KR20010015631A - Bioadhesive compositions and methods for topical administration of active agents - Google Patents

Abstract

The present invention provides a flexible formulation for topical or mucosal topical administration comprising a composition prepared from a mixture of at least one PVP polymer, at least one bioadhesive, and any pharmaceutically acceptable solvent suitable for use with the active agent. Bioadhesive compositions in a form and methods of administering the active agent to a subject. In addition, this bioadhesive composition includes an active agent or a separate source of active agent directly incorporated into the composition.

Description

BIOADHESIVE COMPOSITIONS AND METHODS FOR TOPICAL ADMINISTRATION OF ACTIVE AGENTS

Mucosal membranes, such as oral mucosa, have several physical properties, such as abundant blood supply, making them a preferred site for topical administration of active agents for systemic delivery. In addition, delivery of the active agent through the mucosa also prevents primary metabolism by the liver as well as poor absorption or inactivation through the gastrointestinal pathway. Examples of such active agents include steroids such as estrogens, progestins and related compounds; Androgen and anabolic steroids; Nonsteroidal anti-inflammatory agents such as ketoprofen; Diclofenac; Propranool; Thyroid hormones; pH sensitive peptides and small proteins such as insulin and ACTH; Physostigmine; Scopolamine; Verapamil; And gallopamil.

Moreover, it is often desirable or necessary to deliver medication locally, such as to relieve oral pain.

Oral and / or mucosal delivery compositions, devices and methods are described, for example, in US Pat. No. 3,972,995 (Tsuk et al.), US Pat. No. 4,755,396 (Hsiao et al.), US Pat. No. 4,764,378 (Keith et al.), US Pat. No. 4,740,365 (e.g. Yukimatsu et al., US Pat. No. 4,889,720 (Konishi et al.), US Pat. No. 5,047,244 (Sanvordeker et al.) And Reissue Pat. No. 33,093 (Schiraldi et al.).

The use of bioadhesives to administer active agents to mucous membranes has long been known. The most commonly used bioadhesive compositions include "amorphous materials" (ie, diffusion materials that do not retain their shape) and liquid or semi-liquid carriers such as pastes, gels, lotions, emulsions, creams, sprays, drops or ointments. It contains. As the use of such compositions increases, more recently "finite" carriers (ie, non-diffusing materials that retain their shape), such as coatings, dressings and bands, or lozenges and tablets that start off in a fixed state and are later dissolved Was prepared. The compositions and apparatus were not sufficient to control the release rate of the active agent and to maintain long term adhesion or properties (i.e. simply stay in place) or efficacy. Moreover, they often leave sticky residues unacceptable upon removal.

US Pat. No. 5,446,070 to Mantelle discloses that systems having bioadhesive carriers that do not interfere with the adhesion of the carriers can substantially increase the concentration of dissolved anesthetics and other drugs by 50% by weight. However, to maximize the therapeutic effect systemically and locally, it was necessary to increase the time that such compositions could be maintained at the site of administration.

Successful bioadhesive devices for prolonged topical administration of active agents need to meet a number of physical properties. For example, the release liner should be able to easily peel off from the bioadhesive portion, but the bioadhesion portion may have sufficient adhesion and adhesion to maintain intimate contact with the application site for extended periods of time, typically 1 to 2 hours and for certain active agents up to 24 hours. It must be cohesive. In addition, the bioadhesive composition should retain the active agent at a rate suitable for delayed or controlled delivery under conditions predominantly in a wet environment associated with the mucosa. In addition, the bioadhesive composition must be nontoxic, not cause chemical irritation, and be easily removable with minimal mechanical irritation or damage to the site of application.

In this regard, the composition according to the invention is applied to wet tissues such as mucous membranes for a long time, for example for at least 1 hour, preferably at least 2 hours, more preferably at least 4 hours, even more preferably at least 8 hours, up to 24 hours. Because of the adhesion, such high adhesion provided by the compositions of the present invention ensures the desired therapeutic effect.

The present invention generally relates to bioadhesive compositions and methods of topical administration of active agents to a mammal. More specifically, the present invention relates to compositions which can be used in wet environments, in particular for mucous membranes for a long time. There are no restrictions on the type of drug that can be used in the present invention as long as it can be administered locally. Thus, active agents include both types of drugs that are topically administered for topical effects and drugs that are topically administered for systemic effects.

The present invention provides a mixture of two or more bioadhesive materials, in particular one or more soluble polyvinylpyrrolidone (“PVP”) polymers, which is suitable for use with the active agent, if appropriate. Bioadhesive composition comprising a plasticizer for a coalescing agent). The bioadhesive compositions of the invention are used in such a way as to include one or more active agents that are dissolved in the composition, or by topical administration of one or more active agents together to the site of application, such as a means for adhering the drug reservoir to the site of application. .

According to one aspect of the present invention, an improved bioadhesive composition of the type suitable for long term adhesion to a wet surface for controlled release of an active agent from the composition is characterized in that a polysaccharide, preferably a natural gum (e.g., a Karaya gum) and a soluble PVP Mixtures.

If desired, the bioadhesive composition may also include a pressure sensitive adhesive, preferably a solvent based acrylic polymer.

According to another aspect of the invention, the bioadhesive composition provides topical administration of two or more active agents of different flow rates to achieve long term and / or multiple therapeutic effects.

According to another aspect of the invention, the bioadhesive composition is also used as a pressure sensitive adhesive suitable for long term adhesion to wet or dry surfaces such as skin for controlling the release of the active agent.

The invention also relates to a method of administering the composition.

In particular, the present invention relates to a bioadhesive composition in a flexible stereotyped form for topical administration, wherein the composition

(a) a mixture of two or more bioadhesives in which the one or more bioadhesives are soluble PVP polymers;

(b) a pharmaceutically acceptable solvent, optionally including a plasticizer for bioadhesives, which is an optional component suitable for use with the active agent;

(c) an optional component pressure sensitive adhesive,

The composition is substantially free of water, is substantially insoluble in water, comprises one or more active agents or is used with the active agents.

The present invention also relates to a bioadhesive composition in flexible and stereotyped form for topical administration, the composition

(a) a mixture of two or more bioadhesives in which the one or more bioadhesives are soluble PVP polymers;

(b) a pharmaceutically acceptable solvent, optionally including a plasticizer for bioadhesives, which is an optional component suitable for use with the active agent;

(c) a mixture with two or more active agents,

(i) combinations of free acid, free base and salt forms of the same active agent, or

(ii) two or more active agents comprising a combination of different active agents, each delivered to a subject at a different flow rate; And

(d) pressure sensitive adhesive as an optional component

Wherein the composition is substantially free of water and is substantially insoluble in water.

The invention also relates to a flexible and stereotyping composition for topical administration, which composition

(a) a mixture of two or more bioadhesives in which the one or more bioadhesives are soluble PVP polymers;

(b) any component suitable for use with the active agent, including a pharmaceutically acceptable solvent, optionally including a plasticizer for bioadhesives,

The composition is substantially free of water, substantially insoluble in water, bio-adhesive and pressure-sensitive, and includes one or more active agents or is used with the active agents.

Bioadhesive compositions also include release liners and backing materials that match the shape and size of individual dosage units or delivery systems.

The present invention also relates to a method of long-term topical administration of one or more active agents to a subject,

(a) a mixture of two or more bioadhesives in which (i) the one or more bioadhesives are soluble PVP polymers, and (ii) any pharmaceutically acceptable solvent suitable for use with the active agent, optionally for bioadhesives. A plasticizer), and (iii) a pressure sensitive adhesive that is optional, wherein the composition is substantially free of water and is substantially water-insoluble, flexible and conformable bioadhesive composition, and

(b) contacting the skin or mucosa, preferably the oral mucosa area, with the bioadhesive composition to administer one or more active agents, wherein the composition comprises or is used with one or more active agents. Steps.

The present invention also relates to a method for long-term topical administration of two or more active agents to a subject.

(a) (i) a mixture of two or more bioadhesives in which the one or more bioadhesives are soluble PVP polymers; (ii) a pharmaceutically acceptable solvent, optionally including a plasticizer for bioadhesives, which is an optional component for use with the active agent; (iii) a mixture with two or more active agents, comprising (1) a combination of free acid, free base, and salt forms of the same active agent, or (2) a combination of different active agents, each delivered to a subject at different flow rates Two or more active agents; And (iv) a pressure sensitive adhesive as an optional component, providing a flexible and stereotyped bioadhesive composition that is substantially water free and substantially insoluble in water,

(b) contacting the skin or mucosa, preferably the oral mucosa area, with the bioadhesive composition to administer two or more active agents, wherein the composition comprises or is used with one or more active agents. Steps.

The present invention also includes bioadhesive compositions in flexible form form for topical administration of one or more active agents, the compositions comprising (a) one or more soluble polyvinylpyrrolidone (PVP) polymers; (b) one or more bioadhesives; (c) a therapeutically effective amount of at least one active agent; And (d) at least one solvent which is an optional component.

The invention also relates to (a) at least one active agent source; And (b) an adhesion layer suitable for adhesion to skin or mucosal tissue, wherein the adhesion layer comprises (i) one or more soluble polyvinylpyrrolidone (PVP) polymers; (ii) one or more bioadhesives; And (iii) at least one solvent which is an optional component, wherein the activator source (a) is different from the coalescing layer (b).

Further objects, features and advantages of the present invention will become apparent upon consideration of the detailed description of the preferred embodiments described below.

Detailed Description of the Invention, Including Preferred Embodiments

The present invention relates to bioadhesive compositions for the delivery of active agents with local or systemic action and methods of use thereof. The advantage of these bioadhesive compositions is that they maintain direct or intimate contact with the site of application for a long time, such as at least 1 hour, preferably at least 2 hours, more preferably at least 4 hours, more preferably at least 8 hours, and up to 24 hours. Is in the ability to When other bioadhesives, particularly insoluble bioadhesives such as natural gums, in combination with a solvent comprising a plasticizer for bioadhesives, are used in a solvent containing a plasticizer for the bioadhesives, they are each swelling continuously independently of one another rather than simultaneously as they are applied to the mucosa. That is, it absorbs moisture, thereby increasing and prolonging adhesion to wet surfaces such as mucous membranes and teeth, and is believed to increase effective penetration or absorption and delayed release of the active agent.

Without wishing to be bound by any theory, the inventors believe that a combination of PVP and another bioadhesive agent provides excellent adhesion that cannot be obtained using PVP or other bioadhesives alone. The presence of bioadhesives such as karaya gum has the effect of preferentially absorbing and expanding liquids, such as solvents, plasticizers and saliva, in the absence of which may interfere with the bioadhesion of PVP. Thus, the addition of these other bioadhesives results in faster action and longer adhesion duration.

The composition also provides the active agent in a form and flexible form for conventional topical administration. The compositions of the present invention do not substantially degrade during use and do not cause excessive irritation or side effects that have occurred with other transmucosal compositions of the prior art.

As used herein, the terms "bioadhesives" or "mucoadhesives" are natural, synthetic adhesives, preferably strongly adherent to surfaces such as the skin, teeth, or mucous membranes during wetting or hydration. Or semisynthetic material. In order for a substance to qualify as a bioadhesive it must be able to maintain intimate contact with the wet surface for a minimum amount of time.

The bioadhesive compositions of the present invention are "self-adhesive" and stereotypical in that they can adhere to the site of application without the need to enhance adhesion by using another adhesion agent applied thereon or in the backing.

Bioadhesives are often characterized as having the property of absorbing a certain multiple of their weight in water (ie, water expandability). Depending on the bioadhesive, it can absorb water as low as about 10 times or as high as about 1000 times its weight. An example of a bioadhesive is a natural vegetable gum that absorbs about 30 to about 50 times its weight, depending on the gum selected.

Bioadhesion is often a difficult phenomenon to measure. Bioadhesion strength for the present invention can be measured by standard tests for measuring force (dynes / cm 2) as disclosed in US Pat. No. 4,615,697 (Robinson), with a minimum of 50 dynes / cm 2, more preferably 100-500 dynes / cm 2 or even 1,000 dynes / cm 2.

Bioadhesive materials of the present invention include polymers that are known in the literature as bioadhesives and that are water soluble or insoluble with or without crosslinking agents. Various bio-adhesives may be used in the present invention, examples of which are preferably natural substances such as gum, carmelose, chitosan, carrageenan, yuchuma, fucoidan, hypnia, laminaran, percelanan, agar, Agarose, algin, amylose, scleroglucan, arabinoglactin, galactomannan, starch, alginate (eg, potassium alginate and sodium alginate), pectin, polypeptides (eg, gelatin, collagen, etc.); Substituted and unsubstituted celluloses such as cellulose, ethylcellulose, methylcellulose, nitrocellulose, propylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose and hydroxypropylmethylcellulose, cellulose derivatives, alkylcelluloses and hydroxy Cellulosic materials, including alkylcellulose derivatives, wherein the alkyl group has 1 to 7 carbon atoms, cellulose acetate butyrate, and carboxyalkylcellulose; Synthetic and semisynthetic polymers such as carboxyvinyl copolymers, polyethylene glycols, polyethylene glycol ethers of aliphatic alcohols (such as cetyl, lauryl, oleyl and stearyl), polyhydroxyalkyl methacrylates, propylene glycol alginates, polyethylene oxide, Polyacrylamide and polyacrylic acid; Vinyl polymers such as polyvinyl alcohol, polyvinyl ether, polyvinyl acetate and polyvinylpyrrolidone and hydrophilic and hydrophobic monomers such as hydroxyalkyl esters of acrylic and methacrylamide and N-vinyl-2-pyrrolidone, Copolymerization and / or crosslinking products of alkyl acrylates, alkyl methacrylates, vinyl acetate, acrylonitrile and styrene; And generally any physiologically acceptable polymer that exhibits bioadhesion.

Particularly suitable bioadhesives include natural or synthetic polysaccharides. As used herein, the term "polysaccharide" means a carbohydrate that can be broken down into two or more monosaccharide molecules or derivatives thereof by hydrolysis. Examples of suitable polysaccharides include cellulosic materials as described above, pectin, sulfide sucrose and mixtures of aluminum hydroxide, N-vinyl lactam polysaccharides, most preferably natural gums such as karaya, guar, okra, arabian, acacia , Pectina, gati, tragacanth, xanthan, locust bean, chachose seeds, tamarind, destria, casein.

Some suitable polyacrylic acid polymers include polymers of acrylic acid crosslinked with polyalkenyl ethers (known as common name carbomers) or divinyl glycol (known as common name polycarbophils) under the trade name Carbopol from BF Goodrich, Cincinnati, Ohio. Copolymers or resins available as (Carbopol ^R ), Pemulen ^R polymer emulsifiers and Noveon ^R polycarbophils. Carbopol 934 NF, 934P NF, 940 NF and 971P NF are particularly preferred.

Exemplary polyethylene glycol ethers of aliphatic alcohols include polyoxyethylene (4) lauryl ether, polyoxyethylene (2) oleyl ether and polyoxyethylene (10) oleyl ether, which are ICI Americas Incorporated. (BRIJ ^R ) 30, 93 and 97 and Bridge 35, 52, 56, 58, 72, 76, 78, 92, 96, 700 and 721.

The term "polyvinylpyrrolidone" or "PVP" refers to vinylpyrrolidone (N-vinylpyrrolidone, N-vinyl-2-pyrrolidone and N-vinyl-2-pyrrolidinone as monomer unit). Refers to polymers that are homopolymers or copolymers). PVP polymers include soluble and insoluble homopolymeric PVPs and copolymers such as vinylpyrrolidone / vinyl acetate and vinylpyrrolidone / dimethylamino-ethylmethacrylate. Crosslinked homopolymers are insoluble and are known in the pharmaceutical industry under the common names polyvinylpolypyrrolidone, crospovidone and PVP. Copolymer vinylpyrrolidone-vinyl acetate is known in the pharmaceutical art by the common name copolyvidone, copolyvidone or VP-VAc.

The term "soluble" when used in connection with PVP means that the polymer is water soluble, generally not substantially crosslinked, and having a molecular weight of less than about 2,000,000. See, in general, Buhler, KOLLIDON ^R : POLYVYNYLPYRROLIDONE FOR THE PHARMACEUTICAL INDUSTRY, BASF Aktiengesellscaft (1992). Soluble PVP polymers are referred to by various names in the pharmaceutical industry, the most commonly used names being povidone, polyvidone, polyvidonum, poly (N-vinyl-2-pyrrolidinone), poly (N-vinylbutyrolactam) , Poly (1-vinyl-2-pyrrolidone), poly [1- (2-oxo-1-pyrrolidinyl) ethylene].

As used herein, the term "mucous membrane or mucosa" refers to the surface of oral, buccal, vaginal, rectal, nasal, small intestine and eye.

As used herein, the term "oral" or "oral" refers to the mouth and surrounding esophagus regions, including gums, teeth, palate, tongue, tonsils, and periodontal tissue.

As used herein, "adhesive" means a natural or synthetic material that can be attached to a topical application or administration site.

As used herein, "topical" is used in its ordinary sense to mean direct contact with a site of a mammal, which will be an anatomical site or surface including skin, mucous membranes or hard tissues such as bone, teeth or nails. Can be.

The term "administration" means applying in any formulation to a tissue where the composition is in physical contact with an anatomical site or surface.

The term "subject" is intended to include all warm blooded mammals, preferably humans.

As used herein, "long time" means a time of 30 minutes or more. The composition of the present invention may be used for oral mucosa for up to 24 hours, preferably for about 30 minutes to about 24 hours, more preferably for about 1 hour to about 16 hours, most preferably for about 1 hour to about 12 hours. It can maintain contact with the same mucosa.

As used herein, the term "flow rate" is defined as the amount of absorption of the active agent through the skin or mucous membrane, which can be represented by Fick's first law of diffusion.

In the above formula, J is the flow rate in g / cm 2 / sec, D is the diffusion coefficient of the drug through the skin or mucosa in cm 2 / sec and dC _m / dx is the active agent through the skin or mucosa. Concentration gradient.

"Flexible, orthopedic form" means a solid form that can conform to the surface to be contacted, which is applied topically without causing significant degradation by moisture contact without causing any harmful physiological reactions when administered to the subject. The contact can be maintained in the form of an easy solid.

An important feature of embodiments of the present invention relates to compositions that are substantially water-free and are insoluble in water. The term “substantially free of moisture” means that the composition contains less than about 10%, preferably less than 5%, most preferably less than 3% by weight of moisture prior to topical application. In general, it is desirable to completely exclude the addition of water and to eliminate as much of the water as possible the other components of the composition. The term "substantially insoluble" means that the composition remains in "formal" form and generally does not dissociate from the site of application under normal conditions for an intended use time of at least 3 hours. An advantage of the substantially water-insoluble, water-insoluble nature of the compositions of the present invention is that the active agent can be obtained in high concentrations. Another advantage of such compositions is to minimize the settling of the active agent, which affects the processing of the composition and affects the rate of delivery of the active agent, which in some cases affects the susceptibility of the subject to the active agent. Will be able to have.

In one embodiment of the invention, the composition is the use of two active agents which may be the same or different from one another. For example, one active agent may be in base form and the other active agent may be in the form of an acid or salt. In addition, one active agent that is delivered rapidly at a relatively high flow rate may be present with a second active agent that is delivered over a long time and has a slow flow rate.

In particular, the compositions of the present invention may be administered simultaneously with two or more active agents. For example, the first active agent may be present in the composition to be fully or nearly delivered for about 1 to about 90 minutes, particularly after about 5 to about 60 minutes. At the same time, another active agent may be present in the composition such that this second agent is delivered for a long time, for example up to about 24 hours, in particular about 5 minutes to about 16 hours. In other words, in one embodiment of the present invention, the first agent has a faster total flow rate than the second agent such that the first agent is first consumed from the bioadhesive composition.

The time to deliver the active agent can vary depending on a number of factors, ie, depending on the state of administration, the active agent to be delivered, and the like. For example, in the case of the present invention, it includes a local anesthetic that is delivered rapidly within 20 minutes, and is the same or different from this first anesthetic, and optionally acts on the whole body for a long time, for example 8 hours. Or even a second anesthetic that can be delivered for a period of up to 24 hours. This arrangement is suitable for multiple administrations, such as in dental care.

On the other hand, two or more active agents may be topically administered in order to obtain a long-term therapeutic effect or multiple therapeutic effects. For example, a nonsteroidal anti-inflammatory agent can be administered topically with an anesthetic so that the bioadhesive composition can provide a pain reducing effect by both the analgesic and anesthetic efficacy of the active agent. The intended efficacy of a combination of these agents or multiple combinations of agents can last up to 24 hours or multiple periods within 24 hours for many active agents.

The rate of delivery of the active agent can be controlled by the concentration and / or solubility of the active agent in the bioadhesive composition, the pH of the composition, the thickness of the composition or the size of the system as the final dosage form or the permeability or solubility of the entire composition.

As used herein, "active agent" (and its equivalents, "formulation", "living agent", "drug", "drug" and "medicament") should be construed in a broad sense and all therapeutic, prophylactic, By one or more of the pharmacologically or physiologically active substances or mixtures thereof, it is meant to be delivered to a mammal to produce the usual desired useful efficacy.

In particular, any active agent capable of exhibiting a local or systemic pharmacological response, regardless of treatment, diagnosis or prevention, is considered to be included in the present invention. It is noted that the active agent or drug may be used alone or as a mixture of two or more agents or drugs in a sufficient amount in preventing, curing, diagnosing, alleviating or treating the disease or condition in question. For example:

1. α-adrenergic agonists such as adrafinil, adrenolone, amideprine, apraclonidine, budrazine, clonidine, cyclopentamine, dentomidine, dimethoprine, dipypirine, ephedrine , Epinephrine, phenoxazoline, guanabenz, guanfacin, hydroxyamphetamine, ibopamine, indanazoline, isomeptene, mefentermin, metaramiminol, methoxamine hydrochloride, methylhexanamine, metizolene, middorin, Napazoline, norepinephrine, norphenephrine, octodrine, octopamine, oxymethazolin, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, phenylpropylmethylamine, polledrin, propylhexerine, pseudoephedrine, rylmenidine, Shin ephedrine, tetrahydrozoline, thiamenidine, tramazoline, tuaminoheptane, thymazoline, tyramine and xylometazoline,

2. β-adrenergic agonists such as albuterol, bambuterol, bitolterol, carbuterol, clenbuterol, chlorprenerin, denofamin, dioxetedrin, dopexamine, ephedrine, epinephrine, etaphedrine, Ethyl norepinephrine, phenoterol, formoterol, hexoprelinin, ibopamine, isotarin, isoproterenal, mabuterol, metaproterenol, methoxyphenamine, oxyphedrine, pirbuterol, prenal Terrols, procaterols, protochillols, reproterols, limiterols, lithodrins, soterenol, terbuterol and xsamoterol,

3. α-adrenergic blockers such as amosulalol, arotinolol, dapiprazole, doxazosin, ergoloid mesylate, phenpyrid, indoramine, labetalol, nisergoline, prazosin, terrazosin, Tolazoline, triazocin and yohimbine,

4. β-adrenergic blockers such as acebutolol, alprenolol, amosulolol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, befetolol, Bufuralol, bunitrolol, bupranolol, butidrin hydrochloride, butopyrrolol, carazolol, cateolol, carvedilol, selifrolol, cetamolol, chloranol, dilevalol, epanolol, esmolol, indenolol , Labetalol, levobunol, mepindolol, methipranalol, metoprolol, morphrolol, nadoxolol, nifenalol, nipradilol, oxprenolol, fenbutolol, pindolol, fructolol, pronetol, propranolol, Sotalol, sulfinol, thalolinol, tertatolol, timolol, toliprolol and xybenol,

5. alcohol inhibitors, such as calcium cyanamide citrate, disulfiram, nadide and nitrazoles,

6. aldose reductase inhibitors such as epalestat, ponalestat, sorbviny and tolestat,

7. Non-mobilizing agents such as androisoxazole, androstenediol, bolandiols, bolosterone, clostebol, ethylestrenol, formyldienolone, 4-hydroxy-19-nortestosterone, methanedriol, methe Nolon, Methyltrienolone, Nandrolone, Nandrolone Decanoate, Nandrolone, p-hexyloxyphenylpropionate, Nandrolone phenpropionate, Norbolone, Oxymesterone, Pizotyrin, Quinbolone, Sten Volon and Trenbolone,

8. analgesics (dental) such as chlorobutanol, clover and eugenol,

9. Analgesics (for anesthesia), such as alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzitramide, buprenolpine, butopanol, clonitogen, codeine, codeine methyl bromide, codeine phosphate , Codeine sulfate, desomomolpine, dextromemolamide, dezosin, diopromide, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, dimenoxadol, dimeptanol, dimethylthiambutene, dioxa Petroleum butyrate, dipipanone, epthazosin, etoheptazine, ethylmethylthiambutene, ethylmorphine, etonitogen, fentanyl, hydrocodone, hydrocodone bitartrate, hydromolphone, hydroxypettidine, isometadon, Ketobemidone, revolfanol, lofentanil, meperidine, meptazinol, metazosin, methadone hydrochloride, metophon, morphine, morphine derivatives, myropin, nalbuphine, narcein, nicomorphine, norrebolpanol, normethadon, furnace Morphine, norpipanone, opium, oxycodone, oxymolphone, papaveretum, pentazosin, phenadoxin, phenazosine, pheoferidine, pyminodine, pyritramide, proheptazine, promethol, properidine, Propyram, propoxyphene, sufentanil and tilidine,

10. Analgesics (non-anesthetic) such as acetaminophen, acetaminosalol, acetanilide, acetylsalicylic salicylic acid, alclofenac, alminopropene, alkoxyprin, aluminum bis (acetylsalicylate), aminochlor Tenoxazine, 2-amino-4-picolin, aminopropylone, aminopyrine, ammonium salicylate, antipyrine, antipyrine salicylate, anthracenine, apazone, aspirin, bennolate, benoxapropene, benzpiperidone, benzidamine , p-bromoacetanilide, 5-bromosalicylic acid acetate, busetine, bufesa film, butadizone, butacetin, calcium acetylsalicylate, carbamazepine, carbetidine, carbiphene, carsalam, chloral antipyrine , Chlortenosine, choline salicylate, cincopene, siramadol, clomethasine, cropropamide, crotetamide, dexosadrol, dipenamizole, diflunisal, dihydroxyaluminum acetylsalicylate Acid salts, dipyrrocetyl, dipyrone, emofazone, enphenamic acid, pyrisol, ether salate, ethenamide, ethoxazene, etodolak, felbinac, fenofene, flocfenin, flufenamic acid, fluores Hand, flupyrutin, fluproquazone, flurbiprofen, phosphosal, gentisic acid, glafenin, ibufenac, imidazole salicylate, indomethacin, indopropene, isopezolac, isoladol, Isonicsine, ketoprofen, ketorolac, p-lactophenetide, repetamine, loxopropene, lysine acetylsalicylate, acetylsalicylic acid magnesium, methotrimreprazine, metopoline, miraprofen, Morazone, mor Pauline salicylate, naproxen, nepofam, nifenazone, 5'-nitro-2'-propoxyacetanilide, parsalmide, peroxalic acid, phenacetin, phenazopyridine hydrochloride, phenocol, fenofirazone, phenyl acetyl Salicylate, Phenyl Salicylate, Phenylamidol, Pipebuzone, Piperylone, Phosphate Rhodolidine, propacetamol, propapezone, proxazole, quinine salicylate, ramipenazone, limazolium methylsulfate, salacetamide, salicycin, salicylate, salicylate O-acetic acid, salicylic acid, Salsalte, Salverine, Cimetride, Sodium Salicylate, Salamipyrin, Suprofen, Talniflumate, Tenoxycam, Terofenamate, Tetradrin, Tinoridine, Tolenic Acid, Tolpronin, Tramadol, Biminol , Xenbucin and jomepirak,

11. Androgens such as androsterone, boldenone, dehydroepiandrosterone, fluoxymesterone, mestanolone, mesterolone, methanedrostenolone, 17-methyltestosterone, 17α-methyltestosterone, 3-cyclopentyl enol Ethers, noethandrolone, normethaneron, oxandrolone, oxymesterone, oxymetholone, prasterone, stanrolone, stanozolone, testosterone, testosterone 17-chloral hemiacetal, testosterone 17β-sipionate, Testosterone enanthate, testosterone nicotinate, testosterone phenylacetate, testosterone propionate and thiomesterone,

12. Anesthetics such as acetamidoeugenol, alphadolone acetate, alphazalon, amucaine, amolanone, amylocaine hydrochloride, benoxysinate, benzocaine, vetoxycaine, bifenamine, bupivacaine, butycaine , Butaben, butanilicaine, butetamine, butalital sodium, butoxycaine, carticine, 2-chloroprocaine hydrochloride, cocaethylene, cocaine, cyclomethylcaine, dibucaine hydrochloride, dimethoquine, dimethokine , Diferadon hydrochloride, diclonin, exonidine, exonin, ethyl aminobenzoate, ethyl chloride, ethidocaine, ethoxadrol, β-yucaine, euprocin, phenalcomine, formocine, hexobarbital , Hexylcaine hydrochloride, hydroxydione sodium, hydroxyprocaine, hydroxytetracaine, isobutyl p-aminobenzoate, kentamine, rheinokine mesylate, levocadrol, lidocaine, mepivacaine, meprylcaine Hydrochloride, Metabutok Cicaine hydrochloride, methohexyl sodium, methyl chloride, midazolam, mytecaine, naepine, octacaine, orthocaine, oxetazaine, paretoxycaine, phenacaine hydrochloride, phencycline, phenol, pipepe Rocaine, pyridocaine, polydocanol, pramoxin, prilocaine, procaine, propanidated, propanocaine, propparacaine, propofcaine, propofol, propoxycaine hydrochloride, pseudococaine, pyrocaine, quinine Urea hydrochloride, lysocaine, salicylic alcohol, tetracaine hydrochloride, thialbarbital, thymical, thiobutabarbital, thiopental sodium, tolycaine, trimecaine and zolamine,

13. Appetite depressants such as aminorex, amphetchloral, amphetamine, benzapetamine, chlorpentermine, clobenzorex, cloforex, chlortermine, cyclexedrine, destroamphetamine sulfate, diethylpropion, Difemethoxydine, N-ethylamphetamine, phenbutrazate, fenfluramine, phenproforex, furfurylmethylamphetamine, levopacetoferrate, marginol, mefenorex, methamfeproamon, methamphetamine, norshdoephedrine, pendi Metrazine, pendimethazine stannate, phenmetrazine, phenpentermine, phenylpropanolamine hydrochloride and picilorex,

14. Insect repellents (tapeworms) such as arecoline, aspirin, aspirinol, dichlorophene, embelin, cosine, naphthalene, niclosamide, pelerthierin, pelerthierin tannins and quiniclean,

15. Insect repellents (nematodes), such as allantolactone, amoscanate, ascarydol, bephenyupe, bitoscanate, carbon tetrachloride, carbacrolol, cyclobendazole, diethylcarbazine, diphenan, dithiazanine iodine Cargo, Dimantin, Gentian Violet, 4-hexylesorcinol, Caric acid, Mebendazole, 2-naphthol, Oxanthel, Papain, Piperazine, Piperazine Adipate, Piperazine Citrate, Piperazine Edetate Calcium, Piperazine Tartrate, Pyrantel, Pirvinium Pamoate, α-Santhinine, Stilbadium Iodide, Tetrachloroethylene, Tetramisol, Tiabendazole, Timol, Timyl N-isoamylcarbamate, Triclophenol Piperazine and urea stevamine,

16. Insect repellents (worms), such as ivermectin and suramin sodium,

17. Insect repellents (sclerosis) such as amoscanates, amphotides, potassium antimony tartrate, sodium antimonate gluconate, sodium antimony stannate, sodium antimony thioglycolate, antimony thioglycolide, becantone, hycanton, lucanton Hydrochloride, niridazole, oxamniquine, praziquantel, stibocaptate, stibophene and urea stibamin,

18. Insect repellents (absorbent steels) such as antiolimine and tetrachloroethylene,

19. Anti-acne medications such as adafelene, alzestone, acetophenide, azelaic acid, benzoyl peroxide, cithol, cyproterone, motretinide, resorcinol, retinolic acid, tetraquinone and tretinonin,

20. Anti-allergic agents such as Amlexanox, Astemizol, Azelastine, Chromoline, Fenpifran, Histamine, Ibudillast, Nedochromil, Oxatomide, Pentizide, Honeysuckle Extract, Poison lacquer Extracts, poison vein extracts, repirinast, tranilast, trasanox and urushiol,

21. Anti-Amoebases such as Arstinol, Bialamicol, Carvarson, Sephalin, Chlorbetamid, Chloroquinone, Chlorfenoxamide, Chlortetracycline, Dehydroemtin, Dibromopropamidine, Dirox Sanide, Depetarson, Emethin, Fumagiline, Glucacarbin, Glycoviasol, 8-hydroxy-7-iodo-5-quinolinesulfonic acid, Iodochlorhydroxyquine, Iodoquinol, Paromo Mycin, Panquinone, Pearson Sulfoxylate, Polybenzasol, Propamidine, Quinpamide, Senzodazole, Sulfaside, Tecclozan, Tetracycline, Thiocarbamizin, Thiocarbason and Tinida Sol,

22. anti-androgens such as bifluranol, xitol, cyproterone, delmadinone acetate, flutimid, nirutamide and oxendolone,

23. Anti-anginases such as acebutolol, alprenolol, amiodarone, amlodipine, arotinolol, atenolol, bepridil, bevantolol, bucumolol, bufetolol, bufuralol, bunitrolol, bufranolol, caro Solol, Carteolol, Carvedilol, Celifrolol, Cinefazette Maleate, Diltiazem, Epanolol, Ferodipine, Gallopamil, Imolamin, Indenolol, Isosorbide, Dinirate, Isradipine , Limaprost, mepindolol, metoprolol, molecidomin, nadolol, nicardipine, nifedipine, nifenalol, nilvadipine, nipradilol, nisoldipine, nitroglycerin, oxprenolol, oxyphedrine, ozagrel, fenbu Tolol, pentaerythritol tetranitrate, pindolol, pronetrol, propanolol, sotalol, terodilin, timolol, toliprolol and verapamil,

24. Antiarrhythmic agents such as acebutol, acecaine, adenosine, azmalin, alprenolol, amiodarone, amoproxane, apridine, arotinol, atenolol, bevantolol, bretilium tosylate, brimomolol, Bufetolol, bunaftin, bunitrolol, bupranolol, butidrin hydrochloride, butobendine, capovenic acid, carazolol, carteolol, siphenin, chloranol, disopyramid, encainide, esmolol, flecainide , Galopamil, hydroquinidine, incainide, indenolol, ipratropium bromide, lidocaine, lorazmine, lorcanide, meobentin, methifranolol, mexlectin, moriciginol, nadosolol, nifenalol, oxprene Norolol, fenbutolol, pindolol, pyrmenol, fructolol, prasmaline, procaineamide hydrochloride, pronetallol, propaphenone, propranolol, pyrinoline, quinidine sulfate, quinidine, sotalol, thalolinol, thymol Roll, tokai De, verapamil, and non kwidil silbe nolrol,

25. anti-arteriosclerosis such as pyridinol carbamate,

26. Antiarthritis / Antirheumatic agents such as allocupride sodium, oranopine, orothioglucose, orothioglycanide, azathioprine, 3-orthio-2-propanol-1-sulfonic acid calcium, celecoxib , Chloroquine, clobutzart, cuproxolin, diacerane, glucosamine, sodium thiomomaleate, sodium sodium thiosulfate, hydroxychloroquine, kebuzon, robbenzit, melittin, methotrexate, myoral and penicylamine,

27. Antibacterial (antibiotic) drugs, for example:

Aminoglycosides such as amikacin, apramycin, arbecasin, bambermycin, butyrosine, dibecacin, dihydrostreptomycin, fortymycin, gentamycin, ispamycin, kanamycin, micronomycin, Neomycin, neomycin undecylenate, netylmycin, paromomycin, ribostamycin, sisomycin, spectinomycin, streptomycin, streptonicozid and tobramycin;

Amphenicols such as azidamphenicol, chloramphenicol, chloramphenicol palmitate, chloramphenicol, pantothenate, florfenicol and thiamphenicol;

Ansamycins such as rifamide, rifampin, rifamycin and rifassimine;

β-lactams, for example:

Carbapenems such as imipenem;

Cephalosporins such as cephasterol, cephadroxyl, cephamandol, cephatrizine, cephazedone, cefazoline, cepisim, cefemenoxime, cedizime, cenisidide, cepharazone, celanide, cephataxime, cell Thiam, cefepimisol, cefepyrimid, cefpodoxim, proxetyl, ceproxadine, ceftsolodine, certazidim, cefteram, ceftezol, ceftibuten, ceftizone, ceftriazone, cepuroxime, Cefuzonam, cephacetyl sodium, ceparexin, cephaloglycine, cephaloridine, cephalosporin, cephalotin, cefapirine sodium, cepradine and fibcepalectin;

Cephamycins such as cefebuferazone, cefemethazole, cefminox, cefetan and sepoxitin;

Monobactams such as aztreonam, carumone and tizemonam;

Oxasefem such as flomoxef and molaractam;

Penicillins such as amidinocillin, amdinocillin, coatings, amocillin, ampicillin, apalcillin, aspoxylin, azidosilane, azoxysilane, bacampicillin, benzylpenicillin, benzylpenicillin sodium, carbenicillin , Carpecillin Sodium, Carindacillin, Clometocillin, Cloxacillin, Cyclocillin, Dicloxacillin, Diphenicillin Sodium, Epicillin, Penbenicillin, Fluoxycillin, Hetacillin, Renampicillin, Methampi Ccillin, Methicillin Sodium, Mezoxylin, Naphcillin Sodium, Oxacillin, Penamecillin, Penetamate Hydroiodide, Penicillin G Benetamine, Penicillin G Benzatin, Penicillin G Benzhydrylamine, Penicillin G Calcium, Penicillin G Hydrabamine, Penicillin G Potassium, Penicillin G Procaine, Penicillin N, Penicillin O, Penicillin V, Penicillin V Benzatin, Penicillin V Hydrabamin, Penimepicyclin, Penethicillin Potassium, Pi La syringe, blood bapi syringe, syringe cylinder propynyl, quinazolinyl cylinder, sulfonic Benny syringe, deionized rampi syringe, syringe and Temo tea carboxamide;

Lincosamide, such as clindamycin and lincomycin;

Marcolides such as azithromycin, carbomycin, clarithromycin, erythromycin, erythromycin acystrate, erythromycin estoleate, erythromycin glucoheptonate, erythromycin lactobionate, erythromycin propionate, erythromycin propionate Mycin stearate, probemycin, leucomycin, midecamycin, myokamycin, oleandomycin, primycin, locitamycin, rosaramycin, roxytromycin, spiramycin and troleandomycin;

Polypeptides such as ampomycin, baccitracin, capreomycin, colistin, enduracidine, enbiomycin, fusafungin, gramicidine, gramicidine S, mikamycin, polymycin, polymycin B-methanesulfonic acid , Pristinemycin, ristocetin, teicoplanin, thiostrepton, tuberactinomycin, tyrosidine, tyrotrycin, vancomycin, biomycin, biomycin pantothenate, virginiamycin and zinc boxy Tracine;

Tetracyclines such as apicycline, chlortetracycline, clomocycline, demeclocycline, doxycycline, guamecycline, limecycline, meclocycline, metacycline, minocycline, oxytetracycline, phenmepicycline, pipepaline, lolitetra Cyclin, acidic cyclin, cenocycline and tetracycline; And

Other antibiotics such as cycloserine, mupirosine and tuberrine,

28. Antibacterial drugs (synthetic), for example:

2,4-diaminopyrimidines, such as brodimoprim, tetraxoprim and trimetaprim;

Nitrofurans such as furaltadon, furazolium, nifuraden, nifuratel, nipuroline, nifurpynol, nipurrazine, niprotoinol and nitrofrantoin;

Quinolones and analogs such as amifloxacin, synoxacin, ciprofloxacin, difloxacin, enoxacin, plexaxacin, flumequine, lomefloxacin, miloxacin, nalididisin, norfloxacin, offoxacin, oxolinic acid, Pefloxacin, pipemidic acid, pyromidic acid, roxosacin, temefloxacin and tosulfloxacin;

Sulfonamides such as acetyl sulfamethoxypyrazine, acetyl sulfisoxazole, azosulfamide, benzylsulfamide, chloramine-B, chloramine-T, dichloramine T, formosulfatiazole, N ² formyl sulfisomidine , N ² -β-D-glucosylsulfanamide, mafenide, 4 '-(methylsulfamoyl) sulfanylanilide, p-nitrosulfatazole, noprisulsulamide, phthalylsulfacetamide, phthalylsul Patazole, salazol sulfadimidine, succinyl sulfatiazole, sulfabenzamide, sulfacetamide, sulfachlorpyridazine, sulfacrysodine, sulfacithin, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfadoxin , Sulfaetidol, sulfaguanidine, sulfaguanol, sulfalene, sulfaloxinic acid, sulfamerazine, sulfamet, sulfamethazine, sulfamethazole, sulfamethidine, sulfamethoxazole, sulfamethoxypyridazine, sulfa Metrol, sulfamidocholidine, sulfamoxol, sulfanilamide, sulfanil Midomimethanesulfonic acid triethanolamine salt, 4-sulfanylamidosalicylic acid, N ⁴ -sulfanylylsulfanylamide, sulfanyl urea, N-sulfanylyl-3,4-xylamide, sulfanitran, sulfaferrin, sulfape Nazol, sulfaproxiline, sulfapyrazine, sulfapyridine, sulfasomizol, sulfasimazine, sulfatiazole, sulfatiurea, sulfatolamide, sulfisomidine and sulfisoxazole,

Sulfones such as acedasone, acediasulfone, acetosulfone sodium, dapsone, diathymosulfone, glucosulfone sodium, solarsulfone, succinicone, sulfanilic acid, p-sulfanylbenzylamine, p, p'-sulfonyldianiline -N, N'-digalactoside, sulfoxone sodium and thiazolesulfone; And

Others such as clopotol, hexane, metheneamine, metheneamine anhydromethylene-citrate, methenamin hypofurate, methenamin mandelate, methenamin sulfosalicylate, nitroxolin and xyvonol,

29. Anticholinergic agents such as adiphenin hydrochloride, alberin, ambutonium bromide, aminopentamide, amidetrine, amprotropin phosphate, anisotropin methyl bromide, apoatropine, atropine, atropine N- Oxides, benathizin, benapyrizine, benzimide, benzyllium bromide, benztropin mesylate, bebonium methyl sulfate, biferidene, butopium bromide, N-butylscopol ammonium bromide, Buzefeed, Camilopine, Caramifen Hydrochloride, Chlorbenxamine, Chlorfenoxamine, Cimetropium Bromide, Clidinium Bromide, Cyclodrin, Cyclonium Iodide, Scirimin Hydrochloride, Deptropin, Dexetimide, Dibutolin Sulfate, Dicyclomine Hydrochloride, Dietazine, Difemerine, Dihexiberine, Difemanyl Methyl Sulfate, N- (1,2-diphenylethyl) nicotinamide, Dipiproberin, Diponium Bromide, Emepronium Bromination Endobenziline bromide, etopropazine, etibenztropin, ethylbenzhydramine, ethomidoline, eucartropin, fenfibernium bromide, fentonium bromide, plutopium bromide, glycopyrrolate, rete Rhonium bromide, hexocyclium methyl sulphate, homatropin, hydroxysamine, ifpratropium bromide, isopropamide, levomethate, mecloxamine, mefenzolate bromide, metcarfen , Methanetellin bromide, meticene, metscopolamine bromide, octamilamine, oxybutynin chloride, oxyphencycline, oxyphenonium bromide, pentapiperidide, pentiate bromide, pencarba Mead, penglutarimid, pipefenzolate bromide, piperidolate, piperilate, polydine methylsulfate, pridinol, pripinium bromide, procyclidine, propanetelin bromide, propenzolay , Propyromazine, scopolamine, scopolamine N-oxide, styronium iodide, stramonium, sulphophonium, thihexinol, thifenamyl, thimonium iodide, thimepidium bromide, tiqui Zium bromide, tridihexetyl iodide, trihexhenidyl hydrochloride, trofacin, tropenzyl, trocarmide, tropium chloride, valetamate bromide and xenitropium bromide,

30. Anticonvulsants, such as acetylpheneturide, albutoin, alkoxydone, aminoglutetimides, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, brimate, calcium bromide, carba Mazepine, Cyramide, Clomethiazole, Clonazepam, Decimemide, Dietadione, Dimethadione, Doxenitoin, Ethererobarb, Ethadione, Etosuccimid, Etotoin, Fluoresone, Garbapentin, 5-hydroxytryptophan, lamotrigine, ramotyl, magnesium bromide, magnesium sulfate, mephenytoin, mepobarbital, metharbital, metetoin, metsuccimid, 5-methyl-5- (3- Phenanthryl) hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nimezezepam, nitrazepam, paramethadione, phenacemide, penetharbital, peneturide, phenobarbital, phenobarbital sodium, pensucci Mead, phenylmethylbarbituric acid, phenytoin, fetenylate na Thromium, potassium bromide, pregabatin, primidone, progabide, sodium bromide, sodium valproate, solanium, strontium bromide, suclofenide, sultiam, tetratoin, tiagabine, trimetadione, val Proic acid, valpromide, vigabatrin and zonamide,

31. Antidepressants, for example:

Bicyclics such as vinedalin, caroxazone, citalopram, dimethazane, indalpin, phencamine, fluvoxamine, maleate, indeloxazine hydrochloride, nepofam, nomifensin, oxittriptan, oxyfertin , Paroxetine, sertraline, thiazesim, trazodone, venrapasin and zometapine;

Hydrazide / hydrazines such as benmoxin, iproclozide, ifroniazide, isocarboxazide, nialamide, octamoxine and phenelzin;

Pyrrolidones such as cotinine, rolycirine and rolyphram;

Tetracyclics such as maprotiline, methalindol, myanserine and oxyprotiline;

Tricyclics such as adinazolam, amitriptyline, amitriptyline oxide, amoxapine, butliptilin, clomipramine, demexiftiline, decipramine, dibenzepine, dimethacrine, dothier Pin, doxepin, fluasizin, imipramine, imipramine N-oxide, ifrindol, lofepramine, melitracene, metapramine, nortriptyline, oxiftiline, opipramol, pizotiline , Propizepine, protriptiline, quinupuramin, tianeptin and trimipramine;

Others, such as adrafinyl, benactin, bupropion, butacetin, deanol, deanol aceglumate, deanol acetamidobenzoate, dioxadol, etoferidone, febarbamate, femosetrin, fenpentadiol , Fluoxetine, fluvoxamine, hematoporphyrin, hypercinin, levopacetoferan, medipoxamine, minafrine, moklobemide, oxaflozan, fiberalline, prolinetan, pyrisuccideanol, chloride Rubidium, sulfides, sulfofrides, tenniloxazine, tozalinone, tofenacin, toloxatone, tranilcipromine, L-tryptophan, biloxazine and gimeldine,

32. Antidiabetics, for example:

Biguanides such as buformin, metformin and phenformin;

Hormones such as glucagon, insulin, insulin injections, insulin zinc suspension, isophan insulin suspension, protamine zinc insulin suspension and zinc insulin crystals;

Sulfonylurea derivatives such as acetohexamide, 1-butyl-3-methanylylurea, carbutamide, chlorpropamide, glybornuride, glyclazide, glyphide, glyquidone, glyoxepide, gly Burid, glybutthiazole, glybuzol, glyhexamide, glymidine, glyfinamide, fenbutamide, tolazamide, tolbutamide and tolcyclamide; And

Others such as acarbose, calcium mesosalate and miglitol,

33. anticorrosive agents such as acetyltannic acid, albumin tannin, alcopanone, aluminum salicylate-basic, catechin, diphenoxine, diphenoxylate, lidamidine, loperamide, mebiquine, trilium and uzalin,

34. Antidiuretics, such as desmopressin, pellipsin, ripressin, ornipressin, oxycincopene, pituitary-lobe, terlippressin and vasopressin,

35. Antiestrogens such as delmadinone acetate, etamoxilipitol, tamoxifen and toremifene, (translation 2)

36. Antifungal drugs (antibiotics), for example:

Polyenes such as amphotericin-B, candicidine, dermostatin, philippines, fungichromin, hockeymycin, hammycin, rhesensomycin, mepartricin, natamycin, nystatin, pecilosin and permycin ; And

Others such as azaserine, griseofulvin, oligomycin, neomycin undecylenate, pyrrolinitrine, saccanine, tubercidine and viridine,

37. Antifungal drugs (synthetic), for example:

Allylamines such as naphthypine and terbinafine;

Imidazoles such as biponazole, buttoconazole, chlordantoin, chlormidazole, cloconazole, clotrimazole, echonazole, enylconazole, penticonazole, isoconazole, ketoconazole, myconazole, omoconazole , Oxyconazole, nitrate, sulfonazole and thioconazole;

Triazoles such as fluconazole, itraconazole and terconazole; And

Others, Acrysorcin, Amololpin, Bifenamine, Bromosalicylchloranilide, Bucloamide, Calcium Propionate, Clofenesin, Cyclopyrox, Cloxiquine, Coparaffinate, Diamtazole, Dihydrochloride, Ex Salamide, flucitosine, haletazole, hexetidine, loflucarban, nifuratel, potassium iodide, propionic acid, pyrithione, salicylicanilide, sodium propionate, sulfentin, tenonitazole, tolclate, tolindate, Tolnaftate, tricetin, iothione, undecylenic acid and zinc propionate,

38. Antiglaucoma drugs such as acetazolamide, befunolol, betaxolol, bufranolol, carteol, dapiprazok, dichlorophenamide, difibrin, epinephrine, levobunol, metazolamide, metifranolol , Pilocarpine, pindolol and timolol,

39. Antiproliferative stimulating hormones such as danazol, guestlinone and paroxypropion,

40. antigout drugs such as allopurinol, caprophene, colchicine, probenside and sulfinpyrazone,

41. Antihistamines, for example:

Alkylamine derivatives such as acribastine, bamipine, brofeniramine, chloropheniramine, dimethindene, metrone S, phenyramine, pyrobutamine, tenaldine, tolpropamine and triprolidine;

Aminoalkyl ethers such as bietaunatin, bromodiphenhydramine, carbinoxamine, clemastine, diphenylpyraline, doxylamine, embramine, medrylamine, mefenpyramine, p-methyldiphenhydra Min, orfenadrin, phenyltoloxamine, fibrinhydrinate and cetasin;

Ethylenediamine Derivatives such as alloclamide, p-bromtripreneamine, chloropyramine, chlorotene, histapyrrodine, metafurylene, metaphenylene, metapyylene, phenbenzamine, pyrylamine, thalastine, tenyl Diamines, tonnageamine hydrochlorides, tripelenamines and zolamines;

Piperazines such as cetirizine, chlorocycline, cinnarizine, closinigine and hydroxyazine;

Ternary compounds, for example:

Phenothiazines such as ahistan, ethimethazine, penetazine, N-hydroxyethylpromethazine chloride, isopromethazine, mequitazine, promethazine, pyratazine and thiazinemium methyl sulfate; And

Others such as azatadine, chlorobenzepam, ciproheptadine, deptropin, isotifendil, loratadine and protifendil; And

Other antihistamines such as antazoline, astemizol, azelastine, cetoxim, clemizol, clobenztropin, dipenazoline, diphenhydramine, fluticasone propionate, 멥 hydrin, penindamin, terpenadine And tritoqualine,

42. Antilipoproteinemia, for example:

Aryloxyalkanoic acid derivatives such as beclobrate, bazafibrate, binifibrate, cipropibrate, clinfibrate, clofibrate, clofibric acid, ethfibrate, fenofibrate, gemfibrozil, nicofibrate, Pyrifibrate, ronifibrate, simfibrate, and theofibrate;

Bile acid sequestrants such as cholestyramine resin, cholestipol and polydexide;

HMG CoA reductase inhibitors such as fluvastatin, lovastatin, pravastatin sodium and simvastatin;

Nicotinic acid derivatives, aluminum nicotinate, acipimox, niceritrol, nicoclonate, nicomol and oxynias acid;

Thyroid hormones and analogs such as thyroxate, tyroprop acid and thyroxine; And

Others such as acifran, azacosterol, benfluorex, β-benzalbutylamide, carnitine, chondroitin sulfate, clomestone, detaxtran, dextran sulfate sodium, 5,8,11,14,17- Icosapentaenoic acid, erytadenin, furazball, meglutol, melinamide, mitriatriendiol, ornithine, γ-orizanol, panthetin, pantaerythritol tetraacetate, α-phenylbutyamide, pyrazydil , Probucol, α-sitosterol, sulfosyl acid, piperazine salt, thiadenol, tripanol and xenbucin,

43. Antihypertensive drugs, for example:

Arylethanolamine derivatives such as amosulalol, bufuralol, dilevalol, labetaol, pronetol, sotalol and sulfinol;

Aryloxypropanolamine derivatives such as acebutolol, alprenolol, arotinolol, athenol, betaxolol, bevantolol, bisoprool, bopindolol, bunitrolol, bufranolol, buttopilolol, carazolol, Cartetolol, Carvedilol, Celifolol, Cetamolol, Epanolol, Indenolol, Mepindolol, Methipranol, Metoprool, Moproolol, Nadolol, Nipradilol, Oxpreolol, Penbutolol, Pindolol , Propanolol, thalinol, tetraolol, timolol and toliprolol;

Benzothiadiazine derivatives such as althiazide, bendropulumethiazide, benzthiazide, benzylhydrochlorothiazide, butiazide, chlorothiazide, chlorothalidone, cyclopentthiazide, cyclothiazide, dia Zoxide, Epithiazide, Ethiazide, Penquizone, Hydrochlorothiazide, Hydroflumetiazide, Methiclothiazide, Methichran, Metolazone, Parafluzide, Polythiazide, Tetrachloromethazide And trichloromethiazide;

N-carboxyalkyl (peptide / lactam) derivatives such as alacepril, captopril, silazapril, delapril, enalapril, enalapril, posinopril, risinopril, moveltipril, perindopril , Quinapril and ramipril;

Dihydropyridine derivatives such as ammoldipine, felodipine, isradiffine, nicardipine, nifedipine, nilvadipine, nisoldipine and nirenedipine;

Guadinine derivatives such as betanidine, debrisoquine, guanabenz, guanaclin, guanadrel, guanazodine, guanetidine, guanfacin, guanochlor, guanoxabenz and guanoxane;

Hydrazines and phthalazines such as budralazine, cadmalazine, dihydralazine, endoralazine, hydrcarbazine, hydralazine, phenprazine, fieldralazine and todraazine;

Imidazole derivatives such as clonidine, ropecidine, phentolamine, phentolamine mesylate, thiamenidine and tolonidine;

Quaternary ammonium compounds such as azamethonium bromide, chlorisondamine chloride, hexamethonium, pentacinium bis (methyl sulfate), pentamethonium bromide, pentolinium tartate, penactopinium chloride, and trimethidiunum methotsulfate ;

Quinazoline derivatives such as alfuzosin, bunazosin, doxazosin, prasosin, terrazosin and trimazosine;

Reserpin derivatives such as bietaserpin, deserpidine, rescinamine, reserpin and sirrosine pin;

Sulfonamide derivatives such as ambuside, cloamide, furosemide, indamide, quinetazone, tripamide and xipamide; And

Others such as azmalin, γ-aminobutyric acid, bufeniode, candesartan, chlorthalidone, cyclintaine, cyclocidomin, kryptenamine tannate, eprosartan, fenoldopam, florsequinan, india Leamine, Irbesartan, Ketanserine, Losartan, Metbutamate, Mecamylamine, Methyldopa, Methyl 4-pyridyl ketone thiosemicarbazone, Metolazone, Minoxidil, Muzolimin, Parglin, Fempidine , Finacyldyl, piperonic acid, primaferon, protoveratrin, lauvacin, rescimethol, rilmeniden, sararacin, sodium nitroprusside, tricrinafen, trimetaphan campylate, tyrosinase, urapidil and valsartan ,

44. Antihyperthyroids such as 2-amino-4-methylthiazole, 2-aminothiazole, carbiazole, 3,5-dibromo-L-tyrosine, 3,5-diiodotyrosine, hinderin , Iodine, iothiouracil, methiazole, methylthiouracil, propylthiouracil, sodium perchlorate, tibenzazolin, thiobarbital and 2-thiouracil,

45. Antihypertensive drugs such as amezinium methyl sulfate, angiotensin amide, dimethoprine, dopamine, etifelmin, etireprine, gefeprine, metaaminol, middorin, norepinephrine, polledrinad and cinephrine,

46. Antihypothyroid drugs such as levothyroxine sodium, lyothyronine, thyroids, tyrodine, thyroxine, tyratricol and TSH,

47. Anti-inflammatory (nonsteroidal) drugs, for example:

Aminoarylcarboxylic acid derivatives such as enphenamic acid, etofenamate, flufenamic acid, isonicsin, meclofenamic acid, mepanamic acid, niflumic acid, talniflumate, terofenamate and tolphenamic acid;

Arylacetic acid derivatives such as acemethacin, alclofenac, amphenac, bufexamak, synmethacin, clopilac, diclofenac sodium, etodollac, felbinac, fenclofenac, fenclolac, fencloxaic acid, pentiazac, Glucametacin, ibufenac, indomethacin, isopezolac, isoxepac, ronizolac, methiazine acid, oxametacin, proglumetacin, sullindac, tiaramid, tolmetin and jomepilac;

Arylbutyric acid derivatives such as butadizone, butybufen, fenbufen and xenbucin;

Arylcarboxylic acids such as clidanac, ketorolac and tinolidine;

Arylpropionic acid derivatives such as aminopropene, benoxapropene, bucloxane, carpropene, phenopropene, fluoxapropene, flubiprofen, ibuprofen, ibuprosam, indopropene, ketopro Pens, loxoprofen, miroprofen, naproxen, oxaprozin, piketoprofen, pyrpropene, pranopropene, protiginic acid, suprofen and thiapropenic acid;

Pyrazoles such as dipfenamizol and epirisol;

Pyrazolones such as apazone, benzpiperilone, peprazone, mofebutazone, Morazone, Oxyfenbutazone, Phenylbutazone, Pipebuzone, Propofenazone, Ramipenazone, Succibuzone and Thiazolinobutazone;

Salicylic acid derivatives such as acetaminosalol, aspirin, benolylate, bromosalgenin, calcium acetylsalicylate, diflunisal, ether sallate, pendosal, gentis acid, glycol salicylate, imidazole salicylate , Lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphthyl salicylate, olsalazine, parsalmid, phenyl acetylsalicylate, phenyl salicylate, salcetamide, salicylate Amine O-acetic acid, salicylic sulfuric acid, salsalate and sulfasalazine;

Thiazinecarboxamides, such as doxycam, isoxicam, pyoxycam and tenoxycam; And

Others such as ε-acetamidocaproic acid, S-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amicsetrin, bendazac, benzidamine, bucolom, difenpyramide, ditazole, emorfazone , Guazulene, nabumeton, nimesulide, orgotaine, oxaceprole, paraniline, peroxalic acid, bombime, proquazone, proxazole and tenidab,

48. Antimalarial drugs such as acedafson, amodiaquine, arterter, artemeter, artemisinin, artesunate, bevirin, berberine, kerata, chlorguanide, chloroquine, chloroproguanyl , Cincona, cinconidine, cinconine, cycloguanyl, genthiopicrine, halophantrin, hydroxychloroquine, mefluquine hydrochloride, 3-methylasacetin, pharmaquine, plasmoside, primaquine, Pyrimethamine, quinacrine, quinine, quinine bissulfate, quinine carbonate, quinine dihydrobromide, quinine dihydrochloride, quinine ethylcarbonate, quinine formate, quinine gluconate, quinine hydroiodide, quinine hydro Chloride, quinine salicylate, quinine sulfate, quinine tannate, quinine urea hydrochloride, quinoside, quinoline and sodium arsenate diabasic,

49. Anti-migraine drugs such as alpyroprid, dihydroergotamine, eletriptan, ergocortin, ergokorninine, ergocryptin, ergot, ergotamine, flumeroxone acetate, ponazin, risuride, methyl Sergids, naratriptans, oxetrones, pizotilins, riztriptans and sumatriptans,

50. Antihypertomic drugs such as acetylleucine monoethanolamine, alizaprid, benzquinamide, bietaunatin, bromopride, buclizine, chloropromazine, clevopride, cyclizin, dimenhydrinate, Dipheniodol, Domperidone, Granisetron, Meclizine, Metaltal, Metoclopramide, Metopyazine, Nabilone, Ondansterone, Oxyfendil, Piperazine, Fibrinhydrinate, Prochlorferra Gin, scopolamine, tetrahydrocannabinols, thiethylperazine, thioproperzain and trimetabenzamide,

51. Antitumor drugs, for example:

Alkylating agents, for example:

Alkyl sulfonates such as busulfan, improsulfan and pipeosulfan;

Aziridine such as benzodepa, carbocuone, meturedepa and uredepa;

Ethyleneimines and methylmelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylololmelamine;

Nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, esturamustine, ifosfamide, mechloretamine, mechloretamine oxide, hydrochloride, melphalan, nozambiin, phenesterin, Prednismustine, trophosphamide and uracil mustard,

Nitrosoureas such as carmustine, chlorozotocin, potemustine, lomustine, nimustine and rannimustine, and

Others, such as camptothecin, decarbazine, mannostinth, mitobronitol, mitolactol and pipobroman;

Antibiotics such as alaccinomycin, actinomycin F ₁ , anthracymycin, azaserine, bleomycin, cocktinomycin, carrubicin, carcinophylline, chromomycin, dactinomycin, daunorubicin, 6-diazo -5-oxo-L-norleucine, doxorubicin, epirubicin, mitomycin, mycophenolic acid, nogalamycin, olibomycin, peplomycin, plicamycin, porphyromycin, furomycin, streptonigrin, streptocin Chosin, tubercidin, Ubenimex, Zinostatin and Zorubusin;

Anti metabolites, for example:

Folic acid analogs such as denophtherine, methotrexate, putrophtherin and trimotrexate;

Purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine and thioguanine; And

Pyrimidine analogs such as ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, doxyfluridine, enositabine, phloxuridine, flurouracil and tegapur;

Enzymes such as L-asparaginase; And

Others such as aceglaton, amsacrine, vestrabucil, bisantrene, bryostatin 1, carboplatin, cisplatin, depopamide, demecolsin, diajikuon, elponnitine, eletinium acetate, etogluside , Etoposide, gallium nitrate, hydroxyurea, interferon-α, interferon-β, interferon-γ, interleukin-2, retinan, letrozole, ronidamine, mitoguazone, mitoxantrone, furdamol, Nitracrine, pentostatin, phenammet, pyrarubicin, grapephyllic acid, 2-ethyltidrazide, polynitrokuban, procarbazine, PSK7, lazoic acid, sizopyran, spirogranium, taxol, teniposide, te Nouazone acid, triazcuone, 2,2 ', 2 "-trichlorotriethylamine, urethane, vinblastine, vincristine, vindesine and vinorelbine,

52. Antitumor (hormonal) drugs, for example:

Androgens such as calusosterone, dromostanolone propionate, epithiostanol, mepitiostane and testosterone;

Antiadrenal such as aminoglutetimides, mitotans and trilostane;

Anti-androgens such as flutamide and nilutamide; And

Antiestrogens such as tamoxifen and toremifene,

53. Antitumor adducts, for example folic acid feeds such as proline acid,

54. Anti-Pakison's disease drugs such as amantadine, benserazide, bietaunatin, biferidene, bromocriptine, budipine, cabergoline, carbidopa, deprenyl (a / k / a L-deprenyl, L-deprenyl, L-depressin and selegiline), dexetimide, diethazine, diphenhydramine, hydroxydopa, etopropazine, ethylbenzhydramine, levodopa, sakagus bone Reed, pergolide, pyroheptin, pramipexole, pyridinol, prodipine, quinpyrrole, remasemid, lopinirol, terguride, tigloidine and trihexhenidyl hydrochloride,

55. Antichrome affinity cell tumor drugs, such as metyrosine, phenoxybenzamine and phentolamine,

56. antipneumocytic drugs such as eponitine, pentamidine and sulfamemethazole,

57. Antiprostatic hypertrophy drugs such as gestonone caproate, mepartricin, oxendolone and proscar 7,

58. Antiprotozoal drugs (Lesmania), such as antimony sodium gluconate, ethylstibamine, hydroxystilamidine, N-methylglucamine, pentamidine, stilvamidine and urea stebamine,

59. Antiprotozoal drugs (trichomonas), such as acetarson, aminitrozole, anisomycin, azanidazole, forminitrazole, furazolidone, hockeymycin, lauroguadine, mepartricin, metronidazole, ni Furatel, nifuroxime, nimorazole, cecnidazole, silver picrate, tenonitrozole and tinidazole,

60. Antiprotozoal drugs (Tripanosma), such as benznidazole, eflornithine, melarsoprole, nifurtimox, oxofenarcin, hydrochloride, pentamidine, propamidine, puromycin, quinapiramine , Stilbamidine, sodium suramin, trypan red and tripparamid,

61. Antipuritics such as camphor, ciproheptadine, dichlorisone, glycine, halomethasone, 3-hydroxycamphor, menthol, mesulfen, metdilazine, phenol, polydocanol, lyso Caine, camphor brain, tenaldine, tolpropamine and trimetaprazine,

62. Anti-psoriasis drugs such as acitretin, ammonium salicylate, anthraline, 6-azauridine, bergaptene, chrysarobin, etretinate and pyrogallol,

63. Antipsychotic drugs, for example:

Butyrophenones such as benperidol, bromperidol, droperidol, fluanison, haloperidol, melferon, moferon, fifamferon, sniferon, thymiphenol and tripleluferridol;

Phenothiazines such as acetophenazine, butaperazine, carfenazine, chlorproetazine, chlorpromazine, clospyrazine, cyamagazine, dixiazine, flufenazine, imicloazine, mefazin, mesorizin, Methoxypromazine, methotfenazate, oxafluazine, perazine, ferrazine, permethazine, perphenazine, piperaceazine, pipetazine, prochlorperazine, promazine, sulforidazine, Thiopropazate, thiolidazine, trifluoroperazine and triflupromazine;

Thioxanthenes such as chlorproticsen, clofentic sol, flufentic sol and thiotixene;

Other tricyclic compounds such as benzquinamide, carpipramine, clocapramine, clomacran, clothiapin, clozapine, opprapramol, protifendil, tetrabenazine and jotepin; And

Others such as alizapride, amulfuride, briamate, flupyrrylene, molindon, fenfluridol, pimozide, spirylene and sulfide,

64. Antipyretic agents such as acetaminophen, acetaminosalol, acetanilide, aconin, aconite, aconitine, alclofenac, aluminum bis (acetylsalicylate), aminochlortenoxazine, aminopyrin, aspirin, benoryl , Benzylamine, berberine, p-bromoacetanilide, bufexa film, butadizone, calcium acetylsalicylate, chlortenoxazine, choline salicylate, clidanac, dihydroxyaluminum acetylsalicylate, dipyrosecetyl , Dipyrone, epipyrazole, ether salate, imidazole salicylate, indomethacin, isopezolac, p-lactophenated, lysine acetylsalicylate, magnesium acetylsalicylate, meclofenamic acid, Morazone , Morpholine salicylate, naproxen, nifenazone, 5'-nitro-2'-propoxyacetanilide, phenacetin, phencarbazide, phenocol, fenofirazone, phenyl acetylsallie Latex, phenyl salicylate, pipebuzone, propacetamol, propapezone, ramipenazone, salacetamide, salicylate O-acetic acid, sodium salicylate, sulfamipyrin, tetrandrine and tinoolidine ,

65. Anti-Likechegic drugs such as p-aminobenzoic acid, chloramphenicol, chloramphenicol palmitate, chloramphenicol pantothenate and tetracycline,

66. Anti-seborrheic drugs such as chloroxine, 3-O-lauroylpyridoxol diacetate, pyrocton, pyrithione, resorcinol, selenium sulfide and thioxolone,

67. Antiseptic agents, for example:

Guanidines such as alexidine, ambazone, chlorhexidine and picoxydine;

Halogens and halogen compounds such as bismuth iodide oxide, bismuth iodosubgallate, bismuth tribromophenate, boron chloride, calcium iodate, chlorinated lime, cloflucarban, fluorosalan, iodic acid, iodine, monochloride Iodine, iodine trichloride, iodoform, metheneamine tetraiodine, oxychlorocene, povidin-iodine, sodium hypochlorite, sodium iodate, simclocene, thymol iodide, triclocarban, triclosan and troclocene potassium;

Mercury compounds such as hydragafen, merlane sodium, merbromine, mercury (II) chloride, ammoniaated, mercury (II) sodium p-phenolsulfonate, mercury (II) succinimide, mercury sulfide (II) , Red, mercurophene, mercury (II) acetate, mercury chloride (I), mercury iodide (I), nitromersol, potassium tetraiodomercurate (II), potassium triiodomercurate (II) solution, thime Leponate sodium and thimerosal;

Nitrofurans such as furazolidone, 2- (methoxymethyl) -5-nitrofuran, nidroxone, nifuroxime, nipurazide and nitrofurazone;

Phenols such as acetomeritol, bithionol, cadmium salicylate, carbacroll, chloroxylenol, chlorophene, cresote, cresol, p-cresol, pentylchlore, hexachlorophene, 1-naphthyl salicylate, 2-naphthyl salicylate, 2,4,6-tribromo-m-cresol, and 3 ', 4', 5-trichlorosalicylanilide;

Quinolines such as aminoquinurides, benzoxiquines, broxyquinolines, chloroxins, chloroquindols, clocksquines, ethylhydrocuprene, euprocin, haquinols, hydrastins, 8-hydroxyquinolines, 8-hydroxys Quinoline sulfate and iodochlorohydroxyquine; And

Others such as aluminum acetate solution, aluminum subacetate solution, aluminum sulfate, 3-amino-4-hydroxybutyric acid, boric acid, chlorhexidine, chlorazodine, m-cresyl acetate, copper (II) sulfate, dibromopropamidine , Itstamol, Negitol7, Noxitolin, Ornidazole, β-propiolactone, α-terpineol,

68. Anticonvulsant drugs such as alibendol, ampusetamide, aminopromazine, apoatroffin, bebonium methyl sulfate, vietamiberine, butaberine, butopium bromide, N-butylscopolammonium bromide, caroberin, Cimetropium bromide, cinnamicrin, clevopride, conin hydrobromide, conin hydrochloride, cycloidide iodide, difemerine, diisopromine, dioxafetyl butyrate, diponium bromide, drophenin, emepronium bromide, eta Berine, phelecamine, phenalamide, phenoverine, fenpifran, fenfibernium bromide, fentonium bromide, flavoxate, flopropionate, gluconic acid, guaiactamine, hydramitrazine, hymecromon , Rayopyrrole, Meverin, Moxaberin, Nafiberin, Octamylamine, Octaberine, Pentapiperid, Phenamaside Hydrochloride, Pluglu Synols, pinaberium bromide, piperilate, pipoxolane hydrochloride, pramiberine, pripinium bromide, properidine, propiban, propyromazine, prozapine, racefemin, roseverine, spasmolitol, stillo Iodide, sulfophonium, thimonium iodide, thiquibium bromide, tyropramide, trepibutone, trichromil, tripolium, trimebutin, N, N-1-trimethyl-3,3-di Phenyl-propylamine, tropenzyl, trosfum chloride and xenittropium bromide,

69. Antithrombotic drugs such as anagrelide, argatrovan, cilostazol, chrysoptin, datrovan, depibrotid, enoxaparin, proxiparin 7, indobufen, lamoparan, ozagrerel, Picotamide, flapibride, leviparin, tedelparin, ticlopidine, triflusal and warfarin,

70. Anti-invasive drugs such as alkamide, amibone, benproperin, benzonatate, bibenzoium bromide, bromoform, butamirate, butamate, caramifen ethanedisulfonate, carbetapentane , Clopedinol, clobutinol, cloperastine, codeine, codeine methyl bromide, codeine N-oxide, codeine phosphate, codeine sulfate, cyclexanone, dextromethorphan, dibutate sodium, dihydrocodeine, di Hydrocodeinone enol acetate, dimemorphan, dimethoxanate, α, α-diphenyl-2-piperidinepropanol, dropropazine, drothebanol, eprazinone, ethyl dibutate, ethylmorphine, pomino Ben, guiiapatate, hydrocodone, isoaminyl, levopropoxyphene, morphlophone, narcein, normethadon, noscapin, oxeladine, oxalamine, polcodine, picoperin, pipazate, Piperidinone, fr Rust CD-triazine, hydrochloride, La seme tor plate, the non-free ride hydrochloride, tea pepi Dean and not pepeu roll,

71. Anti-ulcer drugs such as aceglutamide aluminum complex, ε-acetamidocaproic acid zinc salt, acetoxolone, arbaprostill, benexate hydrochloride, bismuth subcitrate sol (dried), carbenox Solon, Setraxate, Cimetidine, Enprosteel, Esaprazole, Famotidine, Pxacillide, Gefarnate, Guazulene, Irsogladine, Misoprostol, Nizatidine, Omeprazole, Ornopro Still, γ-orizanol, fiparinine, pyrenzepine, flaunotol, ranitidine, lioprostil, rosaprostol, rotlactate, roxatidine acetate, solfacon, spizofuron, sucralate, teprenone, tri Morphprostill, trithiozin, tropidide and zolimidine,

72. anti-caucary drugs such as acetohydroxysamic acid, alupurinol, potassium citrate and succinimide,

73. antivenin drugs such as Riobac 7 antibenin,

74. Antiviral drugs, for example:

Purines and pyrimidinones such as acyclovir, cytarabine, dideoxyadenosine, dideoxycytidine, dideoxyinosine, edoxoudine, phloxuridine, gangcyclovir, idoxuridine, inosine pranovex, MADU, Fencyclovir, trifluidine, bidrarvine and zidobudiine; And

Others such as acetylleucine, monoethanolamine, amantadine, amidinomycin, cosalan, cuminaldehyde thiosemicarbzone, phosphcarnet sodium, imiquimod, interferon-α, interferon-β, interferon-γ, ketoxal, Lysozyme, methisazone, morphoxydine, grapephytotoxin, ribavirin, rimantadine, stalymycin, statolone, tromantadine and xenazoic acid,

75. Anxiolytics, for example:

Arylpiperazines such as buspyron, gepyron, ifsapyron and tondospyron;

Benzodiazepines derivatives, such as alprazolam, bromazepam, chamazepam, chlordiazepoxide, clovazam, clolazate, cotiazepam, xaxazolam, diazepam, ethyl roplacezate, etizolam, fluidazepam, flu Tazolam, flutoprazepam, halazepam, ketazolam, lorazepam, roxapin, medazepam, metaclazepam, mexazolam, nordazepam, oxazepam, oxazolam, pinazepham, prazepam and topisopam;

Carbamates such as cyclabamate, emylcarmate, hydroxyphenamate, meprobamate, phenprobamate and tibamate; And

Others such as alpidem, benzoxamine, captodiamine, chlormezanone, ethoxyxin, plesinoxane, fluoresone, glutamic acid, hydroxyzine, resopitron, mechloralurea, mefenoxalone, mirtazepine, Oxanamide, phenaglycodol, hydroclonal and jatosetron,

76. benzodiazepine antagonists such as flumazenyl,

77. Bronchodilators, for example:

Ephedrine derivatives such as albuterol, bambuterol, bitolterol, carbuterol, clebuterol, chlorprelinin, dioxetedrin, ephedrine, epiniphrine, eprogenol, etaphedrine, ethylnorpinephrine, pheno Terrol, hexoprelinin, isotarin, isoproterenol, mabuterol, metaproterenol, N-methylephedrine, pirbuterol, procaterol, protokillol, leproterol, limitrol, salmeterol, Soterenol, terbutalin and tulobuterol;

Quaternary ammonium compounds such as bebonium methyl sulphate, glutropium bromide, ifpratropium bromide and oxytropium bromide;

Xanthine derivatives, such as acephylline, acepiline piperazine, ambuphylline, aminophylline, barmiphylline, choline, theophyllineate, doxophylline, diphylline, enpropyline, etamiphyline, etophylline, guatilin Proxiephylline, theobromine, 1-theobromineacetic acid and theophylline; And

Others such as phenspiride, methazazine, montekulast, methoxyphenyme, tretoquinol and zafirkulast,

78. Calcium channel blockers, for example:

Arylalkylamines such as bepridil, dithiazem, pendylin, gallopanyl, prenylamine, terodidyne and verapamil;

Dihydropyridine derivatives such as felodipine, isradipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine and nirenedipine;

Piperazine derivatives such as cinnarizine, flunalysine and lidofazine; And

Others such as bencyclane, etaphenone and perhexylline,

79. Calcium modulators such as calcifediol, calcitonin, calcitriol, clodronic acid, dihydrotachisterol, elcatonin, etidronic acid, ifriflavone, pamidronic acid, parathyroid hormone and teriparatide acetate,

80. Cardiac agents such as acephylline, acetyldigitytoxin, 2-amino-4-picoline, amlinone, benfurodil hemisuccinate, bucladesin, cerberoside, camphoramide, convalatoxin, Shimaline, Denophamine, Desranoside, Dietin, Digitalis, Digitoxin, Digoxin, Dobutamine, Dopamine, Dopexamine, Enoximone, Erythroplane, Phenalcomine, Gytalin, Gitoxin, Glycosiamine, Heptaminol, Hydrastinin, Ibopamine, Lanotodises, Metamibam, Milinone, Nelipoline, Oleandrin, Ouavine, Oxyphedrine, Prenalterol, Prosilaridine, Recibufogenin, Silane , Silalenin, stropantin, sulmazole, theobromine and xamotrol,

81. Chelating agents such as deferozmine, dithiocarb sodium, edetate calcium disodium, edetate disodium, edate sodium, triate sodium, penicylamine, pentate calcium trisodium, pentectic acid, succinate Shimmer and trientin,

82. cholecystokinin antagonists such as proglumid,

83. Gallstone disintegrating agents such as kenodiol, methyl t-butyl ether, monooctanoin and ursodiol,

84. Bile secretagogues such as alibendol, anetol trithion, azintamide, cholic acid, cyclotosan, clanobutin, cyclobutyrol, cyclovalon, cinnarin, dehydrocholic acid, deoxycholic acid, dimacrotic acid , α-ethylbenzyl alcohol, exciproben, pegprolol, pencibutyrol, pheniftol, floranthrone, hymecromon, menbutone, 3- (o-methoxyphenyl) -2-phenylacrylic acid, metochalcone , Moquizone, oxamide, ox bile extract, 4,4'-oxydi-2-butanol, fiprozoline, prozapine, 4-salicyl oil morpholine, cincide, taurocholic acid, thymonoxane, tocampil , Trepibutone and vanitiolide,

85. Cholinergic agents, such as aceclidine, acetylcholine bromide, acetylcholide chloride, aclatonium napadisylate, benzpyrinium bromide, betancol chloride, carbacol, carpronium chloride, demecarium bromide, dex Panthenol, diisopropyl paraoxone, ecothioate iodide, edrofomium chloride, eseridine, furtretonium, isofluroate, methacholine chloride, muscarinic, neostigmine, oxa propanium iodide , Physostigmine and pyridostigmine bromide,

86. Cholinesterase inhibitors such as ambenonium chloride, distigmine bromide and galantamine,

87. Cholinesterase reactivators such as obidoximin chloride and pralidoxime chloride,

88. Central nervous system stimulants such as amineeptin, amphetamines, amphetamines, bemeglides, benzpetamines, brucins, caffeine, chlorpentermines, clofencycllans, chlortermines, coca, demanyl phosphate , Dexoxadrol, dextroamphetamine sulfate, diethylpropion, N-ethylamphetamine, ethamiban, etifelmin, etriptamine, phencampamine, phenethylin, phenosolone, flurotil, galantamine, hexacyclonate sodium , Homocampin, marginol, mexamide, methamphetamine, methylphenidate, niketamide, phenomeline, pentylenetezazole, phenidimethazine, phenmetrazine, phentermine, picrotoxin, fipradrol, proline Shot and fatigue valeron,

89. Decongestants, for example amideprine, capaminol, cyclopentamine, ephedrine, epinephrine, phenoxazolin, indazolin, methizoline, napazoline, nordephrine hydrochloride, octodrine, oxymethazolin, phenyl Ephrin hydrochloride, phenylpropanolamine hydrochloride, phenylpropylmethylamine, propylhexerin, pseudoephedrine, tetrahydrozoline, thimazoline and xylometazoline,

90. Dental actives, for example:

Bisphosphonates (antiperipheral disease and bone resorption), such as alendronate, clathronate, ethidronate, pamidronate and tiludronate; Carrier inhibitors such as arginine and sodium fluoride; Desensitizers such as potassium nitrate and citric acid oxalate,

91. bleaching agents such as hydroquinine, hydroquinone and monobenzone,

92. Diuretics, for example:

Organic mercury compounds such as chlormerodins, meralurides, mercampamides, mercaptomerine sodium, mercumalicylic acid, sodium mercoumatilin, mercury chloride and mersalyl;

Putterines such as puterene and triamterene;

Purines such as acephylline, 7-morpholinomethyltheophylline, permabromide, proteobromine and theobromine;

Steroids such as canrenones, oleandrones and spironolactones;

Sulfonamides such as acetazolamide, ambuside, azocemide, bumetanide, butazolamide, chloraminophenamide, clofenamide, clofamid, clolexsolene, diphenylmethane-4,4'- Disulfonamide, disulfamide, ethoxzolamide, furosemide, indamide, mefruside, metazolamide, pyretanide, quinetazone, torracemide, tripamide and zipamide;

Uracils such as aminometradine and amisomethradine;

Others such as amanozin, amylolide, arbutin, chlorazanyl, ecronic acid, etozoline, hydrcarbazine, isosorbide, mannitol, metochalcone, muzolimine, perhexylline, ticlifen and urea,

93. Dopamine receptor agonists such as bromocriptine, dopexamine, fenoldopam, ibopamine, risulide, lacgolide and pergolide,

94. Amitraz, Benzyl Benzoate, Carbaryl, Crotamiton, DDT, Dixanthogen, Isobornyl Thiocanoacetate-Industrial, Lime Sulfide Solution, Lindane, Malathion, Mercury (II), Mesulfen And sulfur pharmaceuticals,

95. Enzymes, for example:

Digestive enzymes such as α-amylase (pig pancreas), lipase, pancrelipase, pepsin and renin;

Mucolytic enzymes such as lysosomes;

Penicillin inactivating enzymes such as penicillinase; And

Proteolytic enzymes such as collagenase, chymopapine, chymotrypsin, papain and trypsin,

96. enzyme-inducing substances (liver), such as flumesinol,

97. Estrogens, for example

Nonsteroidal estrogens such as benzestrol, brofaroestrol, chlorotrianicene, dienesrol, diethylstilbestrol, diethylstilbestrol dipropionate, dimethrol, phosphestrol, hexestrol , Metallenestrils and metest rolls; And

Steroidal estrogens such as kolpormon, conjugated estrogen hormone, iquilenin, iquilin, estradiol, estradiol benzoate, estradiol 17β-cyionate, estriol, estrone, ethynyl estradiol, estranol, metheline Stanol, mockestrol, mitatrienediol, quinestradiol and quinestrol,

98. gastric juice secretion inhibitors such as entergastron and octreotide,

99. Glucocorticoids such as 21-acetoxyprifenenolone, aclomethasone, algston, amicinononide, beclomethasone, betamethasone, budesonide, chloroprednone, clobetasol, blobetason, clocor Tolon, Clofredol, Corticosterone, Cortisone, Cortibazole, Deplazacoat, Desonide, Desoxymethazone, Dexamethasone, Diflorasone, Diflucortolone, Difluprenate, Enoxolone, Fluaza Coats, fluchloronide, flumethasone, flunisolide, fluorinolone acetonide, fluorosinide, fluorocortin butyl, fluorocortolone, fluorometholone, fluperolone acetate, fluprednide acetate, fluprednini Zolon, fluandrenolide, formocortal, hacinononide, halometason, halopredone acetate, hydrocortamate, hydrocortisone, hy Locortisone Acetate, Hydrocortisone Phosphate, Hydrocortisone 21-Sodium Succinate, Hydrocortisone Tebutate, Margepredone, Medridone, Meprednisone, Methioprednisolone, Mometasone Furoate, Paramethasone, Predniscarbate, Prednisolone, prednisolone 21-diethylaminoacetate, prednisolone sodium phosphate, prednisolone sodium succinate, prednisolone sodium 21-m-sulfobenzoate, prednisolone 21-stearoyl glycolate, prednisolone tebutate, prednisolone 21-trimethyl Acetate, prednisone, prednibal, prednilidene, prednilidene 21-diethylaminoacetate, thixocortal, triamcinolone, triamcinolone acetonide, triamcinolone bentonide and triamcinolone hexacetonide,

100. Gonadotropin components such as buserelin, clomiphene, cyclophenyl, epimestrol, FSH, HCG and LH-RH,

101. gonadotropin-based hormones such as LH and PMSG,

102. growth hormone inhibitors such as octreotide and somatostatin,

103. Growth hormone releasing factors such as cemorelin,

104. growth stimulants, such as somatotropin,

105. Hemolytic agents such as phenylhydrazine and phenylhydrazine hydrochloride,

106. Heparin antagonists such as hexabromide hexadimethrin and protamines,

107. Hepatoprotectants such as S-adenosylmethionine, betaine, catechin, cytolone, malolate, orazamide, phosphorylcholine, protoporphyrin IX, silymarin group, thiotic acid and thiopronin,

108. Immunomodulators such as amiprilose, busilamine, dithiocarb sodium, inosine pranovex, interferon-y, interleukin-2, lentinan, muroctacin, platonin, procodazole, tetramisol, timomodulin , Thymopentin and ubenimex,

109. immunosuppressive agents such as azathioprine, cyclosporin and myzoribin,

110. Ion exchange resins such as carbakryl resins, cholestyramine resins, cholestipol, polydexides, lesodecs and sodium polystyrene sulfonates,

111. Lactation stimulating hormones such as prolactin,

112. LH-RH agonists such as buserelin, goserelin, leuprolide, naparelin and tryptorelin,

113. Fat increasing agents such as N-acetylmethionine, choline chloride, choline dehydrocholate, choline dihydrogen citrate, inositol, lecithin and methionine,

114. Lupus erythematosus inhibitors such as bismuth sodium triglycolate, bismuth subsalicylate, chloroquine and hydroxychloroquine,

115. Mineral corticoids such as aldosterone, deoxycorticosterone, deoxycorticosterone acetate and fludrocortisone,

116. Pupil reducers such as carbacol, physostigmine, pilocarpine and pilocarpus,

117. Monoamine oxidase inhibitors, such as deprenyl, iproclozide, iproniazide, isocarboxide, moclobemide, octopoxin, pargiline, phenelzin, phenoxypropazine, pivalylbenzhydrazine , Prodipine, toloxatone and trinilcypromine,

118. Mucosa solubilizers such as acetylcysteine, brohexine, carbocysteine, dominiodol, letosteine, lysozyme, messteine hydrochloride, mesna, sobreol, stepronin, thiopronin and tyloxapol,

119. Muscle relaxants (skeleton), such as aflocualone, alcuronium, atracurium besylate, baclofen, benzoxamine, benzoquinononium chloride, C-calcevacin, carisoprodol, chlormezanone, chlor Lephenesin carbamate, chlorproetazine, chloroxazone, curare, cyclavarmate, cyclobenzaprine, dantrolene, bromide decamethonium, diazepam, eferison, bromide pajadinium, flumetramide, Galamine triethiodide, hexacarbacholine bromide, hexafluorenium bromide, idrosilamide, lauxium methyl sulphate, leptodactin, memantine, mephenesin, mefenoxalone, metaxalon, metocarbamol, Iodide methotrine, nimezepam, orfenadrine, pancuronium bromium, phenprobamate, penamimidol, pipepicurium bromide, promoxolan, quinine sulfate, styramate, brominated succinylcholine, succinyl chloride Choline, Succinylcholine Io Bromide, benzethonium sukse, tetra jepam, thio call Chico side, tizanidine, tolyl Perry hand, chloride-to-Namboku rarin, bromide and iodonium group beku solar min,

120. Anesthetic antagonists such as amifenazole, cyclazosin, revalorphan, nadide, nalmpene, nalpine, nalpinine nicotinate, naloxone and naltrexone,

121. Neuroprotective agents such as dizocilpin,

122. Nootropics such as aceglutamide, acetylcarnitine, anicetam, bifematlan, excipon, pepecide, idebenone, indeloxaven hydrochloride, nizophenone, oxyracetam, piracetam, Propentophylline, pyrithiol and tacrine,

123. Ophthalmic actives such as 15-ketoprostaglandin,

124, ovarian hormones such as relaxin,

125. Uterine contractiles such as carboprost, cargutocin, deaminooxytocin, ergonobin, gemeprost, methylergonobin, oxytocin, pituitary (posterior lobe), prostaglandin E ₂ , prostaglandin F _2α and spartane,

126. Hepsin inhibitors such as sodium amylosulfate,

127. peristalsis promoters such as cisapride,

128. Progestogens such as allylestrenol, anageston, chlormadinone acetate, delmadinone acetate, demegestone, desogestrel, dimethysterone, didrogesterone, etisterone, ethinodiol , Plurogestone Acetate, Gestodene, Gestonolone Caproate, Haloprogesterone, 17-hydroxy-16-methylene-progesterone, 17α-hydroxyprogesterone, 17α-hydroxygesterone caproate, linestrenol , Medrogeston, medroxyprogesterone, megestrol acetate, melengestrol, norethine drone, noethinodrel, norgestosterone, norgestimate, norgestrel, norgestrienone, norbinosterone , Pentagestrone, progesterone, promegueston, queengestron and trengestone,

129. Prolactin inhibitors such as methagoline,

130. Prostaglandins and prostaglandin analogs, such as arbaprostill, carboprost, enprostill, bemeprost, limaprost, misproprostol, ornoprostill, prostacycline, prostaglandin E ₁ , prostaglandin E ₂ , prostaglandin F _2α , Rioprostil, Rosaprostol, Sulprostone and Trimoprosteel,

131. Protease inhibitors such as aprotinin, chamostat, gabexate and napamostat,

132. Respiratory stimulants such as amitrin, bemeglide, carbon dioxide, cropropamide, crotetamide, dimeplin, dimorpholamine, doxapram, etamiban, pominobene, lobelin, mepixanox, Metamibam, niketamide, picrotoxin, pimeclone, pyridophylline, sodium succinate and tacrine,

133. Curing agents such as ethanolamine, ethylamine, 2-hexyldecanoic acid, polydocanol, quinine bisulfate, quinine urea hydrochloride, sodium ricinolate, sodium tetradecyl sulfate and tribenoside,

134. Sedatives and hypnotics, for example:

Acyclic fluorides such as acecarbromal, aprolide, bomisovalum, capride, carbromal and acetylurea;

Alcohols such as chlorhexadol, ethchlorbinol, meparfinol, 4-methyl-5-thiazoleethanol, t-pentyl alcohol and 2,2,2-trichloroethanol;

Amides such as butotamide, diethylbromoacetamide, ibrotamide, isovaleryl, diethylamide, niaprazine, tricetamide, trimetazine, zolpidem and zodiacone,

Barbituric acid derivatives such as allobarbital, amobarbital, aprobarbital, barbital, bralabarbital, butabarbital sodium, butalbital, butalilonal, butatetal, carbubarb, cyclobarbital, cyclo Pentobarbital, enalylpropyl, 5-ethyl-5- (1-piperidyl) barbituric acid, 5-perfuryl-5-isopropylbarbituric acid, heptabarbital, hextal sodium, hexobarbital , Mepobarbital, methitural, narcobarbital, nealbarbital, pentobarbital sodium, penalylmal, phenobarbital, phenobarbital sodium, phenylmethylbarbituric acid, probarbital, propalillonal, proxybarbal, reposal , Secobarbital sodium, debutal, tetrabarbital, vinbarbital sodium and vinylbital;

Benzodiazepine derivatives such as brotizolam, doxezezepam, estazolam, flunitrazepam, flulazepam, haloxazolam, loxazolam, lormezepam, nitrazepam, quasepam, temazepam and triazolam;

Bromide such as ammonium bromide, calcium bromide, calcium bromolactobionate, lithium bromide, magnesium bromide, potassium bromide and sodium bromide;

Carbamates such as tertiary amyl carbamate, ethinamate, hexaprephymate, meparfinol carbamate, norbonal and tricholourethane;

Chloral derivatives such as carbochloral, chloral betaine, chloral formamide, chloral hydrate, chloral antipyrine, dichloralfenazone, pentaerythritol chloral and triclofos;

Piperidinediones such as glutimide, methiprilon, piperidone, pyridyldione, tagglutimid and thalidomide;

Quinazolone derivatives such as etacualone, meclocualone and metaquaalone; And

Others such as acetal, acetophenone, aldol, ammonium valerate, amphenidone, d-bornyl α-bromoisovalerate, d-bornyl isovalerate, bromoform, calcium 2-ethylbutanoate, Carfinate, α-chlorolose, clomeththiazole, cyprifendium, doxylamine, etodroxyzine, etomidate, phenadizol, homophenazine, hydrobromic acid, mecloxamine, menthyl valerate, Opaum, paraaldehyde, paraffin, propiomazine, lylzafon, sodium oxybate, sulfonethylmethane and sulfonmethane,

135. Thrombolytic agents such as APSAC, plasmin, prourokinase, streptokinase, tissue plasminogen activator and urokinase,

136. Thyroid stimulating hormones such as TRH and THS,

137. Uricosurics such as benzbromarone, etebeneside, orotic acid, oxycincopene, provenedide, sulfinpyrazone, ticrinafen and yoxazolamine,

138. Vasodilators (cerebral) such as bencyclane, cinnarizine, citcholine, cyclandelate, cyclonickate, diisopropylamine dichloracetate, evernnamonine, phenoxilyl, flunarizine, ibudilast, Ifenprodil, napronyl, nicamethate, nisergoline, nimodipine, papaverine, pentiphylline, tinophedrine, vincarmine, vinpocetin and biquidyl,

139. Vasodilators (tubular), such as amotrifen, bendazole, benfurodil hemisuccinate, benziodarone, chlorasigin, chromonalar, clobenfurol, clonitrate, dilazeph, dipyridamole Droprenylamine, eproxate, erythritol, erythryl tetranitrate, etaphenone, pendylin, floredil, ganglenfen, hexestrol, bis (β-diethylaminoethyl ether), hexobendine, Itramine tosylate, kelin, lidofrazine, mannitol hexane nitrate, methazazine, nicorandil, nitroglycerin, pentaerythritol tetranitrate, pentrinitrol, perhexylline, pimephylline, prenylamine, propargyl Nitrate, pyridophylline, trapidyl, trichromil, trimetazidine, trolnitrate phosphate and bisnadine,

140. Vasodilation agents (peripheral), such as aluminum nicotinate, methane, bencyclane, betahistin, bradykinin, brovincarmine, buponiode, buflomedil, butalamine, cethiedil, cycloni Kate, cinefazide, cinnarizine, cyclandelate, diisopropylamine, dichloroacetate, eleidocin, phenoxydyl, flunalysine, heronicate, fenprodil, inositol, niacinate, isoxsuphrine , Carridine, kallikrein, oxycilite, napronyl, nicometate, nisergoline, nicofuranose, nicotinyl alcohol, niliderin, pentiphylline, pentoxifylline, pyrivedyl, prostaglandin E ₁ , sulloctidil And xanthinal niacinate,

141. Vascular protective agents such as benzaron, bioflavonoids, chromocarb, clovioside, diosmin, dovesylate calcium, escin, rollescutol, leucocyanidine, meteskuphylline, quercetin, rutin and troxrose Routine,

142. Vitamins, vitamin sources and vitamin extracts, such as vitamins A, B, C, D, E and K and derivatives thereof, calciferol, glycyriza and mecobalamin,

143. Wound healing agents such as acetylcysteine, allantoin, asiaticoside, cardexomer iodine, chitin, dextranomer and oxaceprolol,

144. anticoagulants such as heparin, and

145. Heterogeneous mixtures such as erythropoietin (hematin), filgrastim, finasteride (positive prostate hyperplasia) and interferon beta 1-alpha (multiple sclerosis).

The active ingredients listed above are described in The Merck Index, 12th Edition, Merck & Co. Rahway, N.J. (1996)], based on the drug categories and drug species presented on pages THER-1 to THER-28. This reference is incorporated herein by reference in its entirety.

The active ingredients contained in the bioadhesive composition may be neutral molecules, components of molecular complexes, and their pharmaceutically acceptable salts, free acids, free bases, or quaternary salts, or combinations thereof, depending on the desired solubility and release properties. It may exist in other forms such as form. In addition, simple derivatives, enzymes, proactive forms, prodrugs and the like of pharmacologically acceptable ethers, esters, amides and the like, which have desirable retention and release properties but are readily metabolized at body pH, can also be used.

The active agent may contain local anesthetic bases, including weak organic bases that are lipophilic and thus have poor water solubility. However, such bases typically react with organic or inorganic acids to form acidic water soluble acid addition salts. Thus, the term "base" refers to an anesthetic of non-ionized form that, when used for anesthetics, can provide electron pairs to form covalent bonds. The term "acid" when used with anesthetics means a form formed by anesthetic bases upon reaction with organic or inorganic acids.

Suitable local anesthetics for use in the practice of the present invention include amides and esters. Examples of amides are lidocaine, prilocaine, mepivacaine, bupivacaine, dibucaine and ethidocaine. Esters include procaine, tetracaine, propoxycaine, chloroprocaine, benzocaine, butambene picrate, cocaine, hexylcaine, piperocaine, oxyprocaine and propparacaine. Other suitable topical anesthetics used in the practice of the present invention include cyclomethicaine, dimethisoquine, ketocaine, diperodon, diclonin and pramoxin, all of which are typically administered in the form of acid addition hydrochloride or sulfate do.

Acid addition salts of anesthetics suitable for the present invention are any non-toxic pharmaceutically acceptable organic or inorganic salts, which in certain embodiments are salicylates. Typical inorganic salts are hydrogen halides, in particular hydrochloride, carbonate, borate, phosphate, sulfate, hydrogen sulphate, hydrobromide, nitrate, sulfite and arsenate. Common organic salts are salts of monocarboxylic and polycarboxylic acids, for example citrate, tartarate, malate, cinnamate, oxalate, formate, succinate and phthalate. The base and salt forms of suitable anesthetics incorporated into the compositions of the present invention preferably use different anesthetics to maximize the duration of the combined anesthetic effect. The term “different” as used for anesthetics means that any salt form to be combined is not a salt of the base form used in the existing combination.

In certain embodiments of the present invention, the active agent is in the form of a free base local anesthetic and salt selected from lidocaine, procaine, propoxycaine, mepivacaine, prilocaine, diclonin, pramoxin, benzocaine and chloropromcaine. Contains other anesthetics. The salt form is preferably selected from the group comprising the prilocaine, tetracaine, bupivacaine, diclonin, dibucaine, ethidocaine and lidocaine salts.

In an embodiment of the invention comprising a combination of free base form and salt form anesthetic, the ratio of free base form to salt form in the composition is determined by several factors: (1) the type of salt and base used, (2 ) Desired duration of action, and (3) rapidity of the desired anesthetic effect. Typically for mucosal application, the ratio of base to salt exhibits its best effect within about 2 to 30 minutes of free base form penetrating the mucosa, while the salt form penetrates the mucous membrane and within about 10 to 75 minutes. It is desirable to determine the best effect. Anesthesia periods range from about 2 minutes to several hours, even up to 24 hours, depending on the base / salt combination and application time selected. Indeed, to achieve this effect, the weight of the base form usually exceeds the weight of the salt form.

The term "initiation of anesthesia" means a time at which an effect on each nerve occurs. Anesthesia initiation depends primarily on the lipid solubility, molecular sieve and amount of the localized anesthetic in a useful non-ionized form. Thus, anesthetics with high lipid solubility or low pK ₁ or both provide a faster anesthetic initiation effect.

As used herein, “anesthesia period” means a period during which local anesthetics measurably block nerve induction. This depends on the protein binding of the anesthetic as well as all the factors listed in relation to the initiation of anesthesia.

Anesthetics in the form of free base can penetrate the skin to a limited extent and, if the keratin layer is peeled off, will penetrate the skin more rapidly. In the case of mucous membranes, the anesthetic in the form of free base is more easily penetrated due to the different keratin composition and its hydrophilicity compared to the stratum corneum of healthy skin.

Typically, salt forms of anesthetics do not penetrate healthy skin very well, but non-ionized bases penetrate to a limited extent. Both salt form and base form penetrate the stripped keratin layer. The salt and base forms penetrate the mucosa to varying degrees due to the hydrophilicity of the mucosa when compared to the stratum corneum of healthy skin. Typically, the higher the lipid content of the mucosa, the more rapidly the base anesthetic is absorbed. Therefore, when the bioadhesive composition is used for nasal mucosal application, it should be borne in mind that the lipid content of gums and alveolar mucosa must be different in order to achieve an appropriate penetration rate.

Applicants do not intend to establish any theory or proposed mechanism of action, but the rapid initiation of anesthesia is achieved because the lipophilic base form of anesthetic agent enters the lipoprotein neural membrane and prevents the depolarization and ionic effects that occur during the stimulus induction process. Provide effect. On the other hand, the non-lipophilic salt form of anesthesia passes through the lipoprotein neural membrane only after the salt has been converted to a base by the buffering capacity of the skin or mucosal tissue, ultimately resulting in slow anesthesia.

Anesthetics in salt form are selected based on the period of anesthesia and the onset of anesthesia. Regulation of the ratio of base to salt affects the relative onset and duration of anesthesia. When the amount of anesthetic agent having a rapid onset effect is large, the anesthetic start time is shortened. Similarly, larger amounts of anesthetic with longer anesthesia times result in longer anesthesia times. In addition, the composition may include other drugs used incidentally.

Table 1 below summarizes the duration of action and peaks of selected local anesthetics based primarily on application to the skin or mucous membranes.

Local anesthesia Adult Minimum Dose Adult maximum dose (mg) Maximum effect (minutes) Duration of effect in minutes Dubicaine 25 <15 120-240 Lidocaine 750 2-5 30-60 Benzocaine 5000 One 30-60 cocaine 50 2-5 30-120 Tetracaine 50 3-8 30-60 Dichloin 100 <10 <60 Pramoxin 200 3-5 none Source: Drugs and Comparisons, 1990 edition, p. 601, J.B. Lippincott Company (St. Louis, MO)

In general, for anesthetics of any particular form, the relative rate at which anesthesia is initiated and sustained can be determined through standard tests for transmucosal doses or can be known from the literature.

The start time as well as the duration of anesthesia may vary depending on the site of application and the individual. When the composition is administered to high keratinized skin tissue, it may take a long time for 2-4 hours before the anesthetic is started.

By "therapeutically effective amount" in the context of an active agent is meant an amount of active agent that, when administered topically, is sufficient to produce the desired effect that is sustained in use in the intended use, that is, a local or systemic sustained effect. The amount required is known in the literature or can be determined according to methods known in the art. Generally, however, an amount of about 0.1 to 20,000 mg, preferably about 0.1-1000 mg, more preferably about 0.1-500 mg is used for about 75 kg of adult body weight, depending on the active agent selected and the application site. The upper limit value of the active agent herein refers to an amount in which the composition should be substantially free of crystals of the active agent and that the amount of solvent used is not sufficient to adversely affect the properties of the bioadhesive of the composition.

Therapeutic doses and dosage unit doses can be assessed by flux data conducted in vitro using human body skin or animal skin described in US Pat. No. 4,751,087.

The amount of active agent and its concentration per unit area, ie 1 cm 2 or 1 cm 3, vary independently of each other so that the desired therapeutic effect can be achieved. For example, high concentrations of anesthetic base contained in a reduced thickness dosage form result in fast onset and short duration of anesthetic effect. The presence of high concentrations of anesthetic base contained in an increased thickness dosage form (high concentrations of anesthetics per 1 cm 2 or 1 cm 3) results in a strong anesthetic effect of fast onset time and long duration. The low concentration of anesthetic base contained in the reduced thickness dosage forms results in a mild anesthetic effect of long onset and short duration. The low concentration of anesthetic base contained in the dosage form of increased thickness results in a mild anesthetic effect of longer onset time and longer duration. As noted above, from the point of view of the ability to coat thin (about 0.001 inch) or thick (about 0.500 inch or more), the concentration of the active agent may vary from very low (about 1%) to high (more than 40%). The ability allows the practitioner of the present invention to vary the dosages required for topical administration and therapeutic effect at specific sites.

The bioadhesive composition of the present invention may also contain one or more solvents or cosolvents. Such solvents and cosolvents are non-toxic and pharmaceutically acceptable ingredients that are known in the art, which do not substantially affect the properties of the bioadhesives or the solubility of the active agent at the concentrations employed. It is preferable that it is not a liquid. In the case of bioadhesive materials or active agents or both, solvents and cosolvents can be used. The solvent is preferably a polyhydric alcohol or a combination of polyhydric alcohols. The solvent comprises from about 5% to about 50%, preferably from about 10% to about 30% of the dry weight of the overall bioadhesive composition containing a solvent known to plasticize the bioadhesive composition. In particular, effective plasticizers include glycols such as dipropylene glycol and propylene, fatty acids such as oleic and linoleic acid, fatty acid esters such as isopropyl myristate, hydrogenated castor oil, canola, cod liver oil, and vegetable oils such as lanolin, animal oils, and Fish oil, and mineral oil, glycerin, lecithin, tocopherol and tocopheryl acetate. Alternatively, drugs that are liquid at room temperature, such as, for example, nitroglycerin, nicotine, selegiline and the like can also be used as plasticizers.

The use of solvents (including both solvents and plasticizers) has been found to improve tissue and appearance, particularly in processed compositions such as PVP and karaya gum. More specifically, the incorporation of a solvent in the bioadhesive composition causes the powdered Karaya gum particles to swell or gel when added to a mixture or blend containing PVP, solvent, and an active agent, provided the bioadhesion is present. If the composition is not used as a separate adhesive). When processed, the bioadhesive composition is processed to be softer and softer than the bioadhesive composition in the absence of a solvent. Bioadhesive compositions that do not contain any solvent generally fall within the scope of the present invention because they have suitable wear characteristics. However, using a solvent is preferable in view of the foregoing.

"Polyal alcohol" means any organic polyalcohol, and may include dipropylene glycol, propylene glycol, polyethylene glycol, glycerin, butylene glycol, hexylene glycol, polyoxyethylene, polypropylene glycol, sorbitol, ethylene glycol, and the like. have. Other suitable solvents are fatty acids such as oleic acid, linolenic acid, capric acid, and esters of polyethylene, polypropylene and fatty acids, as well as fatty esters or alcohols. Further suitable solvents are nontoxic nonvolatile solvents used in transdermal or transmucosal compositions that solubilize other activators.

The above-mentioned polyhydric alcohols are those having 2-6 alcohol hydroxyl groups. Such polyhydric alcohols include glycols, triols, polyols having 4-6 alcohol hydroxyl groups, and the like. Typical examples of such glycols are glycols of 2-6 carbon atoms, such as ethylene glycol, propylene glycol, butylene glycol, polyethylene glycol, and the like (average molecular weight about 200-8000, preferably about 200-6000). Examples of the triol include glycerin, trimethylolpropane, and the like. Examples of polyols include sorbitol (sorbet), polyvinylpyrrolidone and the like. These polyhydric alcohols may be used alone or preferably in combination of two or three components. Therefore, glycerin, dipropylene glycol can be used alone or glycerin, dipropylene glycol can be used in admixture with butylene glycol.

Among these polyhydric alcohols, alcohols satisfying the requirements relating to the adjustment and maintenance of the softness of the outer surface of the present invention, the requirements related to compatibility and co-dispersibility with other components, and the appropriate hardness of the composition. You can use it freely. Low volatility alcohols are generally preferred, and in this respect dipropylene glycol, glycerin, propylene glycol, butylene glycol, and sorbitol are suitable solvents for use in the present invention.

The actual amount of polyhydric alcohols, or fatty acids, esters, ethers or alcohols that may be used in the composition depends on the nature and amount of other components and therefore cannot be defined under general conditions, but typically the proportions of the total bioadhesive composition Up to about 30%, preferably from about 5% to about 20%, more preferably from about 5% to about 10% by weight based on dry weight.

The term "solubilized" refers to the determination of the active agent when observed under a microscope with a magnification of 25 times, due to the intimate dispersion of the active agent under crystalline or molecular or ionic levels in the solvent and then in the bioadhesive composition.

In general, the concentration of solubilized pharmaceutical active is from about 1% to about 50%, more preferably from about 2.5% to about 40%, most preferably based on the dry weight of the total bioadhesive composition 5 weight percent to about 30 weight percent. As a preferred embodiment of the present invention, in connection with topical administration of a single active agent, ketoprofen in free acid form is used at a concentration of 2-30% by weight of the dry weight of the total bioadhesive composition.

In general, in order to use the combination of anesthetic for topical administration, the weight ratio of free base to salt form is from 90:10 to about 40:60, preferably from 75:25 to about 50:50, more preferably 70: 30 to about 60:40. For other salts, the center ratio is similar to that described above based on the relative molecular weight. Generally, the weight ratio of base to salt is about 1: 2 to about 4: 1. In a preferred embodiment as a combination of anesthetics, the weight ratio of base to salt is about 2: 1, the base used is lidocaine, and the salt used is freerocaine, bepivacaine, diclonin, mepivacaine, or Tetracaine, preferably a hydrochloride salt.

To increase the concentration of the active agent, i.e. below 50% by weight, the active agent is mixed with a suitable solvent at an elevated temperature, for example at 70-100 ° C., to obtain a mixture, preferably an active agent solution, which is then added to the bioadhesive material. do. If no solvent is used, a final composition filled with crystalline mass or crystalline mass is produced.

The choice of suitable solvent for the active agent combination depends on the form of the active agent, depending on whether it is in the form of a free base, free acid, or acid addition salt.

Suitable solvents for anesthetic salt solutions are generally polar organic solvents. The polar organic solvent is preferably the polyhydric alcohol described above. Suitable other solvents for the organic base or acid addition salt form of anesthetics include cyclic ketones [eg, 2-pyrrolidone; N- (2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-dodecylazacycloheptan-2-one and other N-substituted alkyl-azacycloalkyl-2-ones (Azone)] Solvents known to dissolve one or both of these two types, including dimethylformamide and dimethyl sulfoxide. Other solvents suitable for free base anesthetics may include cell envelope disordering compounds known to be effective in topical pharmaceutical formulations, and the like. This compound is believed to aid mucosal administration by congesting the structure of the stratum cornium cell-envelope. Some of these compounds are represented by the formula:

R-X

Wherein R is straight chain alkyl of about 7-16 carbon atoms, non-terminal alkenyl of about 7-22 carbon atoms, branched alkyl of about 13-22 carbon atoms, X is -OH, -COOCH ₃ , -COOC ₂ H ₅ , -OCOCH ₃ , -SOCH ₃ , -P (CH ₃ ) ₂ O, -COOCH ₂ H ₄ OC ₂ H ₄ OH, -COOCH (CHOH) ₄ CH ₂ OH, -COOCH ₂ CHOHCH ₃ , -COOCH ₂ CH ( OR ") CH ₂ OR",-(OCH ₂ CH ₂ ) _m OH, -COOR ', or -CONR' ₂ , where R is -H, -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ OR , -C ₂ H ₄ OH; R ″ is —H or non-terminal alkenyl having about 7-22 carbon atoms; m is a positive integer of 2-6, provided that R ″ is alkenyl, X is —OH or —COOH, and one or more double bonds are in cis arrangement to be.

The bioadhesive composition may also contain a reagent known to facilitate the transport of the active agent through the skin or mucous membranes. These reagents refer to permeation enhancers or penetration enhancers, promoters, adjuvants and absorption promoters, collectively referred to as "enhancers".

Some examples of enhancers include monohydric alcohols such as ethanol and isopropyl alcohol, butyl alcohol, and benzyl alcohol, or dihydric alcohols such as ethylene glycol, diethylene glycol or propylene glycol dipropylene glycol and trimethylene glycol, or glycerin, sorbitol, and polyethylene glycol The same polyhydric alcohols are exemplified by poly, sold under the trade names BRIJ 30, 93, 97 and 35, 52, 56, 58, 72, 76, 78, 92, 96, 700, and 721 by ICI America. Polyethylene of aliphatic alcohols (e.g., cetyl, lauryl, oleyl and stearyl), including oxyethylene (4) and lauryl ether, polyoxyethylene (2) oleyl ether and polyoxyethylene (10) oleyl ether Glycol ethers; Vegetable oils, animal oils and fish oils such as olive oil, castor oil, squalene, and lanolin; Propyl oleate, decyl oleate, isopropyl palmitate, laurate, dodecyl myristate, isofpophyl myristate, glycol palmitate, glycol stearate fatty acid esters to enhance drug diffusion; Fatty acid alcohols such as oleyl alcohol and derivatives thereof; Fatty acid amides such as oleamide and derivatives thereof; Derivatives such as urea and urea that affect keratin to retain water; As polar solvents, for example, dimethyldecylphosphooxide, methyloctylsulfoxide, dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethyl sulfoxide, decylmethyl sulfoxide and dimethyl formamide, which are Affects the permeability of keratin; Salicylic acid, which softens keratin; Amino acids to assist in permeation; Hair follicle ten benzyl nicotinate; Esters of sorbitol and sorbitol anhydrides such as polysorbate 20, and other polysorbates 21, 40, 60, 61, 65, 80, 81, 85, etc., marketed under the trademark Tween 20 by ICI America There are high molecular weight aliphatic surfactants such as lauryl sulfate salts that improve the surface condition.

Other enhancers include oleic and linoleic acid, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopherol acetate tocopheryl linolade, and the like.

In one embodiment of the present invention, a composition of bioadhesives comprises a mixture of one or more water-insoluble bioadhesives and one or more water-soluble bioadhesives, active agents and pharmaceuticals, including solvents known to plasticize the entire bioadhesive composition. Acceptable solvents.

In a preferred embodiment, the pharmaceutically acceptable solvent is used in a preferred amount of about 20% to about 53% by weight based on the dry weight of the total composition, and the plasticizer is about 10% by weight based on the dry weight of the total composition To about 30% by weight, and the bioadhesive material is used in the range of about 20% to about 55% by weight based on the dry weight of the total bioadhesive composition. More preferably, the bioadhesive composition of the present invention comprises from about 10% to about 40% by weight polysaccharide bioadhesive, from about 10% to about water soluble bioadhesive based on the dry weight of the total bioadhesive composition 40 wt%, about 10 wt% to about 60 wt% solvent, about 5 wt% to about 40 wt% active agent, and may also contain an amount of binder sufficient to bind the other components. It is preferred to include a mixture of soluble PVP with other bioadhesives (preferably natural rubber).

In particular, bioadhesion is a pressure sensitive adhesive when karaya gum is used as a polysaccharide bioadhesive with a pharmaceutically acceptable solvent comprising a solvent known to plasticize the entire bioadhesive composition and soluble PVP is used as a water soluble bioadhesive. It was an amazing discovery that I was formed. This is really surprising in that the pressure sensitive adhesive cannot be formed using karaya gum or soluble PVP alone. The bioadhesive / pressure sensitive adhesive composition is formed when karaya gum and PVP are used in a ratio of 1:10 to 10: 1.

In general, the bioadhesive composition may consist of the following types and the following components.

ingredient General use range (% by weight) Preferred range of use (% by weight) Optimal use range (% by weight) Bioadhesive 5-50 10-40 20-30 PVP 5-50 10-40 15-30 menstruum 5-70 10-60 20-53 Active agent 1-50 2.5-40 5-30

The type and amount of PVP required for the preferred embodiment depends not only on the amount and type of drug present in the bioadhesive composition, but also on the type of bioadhesive, but can generally be readily determined through routine procedures.

In general, PVP is present in an amount from about 5% to about 50%, preferably from about 10% to about 40% by weight of the dry weight of the total bioadhesive composition. However, the amount of PVP may be present from 20% to 40% or less, depending on the desired properties of the particular drug and blend used.

The PVP preferably has a molecular weight of about 2,000 to 1,200,000, more preferably 5,000 to 100,000, most preferably 7,000 to 54,000. Preference is also given to PVPs having a molecular weight of about 1,000,000 to about 1,500,000.

The PVP is marketed under the trade name KOLLIDON by BASF AG in Ludwigshafen, Germany, or under PLASDONE, POLYPLASDONE and COPOLYMER 958 in the US, New Jersey, Wayne, ISP Technologies. Preferred PVPs are KOLLIDON 12PF, 17PF, 25, 30, 90 and VA-64.

In a preferred embodiment of the invention, the bioadhesive composition comprises a pressure sensitive adhesive. The term "pressure sensitive adhesive" herein refers to a viscoelastic material that adheres to most surfaces and is permanently tacked upon application of fairly mild pressure. The polymer is a pressure-sensitive adhesive in the sense that if it has a pressure-sensitive adhesive property itself which functions as a pressure-sensitive adhesive when mixed with an adhesive, a plasticizer or other additives, it falls under the meaning of such defining conditions.

Suitable pressure sensitive adhesives are suitable for transdermal devices as hydrophobic adhesives comprising natural or synthetic elastomers such as polyisobutylene, styrene, polybutadiene, styrene isoprene block copolymers, polyurethanes, polyacrylates, polysiloxanes, and styrene / butadiene copolymers. It is meant to include both non-toxic natural and synthetic polymers known to be used.

Particularly preferred pressure sensitive adhesives are acrylic polymers, in particular solvent-based acrylic polymers. "Acrylic polymers" may be used in all of the acrylate polymers, polyacrylates, polyacrylate adhesive polymers disclosed herein and in the art. By "solvent is the main component" is meant that the surfactant is substantially free. (Translation 5)

Acrylic polymers useful in the practice of the present invention are polymers consisting of at least one acrylic acid monomer and other copolymerizable monomers. Acrylic polymers also include copolymers of alkyl acrylates and / or alkyl methacrylates and / or copolymerizable secondary monomers or monomers with functional groups. As is known in the art, varying the amount of each monomer type added can change the cohesive properties of the final acrylic polymer. Typically, acrylic polymers are generally composed of at least 50% by weight of acrylate or alkyl acrylate monomers, 0 to 20% by weight of functional monomers copolymerizable with this acrylate and 0 to 40% by weight of other monomers.

Acrylate monomers that may be used include acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylic Latex, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate and tridecyl Methacrylates.

Usable functional monomers that can be copolymerized with the alkyl acrylates or methacrylates include acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacryl Amides, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, methoxyethyl acrylate, methoxyethyl methacrylate and various monomer units such as alkylene, hydroxy substituted alkylenes, carboxylic acids Substituted alkylene, vinylalkanoate, vinylpyrrolidone, vinylpyridine, vinylpyrazine, vinylpyrrole, vinylimidazole, vinyl caprolactam, vinyloxazole, vinylacetate, vinylpropionate and vinylmorpholine as well as copolymerization Holds one or more unsaturated double bonds involved in the reaction in one molecule, and And other monomers bearing functional groups such as carboxyl groups, hydroxyl groups, sulfoxyl groups, amino groups, amido groups and alkoxyl groups.

Examples and further details of acrylic adhesives suitable for practicing the present invention can be found in Sats, "Acrylic Adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., Pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989).

Suitable acrylic adhesives are commercially available, for example, the National Starch Company (Bridgewater, NJ, USA), trade name DURO-TAK, Monsanto, St. Louis, Missouri, USA. , Trade name HRJ, Schenectady International, Inc., Schenectady, New York, USA; Morton International, Inc., Morton International, Inc., Chicago, Illinois MORSTIK, and polyacrylate adhesives under the trade names EUDRAGIT RL and RS, a product of Roem Parma GmbH, based in Damstad, Germany.

The amount of pressure sensitive adhesive used depends on the concentration of active agent used to achieve the therapeutic effect. Typically, the pressure sensitive adhesive is in an amount of about 10 to about 60 weight percent, preferably about 15 to about 50 weight percent, and most preferably about 20 to about 40 weight percent, based on the dry weight of the total bioadhesive composition. It is common to be used.

In another aspect of the invention, the bioadhesive composition comprises from about 10% to about 60% by weight of the solvent-based acrylic polymer, from about 20% to about 50% by weight of the PVP polymer, based on the dry weight of the total bioadhesive composition. , About 20% to about 53% by weight of one or more solvents and about 10% to about 25% by weight of the active agent, and may further comprise an amount of binder sufficient to bind the other components. Preferred active agents for topical administration may be dissolved in the bioadhesive composition or administered separately.

In addition to the above components, various pharmaceutically acceptable additives and excipients known in the art may be added. Such additives include viscosity giving agents that are particularly useful in embodiments in which the active agent does not plasticize the bioadhesive composition, such as aliphatic hydrocarbons, mixed aliphatic and aromatic hydrocarbons, aromatic hydrocarbons, substituted aromatic hydrocarbons, hydrogenated esters, Polyterpenes and hydrogenated wood rosin. Additional additives include binders, such as lecithin or "silicone-containing" rheology agents (thickeners) that "bond" other components, such as fumed silica, reagent grade sand, precipitated silica, amorphous silica, colloidal silicon dioxide, fused silica, silica gel Silicon commercially available under the trade names Syloid®, Cabosil®, Aerosil® and Whitelite® for the purpose of improving the uniform hardness or continuous formation of quartz and final compositions. There is sex material. Other additives and excipients include diluents, stabilizers, fillers, clays, buffers, biocides, wetting agents, anti-irritants, antioxidants, preservatives, flavors, colorants, pigments and the like. Such additives or excipients are generally used in amounts of up to 25% by weight, preferably from about 0.1% to about 10% by weight of the bioadhesive composition.

The compositions described herein can be prepared by mixing one or more bioadhesives in powder or liquid form with PVP and an active agent, in the presence or absence of a pressure sensitive adhesive, preferably in a low molecular weight solvent of suitable volatility. When a pressure sensitive adhesive is used, the volatile low molecular weight solvent is preferably an organic solvent provided with a pressure sensitive adhesive such as an acrylic adhesive. Conventional liquids used as such volatile solvents are distinguished from those used in emulsion (generally aqueous) polymerizations and are lower molecular weight alkanols used alone or in combination with other volatile solvents and nonvolatile solvents (e.g. isopropanol And volatile polar and nonpolar organic liquids such as ethanol), aromatics such as benzene derivatives (e.g. xylenes and toluene), low molecular weight alkanes and cycloalkanes (e.g. hexanes, heptanes and cyclohexanes) and alkanate esters (e.g. ethyl Acetate or butyl acetate).

This mixture is preferably cast at room temperature and atmospheric pressure and then evaporated the volatile solvent (eg, at a slightly elevated temperature) to form a bioadhesive formulation. Nonvolatile solvents such as polyols or higher temperature boiling point solvents used in the composition remain in the composition.

Each unit or device (sometimes referred to as a "delivery system") comprising the present invention can be manufactured in any manner known in the art. Taking a general manufacturing method as an example.

1. Combine an appropriate amount of PVP polymer, pressure sensitive adhesive, solvent and / or cosolvent, enhancer, additives and excipients and mix thoroughly in a container.

2. Then, if the bioadhesive composition is used as an adhesive source and an activator source, add one or more active agents to the mixture and stir until the actives are mixed uniformly. If not, no active agent is added.

3. Then, an appropriate amount of another bioadhesive material such as karaya rubber is added to the active agent-containing mixture, and mixed thoroughly.

4. The composition is then transferred to a coating work site and coated on a release liner to a specific controlled thickness. The coated composition is then passed through an oven to remove all volatile process solvents.

5. The composition coated on the release liner is then contacted with the backing (layer) and wound into a roll.

6. Die cut and pouch the delivery system of the appropriate size and shape from the roll material.

The order of the steps, the amount of ingredients and the degree and time of stirring or mixing are important process variables that depend on the excipients, additives, enhancers, solvents and / or cosolvents, active agents and the particular polymer used in the composition. This variable can be adjusted by one skilled in the art under consideration of the purpose of obtaining a solubilized active agent and providing a uniform product. Many other methods, such as other methods of coating a backing known in the art (eg, Meyer rods, gravure, knife over rolls, extrusion, casting, calendering and molding) or methods of changing the order of certain steps, such as In one embodiment, the anesthetic may be dissolved in a solvent, preferably a polyhydric alcohol, followed by addition of the resulting mixture to other bioadhesive components prior to coating, which method will also provide desirable results.

However, the inventors have found that adding non-PVP bioadhesives such as karaya rubber to a mixture containing PVP and solvent results in a smoother and softer surface finish of the final bioadhesive composition.

The backing layer, which is generally water barrier, serves to retain and maintain the bioadhesive composition disposed on the layer in a predetermined size and shape, to prevent loss of the active agent and / or enhancer into the environment, and to individual units or delivery. It serves to provide transportability to the system (when holding the release liner together) and to provide barrier properties before and after treatment of the individual unit or delivery system.

Materials suitable for forming the backing layer and which can be used alone or in combinations such as laminates or coextruders are well known in the art, for example polyethylene, polyester, polypropylene, polyurethane, polyolefin, Polyvinyl alcohol, polyvinyl chloride, polyvinylidene, polyamide, vinyl acetate resin, BAREX®, ethylene / vinyl acetate copolymer, film or sheet of ethylene / ethylacrylate copolymer, metal deposited film or Sheets, rubber sheets or films, expanded synthetic resin sheets or films, nonwovens, woven fabrics, knitted fabrics, fabrics, foils and paper.

Generally, the thickness of the backing layer is in the range of 2 to 1000 micrometers, and the thickness of the bioadhesive composition deposited on the backing layer is usually in the range of about 12 to 250 micrometers. The backing layer may be colored, for example colored to harmonize with the treatment site or vice versa, and / or may be colored to easily distinguish from the treatment site and / or the identification and / or tracking of printing, labeling and individual units or the delivery system itself. And other means for use. In addition, the backing layer may be opaque or substantially opaque with metallization, fillers, inks, dyes, etc., to protect photosensitive active agents such as ketoprofen from degradation and / or to prevent photoallergic reactions or irritation to the patient. It may be opaque (i.e. block the penetration or transmission of light or specific energy wavelengths).

It is also generally intended to prevent loss of the active agent and / or enhancer from surroundings, as well as to prevent bioadhesive compositions from contamination, etc., before treatment to the patient, and to individual units or delivery systems (if provided with a backing layer). For the purpose of providing transportability, a release liner or release strip is provided. Typically, the release liner is also impermeable and barrier, but it is essential that it be compatible with the bioadhesive and / or active agent so that the ultimate topical administration and therapeutic effect of the particular bioadhesive and / or active agent are not impeded.

Materials suitable for forming the release liner, which can be used alone or in combination, such as laminates or coextruders, are well known in the art and include all materials suitable for the backing layer. If the release liner is usually composed of a material that does not readily peel off (i.e., is not easily removed or separated from the bioadhesive composition), such as paper, a coating material such as silicone is applied to the release liner using conventional means. can do. Preferred release liners are fluoropolymers under the tradename Mylar® film, a commercial product of DuPont, Wilmington, Delaware, and the trade names FL2000® and MRL2000, which are commercially available products of Rexam release, Oak Brook, Illinois, USA. (Silicone) coating film and a fluoropolymer (silicone) coating film under the trade name ScotchPak® 1022, a commercially available product of 3M Corporation, St. Paul, Minn., USA.

The form of the individual units or delivery systems described herein may be of any form, but is preferably of the desired geometry and size (ie treatment area), if desired or desired. The form can be made by conventional techniques, such as cutting or punching, and the like are described in US Pat. Nos. 5,032,207, 5,405,486 and 5,656,285. The desired site of administration is an important factor in determining the size and shape of the individual units or delivery systems of the present invention and those skilled in the art can adjust as necessary to achieve a therapeutic effect. In general, the size should not exceed 100 cm 2. Preferred sizes range from about 0.1 cm 2 to about 60 cm 2, more preferred sizes range from about 1.5 cm 2 to about 30 cm 2, optimally from about 2.0 cm 2 to about 10 cm 2.

In the bioadhesive composition of the present invention, it is preferable that the active agent is dissolved so that the release liner is directly attached to the skin or mucous membrane after removing the release liner.

Alternatively, the bioadhesive composition can be used in a multilayer delivery system as an "underlay" adhesive layer (layer that attaches directly to the skin or mucosa after removal of the release liner) without an active agent, wherein the active agent is one or more other Dissolved or included in a separate layer, this other layer may or may not include embodiments of the bioadhesive composition of the present invention.

In another embodiment, the bioadhesive composition of the present invention may be used in a reservoir delivery system as a base adhesive or peripheral adhesive layer or ring without an active agent, wherein the active agent is dissolved or contained in a separate reservoir or reservoir, This reservoir or reservoir may or may not comprise an embodiment of the bioadhesive composition of the present invention.

If the bioadhesive composition is used as an adhesive ring around the active reservoir or drug reservoir, the bioadhesive layer will be provided around the active reservoir. In addition, if the bioadhesive composition is used as the base adhesive layer separately from the active agent containing layer, the adhesive layer is adjacent in contact with the first major surface of the active agent layer. The composition is then contacted with a backing layer in contact with the second major surface of the active agent layer opposite the first major surface of the active agent layer and with a second major surface of the adhesive layer opposite the first major surface of the active agent layer. May comprise a removable release liner.

When the bioadhesive layer is used as a separate base layer without an active agent, the thickness of this base layer is usually in the range of 1 to 10 mil thickness, more preferably 2 to 8 mil, most preferably 4 to 6 mil. good.

One particularly preferred embodiment as a bioadhesive composition is soluble PVP, polysaccharides (preferably natural rubber, more preferably karaya rubber), separate plasticizers (preferably glycerin), separate solvents (preferably polyhydric alcohols, More preferably propylene glycol) and one or more active agents when the source of the active agent is not separated from the bioadhesive composition.

The content of each component (excluding the active agent) is expressed as weight percent based on the mixed anhydrous weight of at least one soluble polyvinylpyrrolidone polymer, karaya rubber, polyhydric alcohol and glycerin.

ingredient General range (% by weight) Preferred range (% by weight) Optimum range (% by weight) Karaya rubber 10 to 50 20 to 40 25 to 35 PVP 5 to 30 7 to 15 9 to 13 Propylene glycol 7 to 40 15 to 35 25 to 30 glycerin 10 to 50 20 to 40 25 to 35

When the bioadhesive composition includes one or more active agents, those skilled in the art can adjust the content of the components according to the amount and type of one or more active agents.

The preferred weight ratio of karaya rubber to glycerin is in the range of 10: 1 to 1: 2, more preferably about 1: 1. The preferred weight ratio of karaya rubber to propylene glycol is 10: 1 to 1: 1, more preferably about 1: 0.8. The preferred weight ratio of PVP to karaya rubber is 1: 1 to 1: 7, more preferably 1: 3 to 1: 4.

When the particularly preferred compositions listed in the table above are used as separate adhesive layers, the compositions are required to adhere to mucosal tissue at the instant of substantial contact without the additional pressure necessary time for the composition to adhere to the mucosal tissue. It was found to reduce.

The following examples illustrate the invention in more detail, which are intended to illustrate but not limit the invention disclosed herein.

% Used in Example 1 refers to the ratio of the liquid composition based on weight to weight, with the temperature in degrees Celsius (° C.).

Example 1

ingredient % (w / w) Bio-Adhesive (Karaya Rubber) 21 Polyvinylpyrrolidone 11 Solvent (propylene glycol) 7 Solvent (Glycerin) 19 Anesthetic Base (Lidocaine Base) 28 Anesthetic salts (prilocaine hydrochloride) 14

The final product is prepared by first combining lidocaine base, prilocaine hydrochloride, propylene glycol, PVP and glycerin at about 70-90 ° C. until all of the drug is dissolved. The solution is then cooled to 20-35 ° C. before karaya rubber is added. Immediately after the karaya rubber was added, the final composition was subjected to a suitable backing, such as a non-woven polyester film (e.g., a film under the trade name Sontara 8100 manufactured by Dupont de Nemurt E. & Co., Wilmington, Delaware, USA). The material is applied and warmed to about 100 ° C. to accelerate the formation of the final desired form.

Example 1a

In Example 1a, the composition was prepared as follows without adding a drug. This composition may then be used alone as the base adhesive layer or an activator may be added prior to removing the volatile processing solvent.

ingredient W / w% (anhydrous) Bio-Adhesive (Karaya Rubber) 31.4 Polyvinylpyrrolidone (Kollidon K90) 10.4 Solvent (propylene glycol) 26.8 Plasticizer (glycerine) 31.4

Example 2

20.59 Wet w / w% Karaya Rubber, 10.59 Wet w / w% Soluble PVP (PLASDONE K90), 7.94 Wet w / w% Oleic Acid, 45.0 w / w% Ethanol and 15.88 Wet W / w% Ketoprofen And mixed, and then thoroughly mixed until the mixture is completely homogeneous to prepare a bioadhesive composition. The resulting composition had the following component concentrations based on the dry weight after removing the volatile process solvent (ethanol).

ingredient weight% Bio-Adhesive (Karaya Rubber) 35.36 Polyvinylpyrrolidone (PLASDONE K90) 19.19 Oleic acid 15.15 Ketoprofen 30.30 100.00

In the examples below, the method of Example 2 was used in an appropriate amount of starting material to obtain a composition in which the component concentrations expressed as anhydrous weight / wt% of the total bioadhesive composition were as follows. Volatile solvents are those indicated by () and do not exist in the final composition.

In addition, the drugs described in Examples 21-29 are dispersed in the final composition rather than dissolved.

ingredient Example 3 4 5 6 7 8 Karaya Gum 40 40 35 45 40 40 Polyvinylpyrrolidone (Kollidon 12PF) 30 0 0 0 0 0 Polyvinylpyrrolidone (Kollidon 17) 0 25 0 0 0 0 Polyvinylpyrrolidone (Kollidon 30) 0 0 30 0 0 0 Polyvinylpyrrolidone (Kollidon 90) 0 0 0 20 0 20 Vinylpyrrolidone / Vinyl Acetate (Kollidon VA64) 0 0 0 0 25 0 Oleic acid 10 15 15 15 15 15 Ketoprofen 20 20 20 20 20 20 Lidocaine (base) 0 0 0 0 0 5 Volatile Solvents (ethanol) (75) (75) (85) (100) (85) (100)

ingredient Example 9 10 11 Karaya Gum 25 35 35 Polyvinylpyrrolidone (Plasdone K90) 25 20 20 Linoleic acid 10 0 25 1,3 butylene glycol 10 25 0 Lidocaine (base) 20 0 0 Bulk Bicaine (Base) 0 20 0 Bulk Bicaine (salt) 10 0 20 ethanol (100) (100) (100)

ingredient Example 12 13 14 Karaya Gum 32 0 0 Soybean polysaccharide (Emcosoy 50) 0 0 50 Vinylpyrrolidone / Vinyl Acetate (Kollidon VA64) 28 40 0 Polyvinylpyrrolidone (Plasdone K90) 0 0 25 Alginic acid NF (Satialgine ^TM H8) 0 32 0 Dipropylene glycol 20 18 0 Oleic acid 0 0 15 Sodium diclofenac 20 10 0 Diclofenac (mountain) 0 0 10 ethanol 0 0 (60) Ethyl acetate (45) (75) 0

ingredient Example 15 16 17 Karaya Gum 30 35 0 Polyvinyl acetate (Sentry Plus PVAc 12) 35 0 0 Polyvinyl acetate (Sentry Plus PVAc 40) 0 35 40 Alginic acid NF (Satialgine ^TM H8) 0 0 30 Propylene glycol 0 20 20 Oleic acid 15 0 0 Ketoprofen 20 0 0 Sodium diclofenac 0 10 0 Sodium naproxen 0 0 10 Ethyl acetate 50 (60) (60)

ingredient Example 18 19 20 Karaya Gum 6 10 12 Vinyl Pyrrolidone / Vinyl Acetate (ISP COPOYMER 958) 70 71 0 Vinyl pyrrolidone / dimethylaminoethyl methacrylate (ISP COPOYMER 5630) 0 0 64 Oleyl alcohol 6 6 6 Dipropylene glycol 8 8 8 Testosterone 10 0 0 Methyl testosterone 0 5 0 Testosterone acetate 0 0 10 ethanol 0 0 (100)

ingredient Example 21 22 23 24 25 26 27 28 Karaya Gum 0 0 0 0 0 0 0 29.9 Soybean polysaccharide (Emcosoy 50) 0 0 0 0 0 0 4.9 0 Ethyl cellulose 4) 0 24 0 9.9 37.9 0 0 0 Polyvinylpyrrolidone (Kollidon 90) 0 0 25 60 60 30 0 45 Vinylpyrrolidone / Vinyl Acetate (Kollidon VA64) 40 50 0 0 0 0 0 0 Polyvinyl acetate (Sentry Plus PVAc 12) 0 0 0 0 0 0 40 0 Ethyl cellulose 10) 19 0 0 0 0 0 25 0 Ethyl cellulose 100) 0 0 14 0 0 19.9 0 0 Oleic acid 40 25 60 0 0 0 30 25 Polyoxyethylene (2) oleyl ether (BR1J 93) 0 0 0 2 2 0 0 0 1,3-butylene glycol 0 0 0 28 0 50 0 0 insulin One One One 0.1 0 0 0 0 Arg Vasopressin 0 0 0 0 0.1 0 0.1 0 Calatonin 0 0 0 0 0 0.1 0 0.1 Ethyl acetate (100) (100) (150) (200) (100) (100) (75)

Acetone 0 0 0 0 (200) 0 0 0

ingredient Example 29 30 31 32 33 34 35 36 Ethyl cellulose 7) 36.5 36.5 32.9 33.0 29.4 29.4 0 0 Ethyl cellulose 4) 0 0 0 0 0 0 33.0 36.7 Karaya Gum 13.1 9.8 13.2 16.5 19.9 19.9 13.2 13.1 Polyvinylpyrrolidone (Kollidon 30) 3.4 3.4 6.9 3.4 3.4 3.5 6.9 0 Vinylpyrrolidone (Kollidon 90) 10.5 13.9 10.4 10.5 10.5 10.5 10.4 10.4 Dipropylene glycol 7.3 7.3 7.3 7.3 7.4 7.4 7.3 7.2 Propylene glycol 11.0 11.0 11.0 11.0 11.0 11.0 11.0 11.0 Ketoprofen 18.2 18.1 18.3 18.3 18.4 18.3 18.2 18.1 Polyethylene Oxide (WSRN 750) 0 0 0 0 0 0 0 3.5

Example ingredient 37 38 39 40 41 42 43 Ketoprofen 10 10 10 10 10 10 10 Dipropylene glycol 4.5 4.5 4.5 4.5 4.5 4.5 4.5 Propylene glycol 4.5 4.5 4.5 4.5 4.5 4.5 4.5 Phosphatidylcholine (lecithin PG) 29 29 29 29 29 29 29 Polyvinylpyrrolidone (Kollidon 12PF) 4.5 0 0 0 0 0 0 Polyvinylpyrrolidone (Kollidon 17PF) 0 4.5 0 0 0 0 0 Polyvinylpyrrolidone (Kollidon 30) 0 0 4.5 0 0 0 0 Polyvinylpyrrolidone (Kollidon CL-M) 0 0 0 4.5 0 0 0 Vinylpyrrolidone / Vinyl Acetate (Kollidon VA64) 0 0 0 0 4.5 0 0 Acrylic Adhesive (Eudragit L100) 0 0 0 0 0 4.5 0 Lactose povidone (crospovidone mixture) (Ludipress ) 0 0 0 0 0 0 4.5 glycerin 18.5 18.5 18.5 18.5 18.5 18.5 18.5 Karaya Gum 29 29 29 29 29 29 29

Example ingredient 44 45 46 47 48 49 50 51 52 Cellulose acetate 25.6 15.5 11.0 10.9 15.5 9.4 0 0 0 Karaya Gum 16.1 18.6 19.8 19.6 18.6 17.0 22.0 17.0 18.8 Polyvinylpyrrolidone (Kollidon 30) 0 0 9.9 21.7 20.6 17.9 23.2 17.2 19.8 Ethyl cellulose 7) 0 0 0 0 0 14.2 0 18.9 20.8 Dipropylene glycol 22.4 25.8 27.5 27.2 25.8 23.6 30.5 18.9 20.8 Ketoprofen 18.0 21.5 21.9 20.6 19.5 17.9 24.3 28.0 19.8 Polyvinylpyrrolidone (Kollidon 90) 17.9 18.6 9.9 0 0 0 0 0 0

Example ingredient 53 54 55 Ketoprofen 19 20 19 Polyvinylpyrrolidone (Kollidon 90) 6 6 0 Polyvinylpyrrolidone (Kollidon 30) 0 0 4 Polyvinylpyrrolidone (Kollidon CL-M) 0 0 6 Ethyl cellulose 7) 4 0 0 Propylene glycol 8 8 10 Phosphatidylcholine (lecithin PG) 21 22 19 glycerin 14 15 14 Karaya Gum 28 29 28

Example ingredient 73 74 75 76 77 78 79 80 81 82 83 84 85 Lidocaine (base) 20 20 20 20 0 0 0 0 0 20 19 20 20 Ketoprofen 0 0 0 0 20 0 0 0 0 0 0 0 0 Diclofenac (mountain) 0 0 0 0 0 0 0 8 8 0 0 0 0 Diclofenac (Sodium) 0 0 0 0 0 0 0 12 12 0 0 0 0 Dipropylene glycol 13 8 8 8 8 10 7 8 8 0 0 0 0 Karaya Gum 29 29 29 29 29 37 35 29 28 29 28 29 29 Polyvinylpyrrolidone (Kollidon 30) 0 0 0 0 0 0 0 0 0 0 0 0 5 Polyvinylpyrrolidone (Kollidon 90) 0 5 0 0 5 6 6 5 5 0 5 0 0 Polyvinylpyrrolidone (Kollidon CM) 0 0 5 0 0 0 0 0 0 0 0 0 0 Acrylic adhesive (Eudragit RS100) 0 0 0 0 0 0 7 0 5 0 5 0 0 Lactose Povidone (Crespovidone Mixture) ) 0 0 0 5 0 0 0 0 0 0 0 0 0 Phosphatidylcholine (lecithin PG) 22 22 22 22 22 28 26 22 20 22 21 22 22 glycerin 16 16 16 16 16 19 19 16 14 16 14 16 16 Ethyl Cellulose 7) 0 0 0 0 0 0 0 0 0 0 0 0 0 Propylene glycol 0 0 0 0 0 0 0 0 0 13 8 13 8

Claims (27)

A biocompatible composition in flexible formal form, prepared from a mixture comprising the following components (a) to (d) and useful for topical administration of one or more active agents characterized by being substantially free of water: (a) at least one soluble polyvinylpyrrolidone (PVP) polymer, (b) at least one bioadhesive, (c) a therapeutically effective amount of at least one active agent, and (d) one or more optional solvents. The method of claim 1, The bioadhesive agent is characterized in that it comprises a polysaccharide. The method of claim 1, The bioadhesive agent is characterized in that it comprises a natural gum. The method of claim 1, The bioadhesive agent is characterized in that it comprises a kayal gum. The method of claim 1, The composition is characterized in that it comprises one or more solvents. The method of claim 5, Wherein said at least one solvent comprises a separate solvent and a separate plasticizer. The method of claim 6, Wherein said at least one bioadhesive comprises a Karaya gum, said separate solvent comprises a polyhydric alcohol, and said separate plasticizer comprises glycerin. The method of claim 7, wherein The at least one soluble PVP is present in an amount of 5 to 30% by weight, the karaya gum is present in an amount of 10 to 50% by weight, the polyhydric alcohol is present in an amount of 7 to 40% by weight, and the glycerin Is present in an amount of from 10 to 50% by weight, all of which are based on the combined weight of one or more soluble PVPs, karaya gums, polyhydric alcohols and glycerin. The method of claim 7, wherein The at least one soluble PVP is present in an amount of 7 to 15% by weight, the karaya gum is present in an amount of 20 to 40% by weight, the polyhydric alcohol is present in an amount of 15 to 35% by weight, and the glycerin Silver is present in an amount of 20 to 40% by weight, all of which are based on the combined weight of one or more soluble PVPs, karaya gums, polyhydric alcohols and glycerin. The method of claim 7, wherein And wherein the weight ratio of said at least one PVP to said Karaya gum is 1: 1 to 1: 7. The method of claim 7, wherein Wherein said weight ratio of said at least one PVP to said Karaya gum is from 1: 3 to 1: 4. The method of claim 7, wherein The weight ratio of the Karaya gum to the glycerin is 10: 1 to 1: 2 characterized in that the composition. The method of claim 7, wherein Wherein the weight ratio of karaya gum to propylene glycol is from 10: 1 to 1: 1. The method of claim 7, wherein Wherein said polyhydric alcohol comprises propylene glycol. The method of claim 1, The at least one active agent is anesthetic, anti-inflammatory, analgesic, anti-migraine, antimicrobial, dental active, antibiotic, appetite-reducing agent, polypeptide drug, protein drug, opioid agonist, opioid antagonist, antiemetic agent, A composition characterized in that it is selected from the group consisting of antitumor agents, antiparkinson's drugs, antidiuretics, hormones, bronchodilators, central nervous system stimulants, uterine contractors and vasodilators. A composition for administration of at least one active agent characterized by comprising the following components (a) and (b): (a) at least one active agent source; And (b) is used to adhere to skin or mucosal tissue, (i) at least one soluble polyvinylpyrrolidone (PVP) polymer; (ii) one or more bioadhesives; And (iii) at least one optional solvent, Cohesion layer different from said source (a). The method of claim 16, The source (a) comprises a separate layer containing at least one active agent, wherein the first major surface of the coalescing layer is adjacent and in contact with the first major surface of the separate layer. The method of claim 17, (c) a backing layer in contact with the second major surface of said separate layer facing the first major surface of said separate layer; And (d) a removable release liner in contact with the second major surface of the coalescing layer facing the first major surface of the separate layer The composition characterized in that it further comprises. The method of claim 16, Wherein said source (a) comprises an activator reservoir and said coalescing layer is present in the periphery of said activator reservoir. The method of claim 16, The coalescing layer comprises at least one solvent, the at least one solvent comprises a separate solvent and a separate plasticizer, wherein the at least one bioadhesive comprises a Karaya gum. The method of claim 20, Wherein said separate solvent comprises a polyhydric alcohol and said separate plasticizer comprises glycerine. A method for long-term topical administration of one or more active agents to a subject, characterized by comprising the following steps (a) and (b): (a) preparing a composition according to claim 1; And (b) administering one or more active agents by contacting a region of the skin or mucous membrane with the composition. A method for long-term topical administration of one or more active agents to a subject, characterized by comprising the following steps (a) and (b): (a) preparing a composition according to claim 16, and (b) administering at least one active agent by contacting a region of skin or mucous membrane with at least the adhesion layer. A method for preparing a composition according to claim 1, comprising mixing the following components (a) to (d) to form a composition: (a) at least one soluble polyvinylpyrrolidone polymer, (b) at least one bioadhesive, (c) a therapeutically effective amount of at least one active agent, and (d) one or more optional solvents. A process for preparing a composition according to claim 16, characterized by comprising the following steps (a) and (b): (a) forming an active agent source comprising at least one active agent, and adhering to skin or mucosal tissue comprising (i) mixing (i) one or more soluble polyvinylpyrrolidone polymers, (ii) one or more bioadhesives, and (iii) one or more optional solvents. Forming a separate coalescing layer used. A time for adhering the composition to mucosal tissues, comprising the step of adhering the composition to mucosal tissues at the moment of substantially contact without applying any additional pressure by applying the composition of claim 16 to the mucosal tissues. How to reduce it. The method of claim 1, Wherein said soluble polyvinylpyrrolidone polymer has a molecular weight of about 1,000,000 to about 1,500,000.