride, lidocaine, and mexiletine hydrochloride.

Examples of anti-emetics include metoclopramide hydrochloride, nabilone, and ondansetron hydrochloride.

Examples of proton pump inhibitors or H receptor blockers include omeprazole, ranitidine, and cimetidine.

Examples of anti-migraine agents include dihydroergotamine mesylate, ergotamine tartrate, sumatriptan succinate, and other triptan drugs.
rug).

Examples of peptide or protein drugs include insulin, buserelin acetate, goserelin acetate, leuprorelin acetate, calcitonin, cyclosporin, gonadrelin, somasatin, vasopressin, oxytocin, interferon, and human growth hormone.

[0202] Examples of antidepressants include fluoxetine hydrochloride, imipramine, maprotiline hydrochloride, and phenelzine sulfate.

Examples of asthma therapeutics include salbutamol, and terbutaline sulfate.

Examples of smoking cessation aids include nicotine, nicotine salts, nicotine polymer conjugates,
And cotinine.

Examples of cosmetics include breath fresheners and tooth whiteners.

Where drug release is restricted to the teeth, suitable agents include tooth bleaching agents such as carbamide peroxide, and tooth pain killers such as potassium nitrate and strontium chloride.

Conditions that are amenable to treatment with the patches described herein include, but are not limited to: oral infections, lesions, hypotension or hypertension, Helicobacter infections, pain, Cough, migraine, vomiting, nausea, inflammation, sleep apnea, snoring, gerd, and reflux disease (reflux dis)
ease). Suitable conditions include yeast infection, periodontal disease, snoring, oral ulcers, or other lesions.

The present invention will now be illustrated in further detail by reference to the following examples, but it should be understood that they are not intended to limit the invention.

Examples Example 1 Long-lasting Release of Highly Soluble Drug Materials and Methods Hydrolyzed gelatin was purchased from Croda.

[0210] Tannic acid USP was purchased from Merck.

Nicotine was purchased from The Nicobrand Company.

Pilocarpine was purchased from Laob.

Preparation of Formulation The hydrolyzed gelatin and the drug (nicotine or pilocarpine) were dissolved in a mixture of ethanol and water (or water alone). A solution of tannic acid in water and ethanol (or water alone) was added. The precipitate formed was air dried to constant weight and ground to a powder.

(In Vitro Release Experiment) The powder (0.5 g) was inserted into a dialysis bag, which was stirred in 100 ml of a phosphate buffer (0.01 M, pH 7.4) at room temperature. A 0.5 ml sample was taken for analysis.

Results Formulations of nicotine and pilocarpine, both highly soluble drugs, were prepared. These formulations used to illustrate the controlled release of highly soluble drugs are shown in Tables 1-2.

[0216]

[Table 1]

[0217]

[Table 2]

The in vitro release of the active ingredient from the powders obtained from these formulations was tested. The results are summarized in Tables 3-4.

[0219]

[Table 3]

[0220]

[Table 4]

The results show that the release of highly soluble drugs can be controlled using these formulations. Release can occur over an extended period of time, with less than half of the drug being released in 8 hours.

Example 2 Control of Drug Release Rate in Long-Term Controlled Release of Highly Soluble Drugs: I) Materials and Methods Hydrolyzed gelatin was purchased from Croda.

The tannic acid USP was purchased from Merck.

[0224] Sodium salicylate was purchased from Merck.

Formulation Preparation A gelatin-tannic acid powder was formulated with the highly soluble drug sodium salicylate,
It was then prepared using two different ratios of ethanol and water. Formulation 24
At 5-66A, the solvent weight ratio was 3: 1 (ethanol: water) and 1: 1 for formulation 245-68A.

(Results) The formulations used are described in Tables 5-6.

[0227]

[Table 5]

[0228]

[Table 6]

In vitro release studies were performed on powders obtained from these formulations as in Example 1.

The results of the in vitro release studies are summarized in Tables 7 and 8.

[0231]

[Table 7]

[0232]

[Table 8]

It can be seen that a higher proportion of water in the solvent mixture reduces the release rate of the active ingredient, while a higher ethanol content increases the release rate. In both cases, the release of the highly soluble substance sodium salicylate from the matrix is prolonged.

Example 3 Control of Drug Release Rate in Long-Term Controlled Release of Highly Soluble Drug: II) (Materials) Hydrolyzed gelatin was purchased from Croda.

[0235] Tannic acid USP was purchased from Merck.

Nicotine was purchased from The Nicobrand Company.

Preparation of Formulations Gelatin-tannic acid powder was formulated with the highly soluble drug nicotine and prepared using two different ratios of ethanol and water. In formulation 245-70, the solvent weight ratio was 3: 1 (ethanol: water) and formulation 245-70 was used.
At 49 it was 1: 1.

Results The formulations are given in Tables 9-10.

[0239]

[Table 9]

[0240]

[Table 10]

[0241] In vitro release studies were performed on powders obtained from these formulations as in Example 1.

The release pattern of nicotine from formulations 245-70 and 241-49 was:
Illustrated in Tables 11 and 12.

[0243]

[Table 11]

[0244]

[Table 12]

As shown for sodium salicylate, the effect of the solvent mixture was also achieved with nicotine. Increased amounts of water in the solvent mixture during preparation of the formulation result in a slower release.

Example 4 Long-Term Release of Nicotine from Pharmaceutical Oral Patches Materials Materials Hydrolyzed gelatin was purchased from Croda.

The tannic acid USP was purchased from Merck.

Eudragit L-100, Eudragit 30D-55, and triethyl citrate NF were purchased from Rhom Pharma.

Nicotine was purchased from The Nicobrand Company.

Formulation Preparation The powder formed from Formulation 245-70 (Table 9) was mixed with Eudragit L-1
A patch was formed by mixing with 00 and a solution of the plasticizer in ethanol.

The mixture was transferred to a plastic mold and dried to form an adhesive pharmaceutical oral patch.

In Vitro Release Dry patches (300 mg) were added to 100 ml of buffer (phosphate, 0.01 M,
pH 7.4) at room temperature. A sample of the solution (0.5 ml) was analyzed.

(Results) An in vitro release experiment was performed. The results are summarized in Table 13.

[0254]

[Table 13]

Example 5 Long-term sustained release of pilocarpine from pharmaceutical oral patch Materials Hydrolyzed gelatin was purchased from Croda.

The tannic acid USP was purchased from Merck.

Eudragit L-100, Eudragit 30D-55, and triethyl citrate NF were purchased from Rhom Pharma.

Pilocarpine was purchased from Laob.

Formulation Preparation The powder formed from Formulation 245-43C (Table 2) was mixed with Eudragit L3
A patch was formed by mixing with an aqueous suspension of 0D-55.

This mixture was transferred to a plastic mold and dried to form a pharmaceutical oral patch.

In Vitro Release Dry patches (300 mg) were added to 100 ml of buffer (phosphate, 0.01 M,
pH 7.4) at room temperature. A sample of the solution (0.5 ml) was analyzed.

(Results) An in vitro release experiment was performed. The results are summarized in Table 14.

[0263]

[Table 14]

The results show that the release of the soluble drug from the pharmaceutical oral patch can be controlled for several hours.

Example 6 In Vitro Release of Nicotine from an Adhesive Pharmaceutical Oral Patch Materials Materials Hydrolyzed gelatin was purchased from Croda.

The tannic acid USP was purchased from Merck.

Eudragit L-100 and triethyl citrate NF were purchased from Rhom P
purchased from Harma.

Nicotine was purchased from The Nicobrand Company.

Formulation Preparation The powder formed from the liquid formulation 158-72 (Table 15) was mixed with Eudragit
A patch was formed by mixing with L-100 and a plasticizer in ethanol solution.

The mixture was transferred to a plastic mold and dried to form an adhesive pharmaceutical oral patch.

[0271]

[Table 15]

In Vivo Release Experiment A pharmaceutical oral patch containing 2 mg of nicotine (190 mg) was adhered to the buccal side of the upper molar by self-adhesion.

[0273] Saliva samples were expectorated at predetermined time intervals and tested for nicotine content.

Results One volunteer wore a pharmaceutical oral patch for 4 hours. The patch conformed to the contours of the teeth and was comfortable to wear. Saliva samples were collected and analyzed by chromatography. The results are listed in Table 16.

[0275]

[Table 16]

The results show that clinically significant concentrations of nicotine (as an example of a soluble drug) can be maintained in the oral cavity for several hours. The pharmaceutical oral patch self-adhered to the teeth during the entire duration of the experiment.

Example 7 In Vivo Release of Nicotine from a Second Adhesive Pharmaceutical Oral Patch Materials Materials Hydrolyzed gelatin was purchased from Croda.

The tannic acid USP was purchased from Merck.

Eudragit 30D-55 and triethyl citrate NF were purchased from Rhom
Purchased from Pharma.

Nicotine was purchased from The Nicobrand Company.

Preparation of Formulation The powder formed from the liquid formulation 41B001SL (Table 17) was mixed with Eudrag.
A patch was formed by mixing with itL30D-55 and an aqueous suspension of the plasticizer.

The mixture was transferred to a plastic mold and dried to form an adhesive pharmaceutical oral patch.

[0283]

[Table 17]

In Vivo Release Experiment A pharmaceutical oral patch containing 2 mg of nicotine (115 mg) was adhered to the buccal side of the upper molar by self-adhesion.

[0285] Saliva samples were expectorated at predetermined time intervals and tested for nicotine content.

Results One volunteer wore a pharmaceutical oral patch for 4 hours. The patch conformed to the contours of the teeth and was comfortable to wear. Saliva samples were collected and analyzed by chromatography. The results are listed in Table 18.

[0287]

[Table 18]

The results show that clinically significant concentrations of nicotine can be maintained in the oral cavity for several hours. The pharmaceutical oral patch self-adhered to the teeth during the entire duration of the experiment.

Example 8 Release of Liposome-Encapsulated Nicotine from Pharmaceutical Oral Patches Nicotine is treated with multilamellar vesicles (MLV) and small unilamellar vesicles (SUV)
Encapsulated in both liposomes of the type. The formulations used for liposome formation are given in Table 19.

[0290]

[Table 19]

In a 100-1000 mL round bottom flask, the phospholipids and lipids were dissolved in 25 ml of chloroform: methanol. The lipid solution was dried for 2 hours using a rotary evaporator apparatus to form a lipid film on the sides of the flask. 10
Add ２０20 ml of H ₂ O or PBS (phosphate buffered saline) solution (0.01 M, pH 7.4) followed by vortexing and stirring for 2-4 hours in a 37 ° C. water bath The lipids were then hydrated to form MLV liposomes. Liposomes were characterized by standard chemical and electron microscopy techniques.

MLV Nicotine Liposomes: The volatile and water-soluble drug nicotine (0.2 ml) was dissolved in an aqueous medium and added to the lipid membrane during the hydration step.

(SUV Nicotine Liposomes) Nicotine (0.2 ml) in an aqueous medium was added to placebo liposomes (MLV), followed by sonication for 1 hour to form SUV-type nicotine liposomes.

The capture rate of nicotine was measured for each type of liposome and is shown in Table 20.

[0295]

[Table 20]

It can be seen that the encapsulation of nicotine in liposomes was as expected for water-soluble drugs. Due to the higher percentage of internal aqueous volume in liposomes of the SUV type, more drug was encapsulated in SUVs than in MLVs.

The liposomes were stored at 4 ° C. (closed).

[0298] Pharmaceutical oral patches were prepared with and without an external polymer matrix.
It was made using nicotine captured in MLV liposomes. The other components of the patch are given in Table 21.

[0299]

[Table 21]

(Batch # 285-23A, 285-23B Patch): MLV liposomes with captured nicotine (2 g) were suspended in water. B
ycoE ^™ was added, and finally an ethanol-water solution of tannic acid was added.
The precipitate was dried at 50 ° C., ground to a powder, and mixed with the Eudragit ^™ based polymer matrix (approximately 1: 1). A polypropylene mold was filled with this mixture (190 mg / well) and dried at 35 ° C. These patches each contain about 2 mg of nicotine and are formed using an external polymer matrix.

(Batch # 285-28 patch): An aqueous solution of tannic acid was dropped into the BycoE ^™ solution. 0.45 g of tannic acid-Byco formulation was added to MLV liposomes containing captured nicotine 0.63
g. Fill a polypropylene mold with this mixture (280 mg / well)
And dried in an oven at 35 ° C. These patches each contain about 2 mg of nicotine and are formed without an external polymer matrix.

(Patch # 49A004 and 158-64 without liposome): Nicotine neutralized with HCl was dissolved in water. BycoE ^™ was added, and finally an ethanol-water solution of tannic acid was added. The precipitate was dried at 50 ° C., ground to a powder, and mixed with the Eudragit ^™ based polymer matrix (approximately 1: 1). Fill the polypropylene mold with the mixture (190 mg / well),
And it dried at 35 degreeC. These patches each contain about 2 mg of nicotine and are formed using an external polymer matrix.

Release Assay: In vitro: Patches containing liposomes were separated by 50,000 molecular weight (cuto)
ff) into dialysis tubing and stirred in a bulk solution of 50-100 ml of phosphate buffered saline (PBS) (0.01 M, pH 7.4). 0.2 ml samples were collected at 0-7 hours. Nicotine was measured by a validated HPLC method.

In vivo: A pharmaceutical oral patch was adhered to the upper posterior teeth. 0 to 1 saliva sample
Collected at 80 minutes. Nicotine was measured by a test HPLC method.

In Vitro Results: The average of the results of the release of nicotine from the in vitro pharmaceutical oral patch is summarized in FIG.

The release of drug from liposome patch # 285-28 (V) was slower than from liposome-free nicotine patch # 49A004 (VI-VIII).
Nicotine release from both of these types of patches is characterized by a single rate constant. In contrast, the release profile of nicotine from liposome patches # 285-23A (I and II) and # 285-23B (III and IV) is characterized by a two-phase release of the drug, and also a liposome-free formulation It was slower than.

In Vivo Results: In vivo nicotine release experiments were performed using centrifuged nicotine liposomes ML.
Performed using patch # 285-28 containing Form V and compared to nicotine patch # 158-64 without liposomes. The results are shown in FIG.

It is understood that the salivary concentration of nicotine was higher for formulations without liposomes. The release profiles were similar.

Example 9 Release of Liposomal Encapsulated Flurbiprofen from Adhesive Pharmaceutical Oral Patches Flurbiprofen was captured in multilamellar vesicle-type liposomes as follows: In a round bottom flask, add 2 g of soy phosphatidylcholine (14 g).
. It was dissolved in 100 ml of ethanol together with 3 gm of flurbiprofen.
The lipid solution was dried for 1.5 hours using a rotary evaporator apparatus to form a lipid film with flurbiprofen dispersed therein on the side of the flask. The lipid was hydrated by addition of 140 ml of H ₂ O, followed by 2 hours of rotation and 1 hour of slow agitation to form MLV liposomes.
The liposomes were characterized by standard chemical and electron microscopy techniques. Unencapsulated flurbiprofen was removed by dialysis. 1 at 10 ° C
The liposomes were obtained by centrifugation at 17,500 rpm for hours.

(Batch # 285-62 patch): 1.3 g of tannic acid (1.7 g) in water was added dropwise to an aqueous solution of 3.1 gm of hydrolyzed gelatin (BycoE ^™ ). Tannic acid-hydrolyzed gelatin formulation,
Mixed with 9.6 g of MLV liposomes containing captured flurbiprofen. The polypropylene mold was filled with the mixture (200 mg / well) and the patches were dried in an oven at 30 ° C.

(Release Assay): In vitro: Patch containing liposomes with 100 ml of PBS (0.01 M, p
H7.4) in a bulk solution. 0.2 ml samples were collected at 0-7 hours. Flurbiprofen was measured by a test HPLC method.

In Vitro Results: The average results of in vitro release of flurbiprofen from a pharmaceutical oral patch are summarized in FIG. The sustained release of flurbiprofen from the patch can clearly be seen.

[0313]

[Table 22]

[Brief description of the drawings]

 (Brief description of drawings)

FIG. 1: In vitro release of nicotine from a patch containing nicotine encapsulated in liposomes compared to a patch containing nicotine not encapsulated in liposomes. FIG. 1 shows patch # 285-23 containing centrifuged MLV liposomes.
Average release of nicotine from A (I, II), 285-23B (III, IV), 285-28 (V) and non-liposomal nicotine patch # 49A00 (V
1 shows a comparison with the release of nicotine from I, VIII). Closed circles are I-II; closed squares are III-IV; open triangles are V, and closed triangles are V1-VIII.

FIG. 2: Comparison of in vivo release of nicotine from a patch containing nicotine encapsulated in liposomes and a patch containing nicotine not encapsulated in liposomes. FIG. 2 shows a comparison of nicotine release from patch # 285-28 with centrifuged MLV-type liposomes and nicotine release from non-liposomal patch # 158-64. Black circles are # 285-28, and black squares are # 158-64.

FIG. 3. In vitro release of flurbiprofen from a patch.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4045 A61K 31/4045 31/4178 31/4178 31/4422 31/4422 31/4439 31/4439 31 / 4985 31/4985 31/5415 31/5415 38/00 47/30 47/30 47/42 47/42 47/46 47/46 37/02 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU) , TJ, TM), AL, AM, AT, AU, AZ, BA, BB BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG , KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Flashner, Mosh Peta-Tikuba 49313, Israel Hafetch-Molde-Chai 15 F term (reference) 4C076 AA11 AA61 AA65 AA67 AA94 BB01 EE32H EE32M EE41H EE41M EE42H EE42M EE43H EE43M FF21 FF31 GG21 4C084 AA01 BA44 MA52 NA12 4C086 AA01 MA02 BC03 MA02 BC01

Claims (41)

[Claims] 1. A liquid composition comprising hydrolyzed gelatin and tannic acid or tannin. 2. A liquid composition comprising hydroxypropyl methylcellulose and tannic acid or tannin. 3. A liquid composition consisting essentially of hydroxyethylcellulose and tannic acid or tannin. 4. A liquid composition comprising a protein and tannic acid or tannin, wherein the liquid composition dries to form a solid composition from which controlled release of the pharmaceutical compound is possible. Alternatively, a liquid composition that forms a precipitate of the protein and tannic acid or tannin, and the precipitate dries to form a solid composition from which controlled release of the pharmaceutical compound can be performed. 5. The liquid composition according to claim 4, wherein said protein is selected from the group consisting of gelatin, hydrolyzed gelatin, collagen and albumin. 6. A liquid composition comprising a cellulosic polymer selected from the group consisting of hydroxyethylcellulose and hydroxypropylmethylcellulose, and tannic acid or tannin, wherein the liquid composition is dried and the pharmaceutical composition is dried therefrom. A liquid composition that forms a solid composition that allows for controlled release of the target compound. 7. A liquid composition comprising a protein and tannic acid or tannin, wherein the liquid composition dries to form an adherent solid composition from which controlled release of a pharmaceutical compound can be performed. Or a liquid composition that forms a precipitate of the protein and tannic acid or tannin, and the precipitate dries to form a solid composition from which controlled release of the pharmaceutical compound is possible. 8. The liquid composition according to claim 7, wherein said protein is selected from the group consisting of gelatin, hydrolyzed gelatin, collagen and albumin. 9. A liquid composition comprising a cellulosic polymer selected from the group consisting of hydroxyethylcellulose and hydroxypropylmethylcellulose, and tannic acid or tannin, wherein the liquid composition is dried and the pharmaceutical composition is dried therefrom. A liquid composition that forms an adherent solid composition that allows for controlled release of the target compound. 10. A liquid composition comprising a protein selected from the group consisting of hydrolyzed gelatin, albumin and collagen, and tannic acid or tannin, and a pharmaceutical compound. 11. A liquid composition comprising hydroxypropyl methylcellulose, and tannic acid or tannin, and a pharmaceutical compound. 12. A liquid composition comprising a protein and a mixture of tannic acid or tannin and a pharmaceutical compound. 13. The liquid composition according to claim 12, wherein said protein is selected from the group consisting of gelatin, hydrolyzed gelatin, albumin and collagen. 14. A liquid composition comprising hydroxyethyl cellulose and a mixture of tannic acid or tannin, and a pharmaceutical compound. 15. A liquid composition comprising a protein, and tannic acid or tannin, and a drug, wherein the liquid composition dries to form a solid composition from which controlled release of the drug is possible. Or a liquid composition that forms a precipitate of the protein and tannic acid or tannin, and the precipitate dries to form a solid composition from which controlled release of the pharmaceutical compound is possible. 16. The liquid composition according to claim 15, wherein said protein is selected from the group consisting of gelatin, hydrolyzed gelatin, collagen and albumin. 17. A liquid composition comprising a cellulosic polymer selected from the group consisting of hydroxyethylcellulose and hydroxypropylmethylcellulose, and tannic acid or tannin, and a drug, wherein the liquid composition is dried, From which it forms a solid composition capable of controlled release of the pharmaceutical compound,
Liquid composition. 18. A liquid composition comprising a protein, and tannic acid or tannin, and a drug, wherein the liquid composition dries and allows controlled release of the drug therefrom. A liquid composition that forms a solid or forms a precipitate of the protein and tannic acid or tannin, and the precipitate dries to form a solid composition from which controlled release of the pharmaceutical compound is possible. 19. The liquid composition according to claim 18, wherein said protein is selected from the group consisting of gelatin, hydrolyzed gelatin, collagen and albumin. 20. A liquid composition comprising a cellulosic polymer selected from the group consisting of hydroxyethylcellulose and hydroxypropylmethylcellulose, and tannic acid or tannin, and a drug, wherein the liquid composition is dried, From which it forms an adhesive solid composition from which controlled release of the drug is possible,
Liquid composition. 21. The pharmaceutical agent according to claim 15, wherein said pharmaceutical agent is encapsulated in liposomes or microcapsules, microspheres, nanocapsules or nanospheres.
21. The liquid composition according to 7, 18 or 20. 22. The liposome according to claim 14, wherein the soybean lecithin, egg lecithin, soybean phosphatidylcholine, egg phosphatidylcholine, synthetic phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol,
22. The liquid composition according to claim 21, comprising a phospholipid and / or a sphingolipid such as phosphatidylethanolamine and sphingomyelin, alone or as a mixture. 23. The microcapsules, microspheres, nanocapsules or nanospheres may comprise polyalkyl methacrylate such as polymethyl methacrylate, polyalkyl cyanoacrylate such as polymethyl cyano methacrylate, polylactic acid and polylactic acid / glycolic acid copolymer. Polyesters such as coalesce, cellulose derivatives such as ethyl cellulose and cellulose acetate, and proteins such as albumin, gelatin, and hydrolyzed gelatin, and polysaccharides such as sodium alginate, pectin, chitosan, guar gum, and xanthan gum. 22. The liquid composition according to claim 21, comprising a polymer. 24. A solid composition comprising a cellulosic polymer selected from the group consisting of hydroxyethylcellulose and hydroxypropylmethylcellulose, and tannic acid or tannin, and a drug, wherein the solid composition is derived therefrom. Solid composition capable of controlled release of 25. A solid composition comprising a protein and a mixture of tannic acid or tannin, and a drug, wherein the solid composition allows for controlled release of the drug therefrom. 26. The solid composition according to claim 22, wherein said protein is selected from the group consisting of gelatin, hydrolyzed gelatin, albumin and collagen. 27. A solid adhesive composition comprising a protein and a mixture of tannic acid or tannin, and a drug, wherein the solid adhesive composition allows controlled release of the drug therefrom. Adhesive composition. 28. The solid adhesive composition according to claim 24, wherein said protein is selected from the group consisting of gelatin, hydrolyzed gelatin, albumin and collagen. 29. A solid adhesive composition comprising a drug, a cellulosic polymer selected from the group consisting of hydroxyethylcellulose and hydroxypropylmethylcellulose, and tannic acid or tannin, wherein the solid adhesive composition comprises A solid adhesive composition capable of controlled release of the drug from the composition. 30. A method for producing a solid composition capable of controlled release of a drug, the method comprising: (1) a group consisting of protein, tannic acid or tannin, and a drug comprising water, alcohol and water: alcohol (2) forming a precipitate between the protein and tannic acid or tannin, thus capturing the drug in the precipitate; (3) the precipitate Drying to thereby form said solid composition. 31. The method of claim 27, wherein release of said drug from said solid composition is controlled by an alcohol: water ratio of said solution. 32. The method of claim 31, wherein said drug is released in a further step: (1) Eudragit ^™ polymer, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, pectin, calcium pectate, alginic acid, calcium alginate, cellulose acetate phthalate, carbopol (Carbopol), guar gum, tragacanth, gum arabic, and chitosan, a second solution or suspension.
28. The method of claim 27, wherein the method is controlled by: adding a polymer of the formula (I) and a plasticizer to the dry precipitate; (2) drying the component of step (1). 33. The Eudragit ^™ polymer is Eudragit ^™ L.
-100, Eudragit ^™ L30D-55, Eudragit ^™ S-10
0, Eudragit ^™ NE-100, Eudragit ^™ NE-30, Eud
selected from the group consisting of R.git ^™ RL and Eudragit ^™ RS;
A method according to claim 29. 34. The method of claim 29, wherein said controlled release is further regulated by an alcohol: water ratio in said solution. 35. The method according to claim 28, wherein the alcohol is ethanol.
The method according to any of the above. 36. The method according to claim 29, wherein the release of the drug is further controlled by adding a pH modifier, a release modifier, or a solubility modifier to the solution or suspension of the second polymer. the method of. 37. The method of claim 29, wherein the drug or a different drug is included in a solution or suspension of the second polymer. 38. The method according to claim 27, wherein said protein is selected from the group consisting of gelatin, hydrolyzed gelatin, albumin and collagen. 39. A method of using a composition according to any of claims 22 to 26, wherein the composition is used to release a drug into the oral cavity. 40. The method of claim 36, wherein said composition is in the form of a dental patch as described herein. (41) the drug is nicotine, nicotine salt, nicotine polymer complex, lidocaine, piroxicam, flurbiprofen, dihydroergotamine mesylate, ergotamine tartrate, sumatriptan succinate, isosorbide dinitrate, isosorbide mononitrate, nifedipine; 38. The method of claim 37, wherein the method is selected from the group consisting of ondansetron hydrochloride, and a peptide drug.