RU2276177C2 - Preparation of hydrophilic pressure-sensitive adhesives with optimized adhesive properties - Google Patents

Abstract

FIELD: adhesives.

SUBSTANCE: preparation of hydrophilic pressure-sensitive adhesives allows obtaining adhesives with a particular optimized degree of adhesion. Composition thus obtained contains hydrophilic polymer and complementary short-chain plasticizer, said polymer and said plasticizer being capable of forming hydrogen and electrostatic bonds with each other and are present in proportion optimizing essential characteristics of adhesive composition such as adhesion strength, cohesion strength, and hydrophilicity. Composition may be, for instance, employed as medicinal adhesive for being applied onto skin or other body surface, in drug transportation systems such as, for instance, topical, transdermal, transmucosal systems, by therapeutical iontophoresis, in medicinal cutaneous plaster, wound-healing products, and in biomedical electrodes.

EFFECT: optimized adhesive properties.

58 cl, 11 dwg, 6 tbl, 82 ex

Description

Technical field

The present invention relates to the production of adhesive compositions. In particular, this invention relates to the production of hydrophilic pressure sensitive adhesive compositions (PSA) with optimized adhesive properties suitable for use in transdermal drug delivery systems and other medical, pharmaceutical and cosmetic products that are attached to skin or other body surface. This invention finds application in a number of areas, including transdermal drug delivery, drug iontophoresis systems, manufacturing of biomedical electrodes, wound healing, skin care products and cosmetic products.

BACKGROUND OF THE INVENTION

Pressure sensitive adhesives are well known and have been used for many years. They are used in industry, commerce and medicine. Pressure sensitive adhesives are usually sticky and provide instant adhesion when applied to a substrate. Many polymers are suitable for the manufacture of pressure sensitive adhesives, such as, for example, homo- or copolymers of an ester of acrylic and methacrylic acid, butyl rubber systems, silicones, urethanes, vinyl esters and amides, olefin copolymers, natural or synthetic rubbers and the like. All PSAs are elastomers, that is, they have the viscoelastic properties characteristic of rubbers.

Pressure sensitive adhesives are widely used in transdermal drug delivery systems or “patches” that adhere to skin or mucous tissue. The ability of polymer composite materials to adhere to the substrate, contain and transfer the drug and the presence of the necessary biological properties - all this makes it possible to use them in transdermal drug delivery systems that perform the following functions:

Adhesive: Strong bonding combined with the optimum transition point between sliding and sticking. Transport: Kinetics of drug release controlled by transdermal delivery rate and functional durability of the device. Storage: Compatibility with the drug substance and the ability to maintain storage stability for the introduction of a particular drug substance into the system. Biological: properties Lack of toxicity, skin irritation and sensitization.

Such conflicting requirements are difficult to combine in one system.

Examples of pressure sensitive adhesives that are intended for transdermal drug delivery systems include polysiloxanes (e.g., polydimethylsiloxanes, polydiphenylsiloxanes and mixtures of siloxanes), polyisobutylenes, polyacrylates, copolymers of acrylic acid and acrylate (e.g., copolymers of acrylic acid with 2- ethylhexyl acrylate or isooctyl acrylate) and adhesive rubbers such as polyisobutylene, polybutadiene, polystyrene and isoprene copolymers, polystyrene butadiene and neo copolymers prene (polychloroprene). All of these PSAs are hydrophobic polymers, and their common drawback is the loss of adhesion when applied to hydrated substrates.

"Bioadhesion" means pressure sensitive adhesion to highly hydrated biological tissues, such as mucous tissue. Unlike conventional PSAs (rubber, polysiloxanes and acrylates), which adhere mainly to dry substrates, bioadhesives (VA) provide good adhesion to a hydrated biological substrate. To achieve bioadhesion, water must have a plasticizing effect on the polymer, that is, the polymer must be hydrophilic. For example, typical bioadhesives contain weakly crosslinked polyacrylic and polymethacrylic acids (European patent No. 00371421), as well as mixtures of hydrophilic cellulose derivatives (40-95%) with polyethylene glycol (PEG) (US patent No. 4713243).

Bioadhesives become sticky when the crosslinked polymer swells in significant amounts of water. The cohesive strength of highly swollen hydrophilic polymers is usually low, and bioadhesives are different from PSA in this regard.

For various practical purposes, it is very useful to have a number of polymeric materials PSA and VA having different hydrophilicity and, therefore, different solubility in water or liquids excreted by the skin and mucous membrane (sweat, mucus, saliva, etc.). Attempts to combine the properties of PSA and BA are described in US Pat. No. 5,700,478 to Biegajski et al., According to which a pressure sensitive water soluble mucosal adhesive is prepared by mixing 95-40% polyvinylpyrrolidone (PVP) with 0-50% hydroxypropyl cellulose (LDCs) and 11-60% glycerol. Other examples of mixtures of hydrophilic polymers that combine the properties of PSA and BA are copolymer complexes of polyacrylic acid and polyvinyl alcohol (PAA-PVA), which are prepared by forming a hydrogen bond between the monomer units of the chains of complementary polymers and plasticize using PEG-200, glycerol or polypropylene glycol (PPG) with a molecular weight of 425 g / mol (German patent application DE 4219368).

An ideal performance adhesive designed to be applied to the skin and / or mucous membrane of a person must meet completely different and contradictory technical requirements. First of all, a pressure sensitive adhesive should be suitable for prolonged contact with skin that is permeable, physically and chemically compatible with the active substance, any skin penetration enhancers and other carriers or additives used. The ideal adhesive should not cause irritation, acne and sensitize the skin, while it should quickly adhere to the skin or mucous tissue in the desired area with very little pressure. This adhesive, if necessary, must maintain adhesion for a long period of time, not give in to accidental removal and at the same time be easily removed without damaging the skin and leaving no residue (acceptable adhesion to the skin is from about 200 to 400 N / m when tested on 180 ° peeling). Strong bonding (i.e., approximately more than 50 g / cm ² ) should be accompanied by an optimal transition point between adhesive failure and cohesive rupture of the adhesive joint. In addition, the adhesive must not lose adhesion or break under the influence of moisture or in high humidity. And finally, in order to protect the wound or to hold an electrode or other device in the place of attachment, this adhesive must be resistant to skin movements and able to transfer mechanical stress from the adhesive substrate to the skin.

For many pharmaceutical preparations, the solubility of the active substance in the reservoir of the transdermal drug delivery device is critical. With higher solubility, the rate of transdermal delivery can be increased (i.e., the rate at which the active substance moves from the system to the skin or mucous tissue). Since many drugs are ionogenic organic substances with a higher solubility in hydrophilic media than in lipophilic media, adhesive reservoirs based on hydrophilic polymers are more versatile than adhesive reservoirs based on hydrophobic polymers. In addition, as indicated above, pressure sensitive adhesives that are intended to be attached to mucous tissue should adhere well to hydrated substrates, so hydrophilic adhesives are most suitable.

Hydrophilic adhesives have the following general advantages:

1. Hydrophilic adhesives provide better adhesion compared to hydrophobic adhesives, since the surface energy of hydrophilic adhesives is usually higher and closer to the specified energy of biological substrates, such as skin and mucous membranes.

2. Hydrophilic adhesives are compatible with a range of drugs, excipients and additives.

3. The plasticizing effect of water absorbed by hydrophilic adhesives from hydrated skin or mucous tissue enhances adhesion, in contrast to hydrophobic adhesives.

4. The higher solubility of drugs in hydrophilic adhesives makes it easier to control the kinetics of drug release.

5. When using hydrophilic adhesives based on hydrophilic polymers, it is possible to control and regulate the adhesion-cohesive balance within a wide range.

6. The adhesive properties of hydrophilic polymers are much less sensitive to molecular weight than the similar properties of hydrophobic polymers, due to the specific intramolecular and intermolecular interaction occurring within hydrophilic adhesives.

To increase the hydrophilicity of the adhesive composition, hydrophobic PSAs are “hydrophilized” by incorporating non-adhesive hydrophilic polymers and fillers into the hydrophobic adhesive. Thus, polyisobutylene (PIB) -based PSAs are hydrophilized by introducing cellulose and cellulose derivatives (US Pat. No. 4,231,369), polyvinyl alcohol (PVA), pectin and gelatin (US Pat. Nos. 4,376,732 and 4,867,748) and SiO ₂ (US Pat. No. 5,643,887) ) Rubber adhesives are also modified by introducing amphiphilic surfactants or by treating the PSA polymer with an oxygen plasma discharge. Acrylic PSA can be hydrophilized by filling PVP (US patent No. 5645855). Hydrophilization of hydrophobic adhesives, although it is somewhat effective, causes a partial loss of adhesion.

Thus, in this area there is a need for a new hydrophilic adhesive composition suitable for use in various applications, for example, in a local drug delivery system that meets the above criteria and provides an effective delivery rate of any active substance, regardless of hydrophilic, ionic or lipophilic nature.

The present invention allows to solve the above problem and to create a number of hydrophilic pressure sensitive adhesives that not only satisfy the above criteria, but also have other advantages. For example, these adhesive compositions combine the properties of pressure-sensitive adhesives and bioadhesives and can be used in a number of applications, including not only transdermal, transmucosal and local drug delivery systems, but also wound healing products, biomedical electrodes, drug systems iontophoresis, bioadhesive pads and the like. In addition, these adhesive compositions can be used with a number of active substances, regardless of their hydrophilicity, hydrophobicity and molecular structure. Adhesive products using the compositions of the present invention can be easily prepared by a simple extrusion method without the use of organic solvents and the time-consuming mixing and watering method. Finally, such an adhesive composition can easily be imparted during manufacture the required properties of hygroscopicity, hydrophilicity, adhesive and cohesive strength, and drug delivery kinetics.

Summary of the invention

The main object of the present invention in order to meet the above needs in this area is a method of producing hydrophilic adhesive compositions, pressure-sensitive, which can be used in transdermal drug delivery systems, drug iontophoresis products, wound healing products, biomedical electrodes and other devices and systems, requiring the use of bioadhesives.

Another object of the present invention is a pressure sensitive hydrophilic adhesive that is optimized for adhesive strength, cohesive strength and hydrophilicity.

Another object of the present invention is a therapeutic system for topical or transdermal administration of a pharmacologically active agent, which contains an adhesive agent representing the above hydrophilic pressure-sensitive adhesive composition.

Additional objects, advantages and new distinctive features of this invention will be discussed in the description of the invention and will partially become apparent to specialists in this field when familiarizing themselves with the following description and in the implementation of this invention.

In one aspect of the present invention, a method for producing an adhesive composition with an optimized degree of adhesion is provided, which is that:

(a) a calculation is made whether the composition has an optimum degree of adhesion by

(i) obtaining a plurality of compositions, each containing a hydrophilic polymer having a glass transition temperature T _{st floor} mixed with a miscible plasticizer having a glass transition temperature T _{st floor} and capable of covalently or non-covalently crosslinking a hydrophilic polymer, wherein the mass fraction of the hydrophilic polymer in each the composition is w _floor , and the mass fraction of plasticizer in each composition is w _pl ;

(ii) the calculation of the predicted glass transition temperature T _{Art. before} For each composition by using the Fox equation (1)

and plotting T _st.depend depending on W _PL for each composition;

(iii) determining the glass transition temperature T _st.fact for each composition and plotting T _st.fact as a function of w _pl for each composition;

(iv) determining the area of graphs (i) and (iii) in which T _{st fact is} less than T _{st prev} , so that a deviation from T _{st prev is negative} ;

(v) in the region identified in paragraph (iv), determining the optimum mass fraction of plasticizer w _pl.optim , in which the negative deviation from T _st.pred is maximum; and

(b) selecting a composition as defined in (a) as having a mass fraction of plasticizer w _{pl. optim} , and

(c) mixing the monomeric precursor of the hydrophilic polymer and the plasticizer under polymerization conditions to obtain an adhesive composition with an optimized degree of adhesion, while the mass fraction of plasticizer in the composition is equal to w _pl.optim and the mass fraction of hydrophilic polymer in the composition is 1-w _pl.optim.

In some cases, for example, when a lower degree of adhesion is required, the selected plasticizer mass fraction may not correspond to the maximum negative deviation of T _st.fact from T _st.red , representing any other predetermined deviation of T _st.fact from T _{st.red .} Therefore, in accordance with another aspect of the present invention, a method for producing an adhesive composition with a predetermined degree of adhesion is provided, which is that:

(a) calculate whether the composition has an optimum degree of adhesion by

(i) producing a plurality of compositions, each containing a hydrophilic polymer having a glass transition temperature T _{st floor} , mixed with a miscible plasticizer having a glass transition temperature T _{st floor} and capable of crosslinking the hydrophilic polymer covalently or non-covalently, wherein the mass fraction of the hydrophilic polymer is each composition is w _floor , and the mass fraction of plasticizer in each composition is w _pl , so that w floor is 1-w _pl ;

(ii) calculating the predicted glass transition temperature T _senior for each composition using the Fox equation (1)

and plotting T _st.speed depending on w _PL for each composition;

(iii) determining the glass transition temperature T _st.fact for each composition and plotting T _st.fact as a function of w _pl for each composition;

(iv) determining the area of the graphs (ii) and (iii) in which T _{senior fact} has a predetermined deviation from T _{senior limit} ; and

(b) selecting a composition as defined in (a) as having a predetermined deviation from T _senior ; and

(c) mixing the monomeric precursor of the hydrophilic polymer and the plasticizer under polymerization conditions to obtain an adhesive composition with an optimized degree of adhesion, wherein the mass fraction of plasticizer in the composition corresponds to the value characteristic of the region identified in (iv).

In accordance with another aspect of the present invention, there is provided a pressure-sensitive hydrophilic adhesive composition that comprises (a) a hydrophilic polymer having a glass transition temperature T _{st floor} , and (b) a complementary short chain plasticizer with a terminal hydroxyl or carboxyl group having a glass transition temperature T _stpl and capable of forming a hydrogen or electrostatic bond with a hydrophilic polymer, while the mass ratio of the hydrophilic polymer and the complementary short-chain plasticizer is selected taking into account the achievement of a predetermined deviation (a) the actual glass transition temperature T _{article the fact of the} composition from (b) the estimated glass transition temperature T _{Art. pred} calculated for the composition using the Fox equation. To achieve maximum adhesion, a predetermined deviation must correspond to the maximum negative deviation T _{Art. fact} from T _{Art. before} The difference between T _{Art. sex} and T _{Art. pl} should preferably be equal to at least about 50 ° C, so that T _{Art. the fact} for each composition is determined only with the help of T _{Art. pl} .

In accordance with yet another aspect of the present invention, there is provided a pressure sensitive hydrophilic adhesive composition that comprises (a) a hydrophilic polymer and (b) a complementary short chain plasticizer with a terminal hydroxyl or carboxyl group capable of forming a hydrogen or electrostatic bond with a hydrophilic polymer, wherein hydrogen bonds to covalent crosslinks and / or the ratio of the hydrophilic polymer to the plasticizer is chosen so as to optimize the hydrophilic nost, adhesive and cohesive strength of the composition.

Another aspect of the present invention is a drug delivery system for topical or transdermal administration of a pharmacologically active agent. The drug delivery system includes:

(A) a drug reservoir containing

(1) a substantially non-aqueous, pressure-sensitive adhesive matrix of a hydrophilic polymer having a glass transition temperature T _{art. floor} , and a complementary short-chain plasticizer with a terminal hydroxyl or carboxyl group having a glass transition temperature T _{st. PL} and capable of forming a hydrogen or electrostatic bond with a hydrophilic polymer, and the mass ratio of the hydrophilic polymer and the complementary short-chain plasticizer is chosen taking into account the achievement of a predetermined deviation (a) of the actual glass transition temperature T _{Art. the fact of the} composition from (b) the estimated glass transition temperature T _{Art. pre} composition calculated using the Fox equation, and

(2) a therapeutically effective amount of an active substance;

(B) a substrate forming a layered structure with a reservoir for a medicinal substance, which serves as the outer surface of the specified device during use.

The adhesive compositions of this invention can also be used in a number of additional applications, for example, in supporting dressings, dressings for wounds and burns, devices for stoma, devices for fastening dentures, face masks, sound, vibration or shock absorbing materials and the like. These compositions can be made electrically conductive by introducing water and / or another electrically conductive substance, so that they can be used to attach electrically conductive products, such as an electrode (for example, an electrode for electrical transdermal nerve stimulation or TENS, an electrosurgical outflow electrode, or electrocardiographic electrode).

Brief Description of the Figures

Figure 1 is a schematic representation of the molecular structure of a crosslinked complex with hydrogen or electrostatic bonds, which is formed by a long chain hydrophilic polymer and a short chain plasticizer.

Figure 2 shows a graph illustrating the adhesion characteristics of a mixture of PVP-PEG (polyvinylpyrrolidone-polyethylene glycol) (molecular weight 400 g / mol) obtained by applying a peeling force at an angle of 180 °, necessary for the destruction of the adhesive compound with a polyethylene (PE) substrate when peeling rate of 10 mm / min, as well as changes in the glass transition temperature, T _{g of the} mixture. Dots indicate experimental data, and the line connecting the T _g values for PVP and PEG-400 was obtained using the Fox equation.

Figure 3 shows a graph of ΔC _p T _g depending on the composition of the mixtures of PVP with PEG-400.

Figure 4 shows the results of the influence of the ratio of the hydrophilic polymer and plasticizer, as well as the relative humidity of the environment on the adhesion of PVP, plasticized PEG-400, obtained by applying a peeling force at an angle of 180 °.

Figure 5 shows a Kovax graph for a compatible PVP-PEG mixture.

Figure 6 illustrates the kinetics of compression of the PVP-PEG adhesive hydrogel under constant compressive load and recovery after unloading. The value h means the distance (mm) between the upper and lower plates of a plane-parallel dilatometer, which is equal to the thickness of the sample.

Figure 7 shows the rheological behavior of the adhesive PVP-PEG hydrogel upon application of a compressive load of 1 N at 20 ° C.

On Fig shows the functions of the elastic rebound after creep for the adhesive hydrogel PVP-PEG compared with polybutadiene (PB) and polyisoprene (PI) rubber.

Figure 9 shows the isotherms of water vapor absorption for PVP and its mixtures with PEG-400 at room temperature.

Figure 10 shows the sorption isotherms of water vapor with polyvinylcaprolactam (PVCap) and PVP at room temperature.

11 shows the effect of relative humidity (RH) on the adhesion of the PVP-PEG and PVCap-PEG hydrogels.

DETAILED DESCRIPTION OF THE INVENTION

Before proceeding with a detailed description of the present invention, it should be noted that, except where otherwise indicated, this invention is not limited to specific therapeutic agents, polymeric materials, drug delivery systems and the like, since all of them can be modified. It should also be indicated that the terminology used in this description of the invention serves only to describe specific embodiments of the invention and is not limited to it.

It should be noted that used in this description of the invention and the attached claims, the singular include the plural, except in cases where the context clearly indicates the opposite. Thus, for example, the term “hydrophilic polymer” means a mixture of two or more such polymers, the term “crosslinking agent” means mixtures of two or more crosslinking agents, and so on.

In the description and claims of the present invention, the following terminology is used in accordance with the following definitions.

The terms "active substance", "drug" and "therapeutic agent" are used interchangeably and mean a chemical substance or compound suitable for transdermal administration or administration through the mucous membrane and providing the desired effect. These terms refer to therapeutic, prophylactic, or cosmetic agents. These terms also apply to derivatives and analogs of these compounds or to specific classes of compounds that also provide the desired effect.

The term "transdermal or transdermal" drug delivery means the application of the drug to the surface of the skin of the subject, so that the drug penetrates the skin tissue and enters the bloodstream of the patient. The term "transdermal" also means the administration of a drug substance through the mucous membrane, that is, the application of a drug substance to the surface of the mucous membrane (for example, sublingually, buccally, vaginally, rectally) of a subject in which the drug penetrates through the mucous tissue and enters the bloodstream of the subject.

The term "local administration" is used in the conventional sense and means the delivery of the active substance to the skin or mucous membrane, as is the case, for example, with the local administration of a medicinal substance for the prevention or treatment of various skin diseases, application of cosmetics and cosmetics (including moisturizers tools, masks, sun protection products, etc.) and the like. Local administration, in contrast to transdermal administration, provides a local rather than systemic effect.

The term "body surface" means skin or mucous tissue, including the inner surface of body cavities having a mucous membrane. The term “skin” includes the term “mucous tissue” and vice versa.

Similarly, when using the term “transdermal” in terms such as “transdermal administration of a drug” and “transdermal drug delivery system”, it should be obvious that, unless otherwise indicated, having a different meaning, is meant to be administered “through the mucous membrane "and the" local "introduction.

"Hydrophobic" and "hydrophilic" polymers have definitions proposed by Zaikov et al. (Zaikov et al. (1987), "Diffusion of electrolytes in polymers", VSP (Utrecht-Tokyo). These definitions are based on the amount of water vapor absorbed by the polymers at 100% relative humidity According to this classification, hydrophobic polymers absorb up to 1 wt.% water at 100% relative humidity ("RH"), while a moderately hydrophilic polymer absorbs 1-10 wt.% water at 100% relative humidity, hydrophilic polymers are capable of absorbing more than 10 wt.% water, while emya as a hygroscopic polymers adsorb more than 20 wt.% water.

The term "crosslinked" means a composition containing intramolecular and / or intermolecular cross-links resulting from covalent or non-covalent binding. "Non-covalent" binding includes the formation of hydrogen bonds, electrostatic (ionic) bonds and absorption.

The terms “sticky” and “stickiness” are quality. However, the terms “generally non-tacky”, “moderately tacky” and “tacky” as used herein can be quantitative definitions if used in accordance with the accepted values in PKI or TRBT methods for determining tack. In this case, the term "mostly not sticky" means a composition whose tack is less than 25 g-cm / sec, the term "moderately sticky" means that the stickiness of such a composition is in the range from 25 g-cm / sec to 100 g cm / sec, and the term "sticky" refers to a composition whose tack is at least 100 g-cm / sec.

In the event that there are no other ways of expression, all values of the molecular weights presented here are considered to be average molecular weights.

In a first embodiment, the present invention relates to a method for producing hydrophilic PSA by mixing a specific amount of a selected hydrophilic polymer with a specific amount of a selected plasticizer using complementary short chain plasticizers capable of forming hydrogen bonds with a hydrophilic polymer. Suitable hydrophilic polymers include repeating units derived from an N-vinyl lactam monomer, a carboxyvinyl monomer, a vinyl ester monomer, a carboxyvinyl monomer ester, a vinyl amide monomer and / or hydroxyvinyl monomer. Such polymers include, for example, poly (N-vinyl lactams), poly (N-vinyl acrylamides), poly (N-alkyl acrylamides), substituted and unsubstituted polymers of acrylic and methacrylic acid, polyvinyl alcohol (PVA), polyvinylamine, their copolymers and copolymers with other types of hydrophilic monomers (e.g., vinyl acetate).

Poly (N-vinyl lactams) suitable for use in the present invention are preferably non-crosslinked homopolymers or copolymers of monomer units of N-vinyl lactam, representing most of the monomer units of a poly (N-vinyl lactam) copolymer. Preferred poly (N-vinyl lactams) for use in the present invention are prepared by polymerizing one or more of the following N-vinyl lactam monomers: N-vinyl-2-pyrrolidone, N-vinyl-2-valerolactam and N-vinyl-2-caprolactam. Non-limiting examples of non-N-vinyl lactams comonomers that can be used with the monomer units of N-vinyl lactam are N, N-dimethyl acrylamide, acrylic acid, methacrylic acid, hydroxyethyl methacrylate, acrylamide, 2-acrylamido-2-methyl-1-propanesulfonic acid or salts and vinyl acetate.

Poly (N-alkyl acrylamides) include, for example, poly (methacrylamide) and poly (N-isopropyl acrylamide) (PNIPAM).

Polymers of carboxyvinyl monomers are usually prepared from acrylic acid, methacrylic acid, crotonic acid, isocrotonic acid, itaconic acid and anhydride, 1,2-dicarboxylic acid such as maleic acid or fumaric acid, maleic anhydride or mixtures thereof, the most preferred in this class are hydrophilic polymers comprising polyacrylic acid or polymethacrylic acid, preferably polyacrylic acid.

Preferred hydrophilic polymers are the following polymers: poly (N-vinyl lactams), in particular polyvinyl pyrrolidone (PVP) and poly (N-vinyl caprolactam) (PVCap); poly (N-vinylacetamides), in particular polyacetamide per se; polymers of carboxyvinyl monomers, in particular polyacrylic acid and polymethacrylic acid; as well as their copolymers and mixtures. PVP and PVCap are particularly preferred.

The molecular weight of the hydrophilic polymer is not critical; however, the weight average molecular weight of the hydrophilic polymer is usually from about 100,000 to 2,000,000, usually from about 500,000 to 1,500,000. The hydrophilic polymer may or may not be adhesive in nature, since the non-adhesive hydrophilic polymer becomes adhesive when mixed with a predetermined amount of plasticizer.

A complementary short-chain plasticizer has terminal hydroxyl, amino or carboxyl groups and is usually a monomeric or oligomeric substance having a glass transition temperature T _g in the range of from about -100 ° C to about -30 ° C and a melting point T _m below about 20 ° C. The plasticizer may also be amorphous. The difference between the T _g values of the polymer and the plasticizer is crucial for the adhesive behavior of the polymer-plasticizer mixture. Said difference should preferably be greater than about 50 ° C, preferably more than about 100 ° C, and even more preferably in the range of about 150 ° C to about 300 ° C. The hydrophilic polymer and the complementary short chain plasticizer must be compatible, that is, able to form a homogeneous mixture that has a single T _g intermediate between the values of unmixed components. The plasticizer typically has a molecular weight in the range of about 45 to about 800, preferably in the range of about 45 to about 600. Examples of suitable plasticizers include, but are not limited to, low molecular weight polyhydric alcohols (eg, glycerol), monomeric or oligoalkylene glycols, such as ethylene glycol and propylene glycol, partial ethers of polyhydric alcohols (e.g. glycol ethers), alkanediols from butanediol to octanediol inclusive, derivatives of polyalkylene glycols with terminal carboxylic and amine nogruppami such as polyethylene glycol-dicarboxylic acid. Polyalkylene glycols, optionally having terminal carboxyl groups, are preferred, and polyethylene glycol with a molecular weight of from about 300 to 600 is an optimal plasticizer.

The hydrophilic polymer and plasticizer must mix well with each other and have different chain lengths (as follows from the foregoing). The ratio of the molecular weight of the hydrophilic polymer to the molecular weight of the short chain plasticizer should be from about 200 to 200,000, preferably from about 1250 to 20,000. In addition, the polymer and plasticizer must have complementary functional groups capable of forming hydrogen or electrostatic bonds with each other. Ideally, the complementary functional groups of the polymer should be part of the polymer units, and the functional groups of the plasticizer should preferably be at both ends of the linear macromolecule and not be present in the main chain if the plasticizer is a polymer or oligomer. The formation of hydrogen or ionic bonds between two terminal functional groups of the plasticizer and the corresponding functional groups located in the main chain of the hydrophilic polymer, allows to obtain non-covalently linked supramolecular network structure, shown in simplified form in figure 1. The strong interaction between the complementary groups of the plasticizer and the hydrophilic polymer gives cohesive strength to the spatial structure. At the same time, due to the corresponding length and flexibility of the plasticizer molecules, they act as spacers, creating a free volume between cohesively interacting macromolecules of a hydrophilic polymer. Thus, they provide the seemingly contradictory functional properties of pressure sensitive adhesives, namely the inherent fluidity of the fluids needed for adhesive bonding, combined with the inherent rubber resistance to shear deformation, necessary to dissipate the delamination energy when the adhesive bond is broken.

In addition, it was found that a plasticizer reduces the glass transition temperature of a composition based on a hydrophilic polymer / plasticizer to a much greater extent than forecasting based on the Fox equation, which can be expressed by equation (1):

where T _{g predicted} is the estimated glass transition temperature of the hydrophilic polymer / plasticizer composition, w is the mass fraction of the hydrophilic polymer in the composition, w is the mass fraction of plasticizer in the composition, T is the glass transition temperature of the hydrophilic polymer and T is the glass transition temperature of the plasticizer. The inventors have found that an adhesive composition with an optimized (e.g., maximum) degree of adhesion can be obtained from a hydrophilic polymer and a complementary plasticizer by selecting components and their relative amounts so as to obtain a predetermined deviation from T _{g predicted} , even if each component individually not sticky. A predetermined deviation from T _{g predicted is} usually the maximum negative deviation so that it is with this composition that the adhesive strength is maximum.

That is, the mass ratio of the hydrophilic polymer to the plasticizer must have a predetermined value so that the mixture of the non-adhesive (non-sticky) hydrophilic polymer and the short-chain complementary plasticizer becomes adhesive. As shown in figure 2, in mixtures of PVP with PEG-400 adhesion is inherent only in those compositions that are characterized by negative deviations from the value of T _g calculated using the Fox equation (1). The larger the negative deviation, the stronger the adhesion. This conclusion is universal and is not limited to PVP-PEG-400 mixtures. The negative deviation is preferably from about 30 ° C to about 150 ° C, preferably from about 50 ° C to about 120 ° C. The magnitude of the negative deviation T depends on the difference between the values of T of the components of the mixture, that is, between T _{Art. sex} and T _{Art. pl} . As a rule, the negative deviation of T _article should be approximately 20-40% of the difference between the values of T _article unmixed polymer and plasticizer.

Another common indicator of the adhesive behavior of the polymer mixture is ΔС _p T _article , where ΔС _p means the change in heat capacity at the transition point of the polymer from the glassy to viscoelastic state. This value allows you to determine the amount of heat required for the transition of the polymer from the glassy to the viscoelastic state and the message of translational mobility to the polymer segments. When mixing PVP with PEG-400, the value of ΔC _p T _article decreases, reaching a minimum value that corresponds to the maximum adhesion of the mixture (figure 3). It is the value ΔС _p T _{article that} distinguishes PSA from non-adhesive polymers (table 1). Values ΔС _p T _st characteristic for adhesive mixtures of PVP-PEG and hydrophobic PSA (polydimethylsiloxane, polyisobutylene and natural rubber) are grouped in a narrow region from 45.0 to 92.0 J / g and are mainly 65-80 J / g . Non-adhesive polymers have higher values ΔС _p T _Art .

Table 1 Glass transition characteristics of polymers Polymer T _Art , K ΔС _p , J / g K ΔС _p T _Art. J / g Polydimethylsiloxane 150 0.30 45.0 Polyisobutylene 200 0.40 79.6 Natural rubber 200 0.46 92.0 Polyethylene 237 0.39 92.5 Peg-400 200 0.51 101,4 Bisphenol Polycarbonate 415 0.25 103.9 Polymethyl methacrylate 385 0.29 112.8 Poly (N-vinylpyrrolidone) 449 0.27 121,2 Polypropylene 253 0.55 139.2 Polystyrene 375 0.38 141.0 Polyvinyl acetate 305 0.50 153.4 Polyethylene terephthalate 340 0.49 165.7 Polyvinyl chloride 355 0.63 229.9

The value of ΔC _p T determines a very delicate balance between the free volume and the cohesive interaction energy in polymers (Feldstein et al. (1999), Polym Mater. Sci. Eng. 81: 467-468). As a rule, for adhesion to occur, it is necessary that the increase in free volume is balanced by a high cohesive interaction energy. An increase in the free volume causes an increase in the molecular mobility of the PSA polymer and its fluidity as a liquid, while the significant cohesive interaction energy determines the cohesive strength and the inherent rubber resistance to flow.

Since the actual glass transition temperature T _{article the fact} for the adhesive compositions of the present invention is usually much lower than the temperature determined using the Fox equation, in particular because the composition of the preferred adhesives is chosen taking into account the achievement of the maximum negative deviation T _{article fact} from T _{Art. before} , the heat required to convert the glassy polymer mixture into a viscoelastic composition is minimal.

At the most fundamental molecular level, all the functional properties of polymer materials are determined by the structure and interaction of the macromolecules of the components of the polymer mixture. It also determines the relationship between diffusivity and stickiness of pressure sensitive adhesives. As has been recently shown (Feldstein et al. (2000), Proceed. 23 ^{rd Annual Meeting Adhesion Soc., Pp.54-56} ) to break the adhesive bond of cohesive type (which is typical for the different polymers and polymer mixtures PSA) peel force P necessary for breaking the adhesive bond depends on the self-diffusion coefficient of the polymer segment PSA, D, using equation (2):

where b is the width and l is the thickness of the adhesive layer, α is the size of the diffusing polymer segment, N is the Avogadro number, r is the relaxation time of the segment, and σ _f is the critical stress during the destruction of the adhesive polymer under the action of a peeling force. Equation (2) establishes a general relationship between the adhesive strength, molecular mobility (D) and cohesive strength (σ _f ) of the PSA polymer.

Without limiting themselves to theory, the authors of the present invention believe that equation (2) explains why the adhesion reaches its maximum value when mixing a hydrophilic polymer with a short-chain plasticizer having complementary reactive functional groups at the ends of the chain. The formation of hydrogen or electrostatic bonds at both end groups of the plasticizer chain causes non-covalent crosslinking of the chains of the hydrophilic polymer into the supramolecular network structure. Due to the considerable length and flexibility of the plasticizer chains, the crosslinked structure has increased free volume and molecular mobility, combined with high cohesive strength, that is, it creates exactly those properties that determine the adhesive behavior of polymer mixtures. As the plasticizer concentration increases, the molecular mobility (D) increases, while the cohesive strength (σ _f ) has the opposite tendency to change. For this reason, a lower relative amount of hydrophilic polymer makes it possible to obtain a liquid or semi-liquid composition, and a higher relative amount of hydrophilic polymer gives a material with high cohesive strength. High cohesive strength, in turn, causes a deterioration in mechanical properties and, in the case of drug delivery systems, slows down the rate of drug release.

As shown in figure 4, the absorption of water has the opposite effect on the adhesion of mixtures of hydrophilic polymers with a low content of short-chain telechelic plasticizer (27.3%) and a high content of such plasticizer (45.8 and 52.9%). The absorption of water vapor is accompanied by a significant plasticizing effect, as evidenced by a significant decrease in the glass transition temperature of the hydrophilic polymer. The left (ascending) part of the curves in figure 3 corresponds to compositions located in close proximity to the glass transition temperature, while water acts here as a plasticizer, stimulating the transition of PSA to a viscoelastic state and increasing adhesion. In contrast, for the rubber-like mixtures shown in the right (downstream) part of the graph, water serves as a co-solvent and helps to reduce adhesion by reducing the cohesive strength of hydrogels (see equation (2)). Thus, by changing the ratio between the plasticizer and the hydrophilic polymer, it is possible to transform the composition from bioadhesive to pressure sensitive adhesive.

The PVP-PEG system is considered as a model in this description of the invention, but it should be noted that the present invention is not limited to this composition, and in its implementation, instead of PVP and PEG, a number of other hydrophilic polymers and plasticizers can be used. The wide applicability of this invention is primarily the result of the properties of plasticizers, and not hydrophilic polymers. This fundamental conclusion has a theoretical foundation. As shown in examples 1-67, the specific type of behavior T _{g of the} composite mixture, determined by the negative deviation from the weight average values calculated using the Fox equation (1), -ΔT _article , and the value ΔС _p T _article , is the factor determining the adhesion. Many equations have been proposed for expressing the dependence of T _article on the composition of compatible polymer blends and plasticized systems (see Aubin (1988), Prud'homme RE "Analysis of the glass transition temperature of miscible polymer blends", Macromolecules 21: 2945-2949). In general, it was found that a change in T _g depends on the composition of the composition, characterized by a rapid initial decrease and subsequent gradual equalization as the plasticizer is added. The difference between the measured values of T _article and the predicted values calculated on the basis of the corresponding equations is usually considered an indicator of the strength of the interaction between the molecules of the components used. The Kovax equation (3) is true if the difference T _st between the glass transition temperature of the plasticizer (PEG) and the glass transition temperature of the polymer (PVP) (and between any other miscible hydrophilic polymer and the complementary plasticizer) is greater than 50 ° C:

where f _g is the partial free volume of PVP at T, Δα means the coefficient of thermal expansion for PEG and φ represents the volume fraction of the polymer in the mixture. It has been found that the coefficient f has the same overall value of about 0.025 for all polymers (see Ferry (1970). Viscoelastic Properties of Polymers, 2nd Ed., Wiley: NY, Chapter 11). The Kovax equation (3) theoretically confirms that the specific behavior of the glass transition temperature of the PVP-PEG system is due to the properties of PEG. In fact, no other factors related to PVP, with the exception of the total value of f _article (which is the common value for different polymers), do not regulate the T _{article of the} mixture. Thus, the Kovax equation in relation to the PVP-PEG system suggests that the difference between the T values of the hydrophilic polymer and the short-chain complementary plasticizer should be greater than 50 ° C in order to achieve pressure-sensitive adhesion in polymer and plasticizer mixtures.

Equation (3) shows that when using any short-chain telehelic plasticizer, the mixture composition, which corresponds to the maximum negative deviation T _{art. fact} from T _{Art. before} and, consequently, maximum adhesion, the structure of the hydrophilic polymer with a higher value of T _{article is} practically not affected. In other words, if the highest degree of adhesive strength occurs in PVP-PEG mixtures at a PEG concentration of 36 wt.%, Mixtures of PEG with other complementary hydrophilic polymers will also have a maximum adhesion at a plasticizer concentration of about 36 wt.%, Provided that T _{article of the} hydrophilic polymer is more than 50 ° C higher than T _{article of} plasticizer.

The hydrophilic polymer and plasticizer are mixed in a ratio that provides optimal adhesive and cohesive strength, as well as hydrophilicity and, consequently, the kinetics of drug delivery in controlled drug delivery systems. This ratio should have the above value, that is, the preferred mass ratio of the hydrophilic polymer and the plasticizer should be in the range determined by the maximum values of the negative deviation T _article from the weight average values calculated using the Fox equation (1) or determined based on the minimum values of the criterion ΔС _p T _Art (figure 2 and 3).

The free volume and cohesion energy of polymer compositions must be in a predetermined ratio so that the composition has pressure sensitive adhesion. See Feldstein et al. (1999), "Quantitative relationship between molecular structure and adhesion PVP-PEG hydrogels", Polym. Mater. Sci. Eng. 81: 465-466; Feldstein et al. (1999), "Contribution of molecular mobility to debonding of pressure sensitive adhesive hydrogels", Polym. Mater. Sci. Ehg. 81: 465-466; Feldstein et al. (1999), "A structure - property relationship and quantitative approach to the development of universal transdermal drug delivery system", in: T. Sohn and VA Voicu (eds.), NBC (Nuclear, Biological, and Chemical) Risks - Current Capabilities and Future Perspectives for Protection, Kluwer Academic Publishers, NATO Science Series: 1, Disarmament Technologies, vol. 25, Dordrecht-Boston-London (1999), pp.441-458; and Feldstein et al. (2000), "Molecular insight into rheological and diffusion determinants of pressure sensitive adhesion", Proceed. 23 ^rd Annual Meeting Adhesion Soc. 2000, pp. 54-56.

To achieve high adhesion, strong cohesive interaction must be balanced by a large free volume. The cohesive interaction energy in adhesive hydrogels is controlled both by the ratio of the concentration of the hydrophilic polymer and the short-chain plasticizer, and by the ratio of the content of the crosslinking agent and the hydrophilic polymer. As a measure of adhesion, you can use the durability of the adhesive compound under the action of a constant peeling force, t * (s), measured by the compression-reduction test, the method of which is described by Kotomin et al. (Kotomin et al. (2000), "Durability and fracture of some viscoelastic alhesives ", Proceed. 23 ^rd Annual Meeting Adhesion Soc., pp. 413-415. The high durability at break of the adhesive bond indicates a high degree of adhesion in a conventional peeling test.

The composition may or may not be hydrated, depending on the desired application. For example, transdermal and mucosal drug delivery systems typically contain 0-7 wt.% Water, while products such as face masks, electrically conductive adhesive products, cosmetic products, topical pharmaceuticals and other products in which a gel type adhesive (i.e., an adhesive in the form of a hydrogel) is needed, typically contain from about 7 wt.% to about 40 wt.% water. The optimum degree of hydration depends on the nature and hygroscopicity of the hydrophilic polymer and short-chain plasticizer. For example, the PVP-PEG-400 system, which is optimal for most applications, contains from 2 to 20 wt.% Residual water, preferably from 2 to 12 wt.% Water, most preferably from 6 to 10 wt.% Water. It should be noted that an increase in the hygroscopicity of the plasticizer with a decrease in the length of the PEG chain leads to an increase in the degree of optimal hydration, while the replacement of highly hygroscopic PVP with less hygroscopic PVCap leads to a decrease in hydration with better adhesion. However, some hydration occurs when the adhesive composition is applied to the skin or other surface of the body. In some cases, it may be desirable to add water or an organic solvent, such as ethyl alcohol, to the adhesive composition prior to its use in order to obtain a hydrogel. Hydrogel may be preferred in a number of cases.

These compositions are self-adhesive and usually do not require the addition of any substances to increase the stickiness. However, other additives may also be incorporated into the adhesive compositions of the present invention if they do not in any way impair the properties of the composition. For example, the following optional components are often present in adhesive formulations; they are given in this description of the invention for illustrative purposes only and do not limit the compositions of the adhesive compositions. These optional components include fillers, polymerization degree regulators designed to change molecular weight (e.g. carbon tetrabromide, mercaptans or alcohols), pigments, dyes, refractive particles, preservatives, stabilizers, hardening agents, antimicrobials (e.g., mercurochromium, silver sulfadiazine, iodpovidone, iodine), cosmetics (e.g. glycerin, urea, allantoin, sulfur, anthraquinone, hydroquinones), wetting agents, moisturizers, anesthetics (e.g. benzoka in), healing agents (for example, collagen) and the like. Insoluble fibrous fillers can be successfully incorporated into such compositions to control the degree of hydration when applying the adhesive to the skin or other surface of the body. Such fillers may include cellulosic materials described in International Patent Publication No. WO 89/03859, for example, paper with an ordered and random arrangement of fibers and cotton materials. Other suitable fillers are inert, i.e. substantially non-adsorbents, and include, for example, polyethylenes, polypropylenes, copolymers of polyurethane, polyether and amide, polyesters and copolymers of polyesters, nylon and man-made fibers. These additives and their amounts are chosen so that they do not significantly affect the polymerization, crosslinking or the required chemical and physical properties of the final adhesive.

Adhesive compositions can be made electrically conductive for use in biomedical electrodes and other areas of electrotherapy, that is, for attaching an electrode or other electrically conductive element to the surface of the body. For example, adhesive compositions can be used to attach an electrode to a patient’s skin or mucous tissue for transdermal nerve stimulation, an electrosurgical outflow electrode, or an electrocardiographic electrode. These applications typically include modifying the adhesive composition by introducing a conductive element into it, whereby the adhesive composition becomes completely conductive. Suitable electrically conductive agents include ion-conductive electrolytes commonly used in conductive adhesives applied to the skin or other surface of the body, which include ionizable inorganic salts, organic compounds, or combinations thereof. Examples of ionic conductivity electrolytes include, but are not limited to, ammonium sulfate, ammonium acetate, monoethanolamine acetate, diethanolamine acetate, sodium lactate, sodium citrate, magnesium acetate, magnesium sulfate, sodium acetate, calcium chloride, magnesium chloride, calcium sulfate, lithium chloride lithium perchlorate, sodium citrate and potassium chloride, and redox pairs, such as mixtures of ferric and ferrous salts, such as sulfates and gluconates. Preferred salts are potassium chloride, sodium chloride, magnesium sulfate and magnesium acetate, with potassium chloride being most preferred for use in electrocardiography. Although the adhesive compositions of this invention may contain virtually any amount of electrolyte, it is desirable that any water-soluble electrolyte be present in a concentration of from about 0.1 to about 15 wt.% Of the mixture. Described in US patent No. 5846558, issued by Nielsen et al., A method for manufacturing biomedical electrodes can be modified for use with the adhesive compositions of the present invention, therefore, this patent is incorporated by reference in this description of the invention. Other suitable manufacturing methods that are known to those skilled in the art can be used.

In specific applications, especially when high cohesive strength is required, the adhesive composition must be covalently crosslinked. Intramolecular or intermolecular covalent crosslinking of the hydrophilic polymer and / or covalent crosslinking of the hydrophilic polymer and plasticizer can be carried out. In the first case, there are no covalent bonds between the hydrophilic polymer and the plasticizer, while in the second case there are covalent cross-links connecting the hydrophilic polymer with the plasticizer. The hydrophilic polymer or hydrophilic polymer and plasticizer can be covalently crosslinked using heat, radiation or a chemical curing (crosslinking) agent.

For thermal crosslinking of the adhesive composition into a polymer mixture, i.e. into a mixture of a hydrophilic polymer and a plasticizer, it is necessary to introduce a free radical polymerization initiator. The free radical initiator can be any known initiator used in the polymerization of unsaturated vinyl monomers, preferably an organic peroxide or azo compound. The initiators can be used in known amounts, usually from 0.01 to 15%, preferably from 0.05 to 10%, more preferably from about 0.1% to about 5%, and in particular from about 0.5% to about 4 wt. .% by weight of the polymerized material. Suitable organic peroxides are dialkyl peroxides such as tert-butyl peroxide and 2,2-bis (tert-butyl peroxy) propane, diacyl peroxides such as benzoyl peroxide and acetyl peroxide, ethers such as tert-butyl perbenzoate and tert-butyl per-2-ethylhexanoate, such as dicetyl peroxydicarbonate and dicyclohexyl peroxydicarbonate, ketone peroxides such as cyclohexanone peroxide and methyl ethyl ketone peroxide, and hydroperoxides such as cumyl hydroperoxide and tert-butyl hydroperoxide. Acceptable azo compounds are azobis (isobutyronitrile) and azobis (2,4-dimethylvaleronitrile). The temperature and thermal crosslinking parameters of the adhesive composition depend on the selected components and can be easily determined by a person skilled in the art, but usually the temperature is from about 80 ° C to about 200 ° C.

A hydrophilic polymer or a hydrophilic polymer and a plasticizer can also be crosslinked by radiation, usually in the presence of a photoinitiator. Irradiation can be performed with ultraviolet radiation, alpha, beta, gamma radiation, electron beam and x-ray radiation, although ultraviolet radiation is preferred. Acceptable photosensitizers are triple sensitizers acting on the principle of hydrogen cleavage, which include benzophenone, substituted benzophenone and acetophenones, such as benzyl dimethyl ketal, 4-acryloxybenzophenone (ABP). 1-hydroxycyclohexylphenylketone, 2,2-diethoxyacetophenone and 2,2-dimethoxy-2-phenylacetophenone, substituted alpha ketones, such as 2-methyl-2-hydroxypropiophenone, benzoin ethers such as benzoin methyl ester and benzoin isopropyl ether substituted anisoin ethers such as anisoin methyl ester, aromatic sulfonyl chlorides such as 2-naphthalenesulfonyl chloride, photoactive oximes such as 1-phenyl-1,2-propanedione-2- (O-ethoxycarbonyl) oxime, thioxanthones, including alkyl and halogen substituted thioxanthones such as 2-isopropyl oksanton, 2-chlorothioxanthone, 2,4-dimetiltioksanon, 2,4-and 2,4-dihlortioksanon dietiltioksanon and acylphosphine oxides. In the implementation of the present invention, irradiation with a wavelength of 200-800 nm, preferably 200-500 nm, is used, while low-intensity ultraviolet light is sufficient to induce crosslinking in most cases. However, when using photosensitizers that act on the principle of hydrogen cleavage, it is necessary to irradiate with ultraviolet light of a higher intensity to achieve a sufficient degree of crosslinking. This effect is provided by processors with a mercury lamp, manufactured by such companies as PPG, Fusion, Xenon, and others. Crosslinking can also be induced by irradiation with gamma radiation or an electron beam. Acceptable radiation parameters, i.e. the type and dose of radiation used for crosslinking, should be known to those skilled in the art.

Suitable chemical curing agents, also referred to as chemical “promoters” for crosslinking, include, but are not limited to, polymer mercaptans such as 2,2-dimercaptodiethyl ether, hexa (3-mercaptopropionate) dipentaerythritol, ethylene bis (3-mercaptoacetate), tetra ( mercaptopropionate) pentaerythritol, pentaerythritol tetratioglycolate, polyethylene glycol dimercaptoacetate, polyethylene glycol di (3-mercaptopropionate), tri (3-mercaptopropionate) trimethylolanthane, trimethylolopentane tritioglycolate, ethylolpropantrythioglycolate, dithioethane, di- or tritiopropane and 1,6-hexanedithiol. The crosslinking promoter is added to an uncrosslinked hydrophilic polymer to stimulate its covalent crosslinking, or to a mixture of an uncrosslinked hydrophilic polymer and a plasticizer to crosslink these components.

The hydrophilic polymer may also be crosslinked prior to mixing with the plasticizer. In this case, it is desirable to synthesize the polymer in crosslinked form by mixing the monomer polymer precursor with a multifunctional comonomer and copolymerizing. Examples of monomeric precursors and corresponding polymer products are: N-vinylamide precursors for poly (N-vinylamide); N-alkyl acrylamides for poly (N-alkyl acrylamide); acrylic acid for polyacrylic acid; methacrylic acid for polymethacrylic acid; acrylonitrile for poly (acrylonitrile) and N-vinylpyrrolidone (NVP) for poly (vinylpyrrolidone) (PVP). The polymerization can be carried out in bulk, in suspension, in solution or in emulsion. Solution polymerization is preferred, and polar organic solvents such as ethyl acetate and lower alkanols (e.g. ethanol, isopropyl alcohol, etc.) are particularly preferred. The synthesis of hydrophilic vinyl polymers is usually carried out by free radical polymerization in the presence of a free radical polymerization initiator, as described above. Multifunctional comonomers are, for example, bisacrylamide, acrylates or methacrylates of diols such as butanediol and hexanediol (1,6-hexanediol diacrylate is preferred), other acrylates such as pentaerythritol tetraacrylate and 1,2-ethylene glycol diacrylate, and 1,12- diacrylate dodecandiol. Other useful multifunctional crosslinking monomers are oligomeric and polymeric multifunctional (meth) acrylates, for example poly (ethylene oxide) diacrylate or poly (ethylene oxide) dimethacrylate; polyvinyl crosslinkers, such as substituted and unsubstituted divinylbenzene; and bifunctional urethane acrylates such as EBECRYL® 270 and EBECRYL® 230 (acrylated urethanes with a weight average molecular weight of 1,500 and a weight average molecular weight of 5,000 from UCB of Smyrna, Ga., respectively) and combinations thereof. When using a chemical crosslinking agent, its amount is preferably selected so that the weight ratio of the crosslinking agent to the hydrophilic polymer is from about 1: 100 to 1: 5. To achieve a higher crosslink frequency, chemical crosslinking is optionally combined with radiation curing.

The adhesive compositions of the present invention can be extruded, so they can be obtained by a simple method, including mixing and extrusion. To this end, necessary quantities of the components of the composition are weighed and mixed, for example, in a Baker Perkins mixer at elevated temperature, although not necessarily, from about 35 ° C to about 90 ° C. Solvents can be added if desired. Preferred solvents are aqueous solvents or alcohols (e.g. ethanol, methanol, isopropanol, etc.). Subsequently, any crosslinking is performed. The resulting composition can be extruded in a single screw or twin screw extruder or granulated.

In the manufacture of a transdermal (or through the mucous membrane) drug delivery system, the adhesive composition can be cast or extruded onto a substrate or a removable release coating of such a system. Such drug delivery systems typically include: (A) a drug reservoir containing a therapeutically effective amount of an active agent; (B) an adhesive for attaching the system to the surface of the body and allowing the transfer of the active substance through the surface of the body; and (C) a substrate that serves as the outer surface of the specified system during use, where (D) the release release coating typically closes the adhesive surface during storage and prior to application.

Using the drug delivery system of the present invention, any number of active substances can be administered. Acceptable active substances are numerous compounds, usually delivered through the surface of the body and mucous membranes. Such active substances are analeptic drugs; analgesic agents; anesthetics; antiarthritis drugs; respiratory drugs, including anti-asthma drugs; anticancer agents, including antitumor agents; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; anti-diarrhea drugs; anthelmintic agents; antihistamines; anti-hyperlipidemia drugs; antihypertensive drugs; antibacterial agents such as antibiotics and antiviral agents; anti-inflammatory drugs; anti-migraine drugs; antiemetics; anti-blastoma drugs; drugs against parkinsonism; antipruritic drugs; antipsychotic drugs; antipyretic drugs; antispasmodics; anti-tuberculosis drugs; antiulcer drugs; antiviral agents; tranquilizers; appetite suppressants; drugs for the treatment of attention deficit disorder (ADD) and attention deficit disorder accompanied by increased activity (ADHD); cardiovascular drugs, including calcium channel blockers, anti-angina pectoris, central nervous system (CNS) treatments, beta-receptor blockers, and anti-arrhythmias; central nervous system stimulants; preparations for cough and colds, including decongestants; diuretics; genetic substances; herbal remedies; hormonal drugs; sleeping pills; hypoglycemic agents; immunosuppressive drugs; leukotriene inhibitors; mitosis inhibitors; muscle relaxants; antagonists of narcotic substances; nicotine; nutrients such as vitamins, essential amino acids and fatty acids; ophthalmic agents, such as anti-glaucoma; parasympatolytic drugs; peptide agents; psychostimulants; sedatives; steroids, including progestogens, estrogens, corticosteroids, androgens and anabolic agents; anti-smoking agents; sympathomimetic agents; tranquilizers and vasodilators, including for coronary, peripheral and cerebral vessels. Specific active substances with which the adhesive compositions of the present invention can be effectively used are, but not limited to, anabazine, capsaicin, isosorbide dinitrate, aminostigmine, glyceryl trinitrate, verapamil, propranolol, silabolin, foridone, clonidine, cytisine, phenazepamfinziforzinfiziforzifizorzinziforzinfiziptizfizorzinziforzinafinzifizorzinfizipalzibtiziptizfalziptizfalziptizinfizipalziptizfalzibtiziptizinfizinfinziforziptizinfinziforzinziforzinziforzinziforzinziforzinziforzinziforzinziforzinziforzinziforzinziforzinziforzinfitsinziforzina and .

Some active substances may need to be administered with a penetration enhancer to create a therapeutically effective flow through the skin. Suitable amplifiers are, for example, sulfoxides, such as dimethyl sulfoxide (DMSO) and decyl methyl sulfoxide (C ₁₀ MSO); ethers, such as diethylene glycol monoethyl ether (commercially available under the trademark Transcutol®) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80) and lecithin (US patent No. 4783450); 1-substituted azacycloheptan-2-ones, in particular 1-n-dodecylcyclazacycloheptan-2-one (manufactured under the trademark Azone® by Nelson Research & Development Co., Irvine, Calif .; see US Patent Nos. 3989816, 4316893, 4405616 and 4557934); alcohols such as ethanol, propanol, octanol, decanol, benzyl alcohol and the like; fatty acids such as lauric acid, oleic acid and valerianic acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methyl propionate and ethyl oleate; polyols and their esters, such as propylene glycol, ethylene glycol, glycerin, butanediol, polyethylene glycol and polyethylene glycol monolaurate ("PEGML"; see, for example, US patent No. 4568343); amides and other nitrogen-containing compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones and organic acids, in particular salicylic acid and salicylates, citric acid and succinic acid. Mixtures of two or more amplifiers may also be used. Ethanol is a preferred enhancer, which not only serves as a permeability enhancer, but also solubilizes many of the active substances of interest and, in addition, improves adhesion. You can also use a mixture of ethanol and water. It should be noted that many of the aforementioned skin permeability enhancers are simultaneously plasticizers in the adhesive composition, for example, polyols such as propylene glycol, ethylene glycol, glycerin, butanediol, hexanediol and polyethylene glycol.

The substrate of the transdermal drug delivery system serves as the main structural element and provides flexibility, shape and, possibly, product integrity. The material used for the substrate must be inert and not able to absorb the drug substance, penetration enhancer, or other components of the pharmaceutical composition contained in this device. The material used for the substrate must ensure that the device matches the contours of the skin and can be comfortably perceived by the skin in areas such as joints and other flexion sites that are usually subjected to mechanical stress, while the delivery system should not be separated from the skin due to varying degrees of flexibility or elasticity of the skin and devices. Examples of materials that can be used to make the substrate are polyesters, polyethylene, polypropylene, polyurethanes and polyester amides. The thickness of said layer is preferably from about 15 microns to about 250 microns, and if desired, the substrate can be pigmented, metallized or a matte coating suitable for recordings can be applied to it. This substrate is preferably permeable (or "breathable"), that is, preferably permeable to moisture.

During storage and prior to use, the laminated structure includes a removable release coating. Immediately before use, this layer is removed so that the system can be attached to the skin. The coating to be removed must be made of a material that is not permeable to the drug substance / carrier and is a disposable element that serves only to protect the device before use. A removable coating is usually made of a material that is not permeable to system components and the pharmaceutical composition contained therein.

These drug delivery systems may also contain additional layers, for example, intermediate tissue layers and / or membranes that control the rate of drug release. Fabric layers can be used to facilitate the manufacture of this device, while a speed-regulating membrane can be used to control the rate of release of a component from the device. The specified component may be a medicinal substance, an enhancer of permeability of the skin, or any other component contained in the drug delivery system.

In any of these transdermal drug delivery systems, it is desirable to place a membrane on the skin side that controls the rate of release of the drug substance from its intended reservoir. The materials used to make such a membrane are selected taking into account the flow restriction of one or more components contained in the drug, and the membrane may be microporous or solid. Typical materials used for the manufacture of speed-regulating membranes are polyolefins such as polyethylene and polypropylene, polyamides, polyesters, ethylene-ethylene acrylate copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate copolymer, ethylene-vinylpropyl acetate copolymer , polyacrylonitrile, a copolymer of ethylene and propylene, a block copolymer of polysiloxane and polycarbonate and the like.

The adhesive compositions of the present invention can be used in any other cases where application of the product to the body surface is necessary or desirable. Such applications are, for example, sticky cushioning arch supports applied to the foot, said arch support may or may not contain a drug for transdermal or topical administration, for example, salicylic acid or the like. Such arch supports usually consist of a flexible, resilient outer layer made of foam material, fabric or the like, and a layer of the adhesive composition of the present invention located on the side in contact with the skin surface. In this embodiment, cohesive strength is important for the product to act as a cushioning arch support, so the hydrophilic polymer must be covalently crosslinked sufficiently to provide the necessary cohesive strength.

Another application of the adhesives of the present invention are dressings for wounds and other medical plasters, such as adhesive bandages or others. Such adhesive compositions may or may not be therapeutic. If they are therapeutic, they usually contain antibacterial agents and / or other types of pharmacologically active agents. Medical plasters, such as adhesive tape and dressings for wounds, can be easily made by known methods, including the method described in US patent No. 5985990, which is incorporated into this description by reference.

Said adhesive compositions can also be used in conjunction with medical devices, diagnostic systems, or devices that are applied to the surface of the body, and in any other applications where attachment to the surface of the body is necessary or desirable.

Thus, the present invention has an important advantage over other pressure sensitive adhesives, in particular compared to bioadhesives. New adhesive compositions adhere well to hydrated surfaces such as mucous tissue. They are suitable for prolonged contact with the skin, do not irritate the skin, do not cause acne and do not sensitize the skin, are permeable, physically and chemically compatible with a number of drugs and classes of drugs and can increase the rate of supply of the active substance to the surface of the body. In addition, the adhesive composition of the present invention can be used in various applications, its properties can easily be brought into line with the required degree of hygroscopicity, hydrophilicity, adhesive and cohesive strength.

In the practice of the present invention, unless otherwise indicated, widely used drug delivery methods and manufacturing methods are known to those skilled in the art. Such methods are comprehensively described in the scientific literature. See Remington: The Science and Practice of Pharmacy, supra, and Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed. (New York: McGraw-Hill, 1996).

It should be noted that, although the invention has been described with reference to preferred specific embodiments thereof, the above description of the invention and the following examples are for illustration only and do not limit the scope of the present invention. Specialists in this field should be obvious other features, advantages and modifications of the invention. All patents, patent applications, journal articles, and other materials cited herein are hereby incorporated by reference in their entirety.

The following examples are provided in order to give those skilled in the art a complete picture of the methods for the manufacture and use of the compounds of the present invention. However, they do not limit the scope of the present invention. Every effort has been made to ensure the accuracy of the numerical data (e.g., quantity, temperature, etc.), and still some errors and deviations are possible. Unless otherwise specified, the parts are mass parts, the temperature is expressed in ° C and the pressure is atmospheric or close to atmospheric.

Examples 1-16

Preparation of PSA Matrices by Mixing PVP and PEG-400: Effect of Composition, Moisture Content, and Adhesive Layer Thickness

Adhesive films with a thickness of 250-300 μm were obtained by dissolving hydrophilic polymers and PEG (M _w = 400) in a common solvent (ethyl alcohol), after which the solution was applied to the substrate in the form of a film and dried. Unsupported PVP-PEG hydrogels were prepared by applying the appropriate solutions to the coating to be removed, followed by drying at room temperature.

The adhesion strength of hydrogels with a standard polyethylene (PE) film 100 μm thick was evaluated using a peeling test at an angle of 180 °, performed using an Instron 1122 dynamometer with a peeling speed of 10 mm / min. A low density polyethylene film with a crystallinity of 45%, a contact angle of 105 °, and a surface energy of 28.5 mJ / m ^{2 was} used as a standard substrate. Adhesives were saturated with water, placing them in desiccators with a water vapor pressure of 50% at room temperature for 6-7 days. The time to reach the maximum strength of the adhesive bond with the substrate was 15-20 minutes. The nature of the destruction of the adhesion was fixed by a television camera attached to an IBM computer and photographed through a microscope. The type of destruction was evaluated by measuring the wetting angle of the peeled surface of the substrate.

The phase behavior of mixtures of hydrophilic polymers with PEG-400 of different compositions was investigated by differential scanning calorimetry (DSC) using a differential scanning calorimeter Mettler TA 4000 / DSC-30, calibrated by indium and gallium. In the DSC instrument, the samples were first sharply cooled with liquid nitrogen from room temperature to -100 ° C for 2-3 minutes and then heated at a speed of 20 ° C min ^-1 to 220 ° C. During heating in mixtures, a jump in heat capacity occurs, followed by the first exotherm in combination with a symmetrical endotherm, and another, high-temperature endotherm. These four transitions are due respectively to glass transition, cold crystallization of PEG, its melting and thermal desorption of water (see Feldstein et al. (2000), "Coherence of thermal transitions in poly (N-vinyl pyrrolidone) - poly (ethylene glycol) compatible blends", Polymer 41 (14): 5327-5359). Glass transition temperatures, T _g , are recorded at the midpoint of the corresponding heat capacity jumps in DSC heating thermograms. All values are average values of two experiments with a deviation of less than 1-2%. Samples weighing 5-15 mg were placed in standard aluminum cups with perforated lids so that the absorbed moisture could evaporate during heating. Samples were purged with argon (50 ml min ^-1 ) to prevent moisture condensation on the sensor. The content of absorbed water in the mixtures was determined by weighing the samples before and after scanning on a Mettler AE 240 analytical balance, with an accuracy of ± 0.01 mg. The mass loss of the sample after scanning was compared with the amount of desorbed water calculated on the basis of the change in enthalpy due to the evaporation of water from the sample during the DSC study.

Sorption of water vapor. The adhesive films were balanced at room temperature in desiccators over aqueous solutions of H ₂ SO ₄ with a controlled density, which kept the required relative humidity from 10 to 90%. The equilibrium sorption of water was measured by the gravimetric method and was confirmed using a McBen vacuum microbalance with a quartz spring.

The viscoelastic properties and durability of adhesive adhesion hydrogel compounds were investigated by compression-reduction method in a DTDM thermomechanical analyzer (microdilatometer), as described by Kotomin et al. (1999), Squeeze-recoil analysis of adhesive hydrogels and elastomers by Polym Mater. Sci. Eng. 81: 425-426 and Kotomin et al. (2000), "Durability and fracture of some viscoelastic adhesives" Proceed. 23 ^rd Adhesion Soc. Annual Meeting, Myrtle Beach, SC, pp. 413-415. placed between two flat surfaces of silicon dioxide formed by a loading rod and a support plate, and subjected to constant c imayuschey load followed by removal of the compressive load to the relaxation of the sample.

results

Table 2 shows the properties of the adhesive mixtures of PVP with PEG-400. In examples 1-4 and figure 2, 3 shows the effect of the composition of the mixtures of PVP-PEG on the adhesive properties. The relationship between adhesion and phase behavior of PVP-PEG mixtures is also shown, presented as a negative deviation of T _st from the weight average values (-ΔT _st ) calculated using the Fox equation (1) and ΔС _p T T _st . In PVP-PEG mixtures, adhesion occurs in a narrow concentration range. The maximum adhesion corresponds to the maximum values of -ΔT _article and the minimum value of ΔC _p T _article . Based on the above result, it can be concluded that adhesion occurs during the formation of a stoichiometric PVP-PEG complex crosslinked by a hydrogen bond. This conclusion can be drawn by comparing the composite adhesion profile with the data on the formation of hydrogen bonds in the PVP-PEG system presented in Feldstein MM, Kuptsov SA, Shandryuk GA, Plate NA, Relation of glass transition temperature to the hydrogen bonding degree and energy in poly ( N-vinyl pyrrolidone) blends with hydroxyl-containing plasticizers: 2. Effects of poly (ethyleneglycol) chain length, Polymer (2001) in print). Studies have shown that adhesion is controlled by a specific balance between increased free volume and strong attraction interaction between the macromolecules of the mixture components: high molecular weight PVP and short-chain PEG macromolecules carrying reactive groups at both ends of the chain (Feldstein MM, Chalykh AE, Chalykh AA, Fleischer G., Siegel RA, Contribution of molecular mobility to debonding of pressure-sensitive adhesive hydrogels, Polym Mater. Sci. Eng., Vol. 81, 1999, p. 467-468).

In examples 1, 5-9 and figure 4 shows the effect of relative humidity (RH) of the environment on the adhesive behavior of mixtures of PVP-PEG. PVP is a hygroscopic polymer that absorbs more than 25% water at high relative humidity (Fig. 9). In mixtures with a high PVP content, with correspondingly high glass transition temperatures, where peeling takes place in accordance with the adhesive mechanism, hydration of the mixture increases the force required to break the adhesive bond. In contrast, in plasticized mixtures with a high PEG content, the effect of a complementary plasticizer, such as water, reduces adhesion. As a result of high fluidity and low cohesive strength of the hydrophilic composite material, an adhesive residue remains on the interface of the substrate during the destruction of the adhesive compound (table 2).

Examples 1, 10, and 11 show the effect of the chain length of a hydrophilic polymer (PVP) on the strength of an adhesive bond. The tensile strength of the adhesive compound usually decreases with a decrease in the molecular weight of the polymer. Examples 12-16 show the effect of the thickness of the adhesive layer on the strength of the adhesive bond. In accordance with Equation 7, the peeling force necessary to break the adhesive joints increases with increasing thickness of the adhesive layer.

Examples 17-47

Obtaining PSA matrices by mixing PVP with various short-chain plasticizers. The influence of the composition and the dependence of adhesion on the phase state

In accordance with the production method and evaluation tests described in Example 1, samples of PVP K-90 mixtures with different plasticizers were obtained and tested at a relative humidity of 50% and room temperature. The results are shown in table 3. Adhesive mixtures can be obtained by mixing PVP with short-chain plasticizers having terminal hydroxyl groups (examples 17-41) or terminal carboxyl groups (examples 42-47), which include: ethylene glycol (examples 17-19) and its polymers (PEG) with a molecular weight of from 200 to 600 g / mol (examples 20-23), low molecular weight 1,3- and 1,2-propylene glycol (PG) (examples 24, 25), alkanediols from propanediol (PG) to pentanediols (PD) and hexanediol (HD), inclusive (examples 27-39). It was found that polypropylene glycol (PPG) has a good plasticizing effect on PVP, but does not cause adhesion and stickiness (example 26). The glass transition temperatures of the studied plasticizers are in the range from -59 to -116 ° C. To cause adhesion, the plasticizer must be either amorphous or crystalline, but the melting point of suitable plasticizers, T _m , is usually lower than 50 ° C, the value set for 1,6-hexanediol (HD) (examples 33-37). Adhesive strength corresponds to a maximum value of -ΔT _st and a minimum value of ΔC _p T _article The highest tensile strength was found in mixtures of PVP with glycerin (Example 41), which is characterized by a maximum density of hydroxyl groups in the molecule. Strictly speaking, the dicarboxylic acids shown in table 3 for examples 44-47, are not plasticizers, but non-covalent crosslinking agents, acting as enhancers of cohesive interaction. To achieve the required adhesion, these substances can be used in combination with plasticizers, which reduce T _article or indicators inherent in PSA. This approach was used to obtain a Plastoid adhesive mixture (US Pat. Nos. 5,730,999 and 5,993,849, European Patent No. 848960 A3), where EUDRAGIT E-100 is crosslinked with succinic acid and plasticized with tributyl citrate. It was found that dry mixtures of PVP with 50% dicarboxylic acids have high values of T _article (28, -34, -43 and 24 ° C, respectively for SA, MA, GA and AA) and therefore do not cause adhesion. However, due to the wetting of these mixtures, their glass transition temperatures decrease in the range from -55 ° C to -65 ° C, resulting in adhesion (see examples 44-47). PEG-600 having terminal carboxyl groups (Examples 42, 43) combines the properties of a crosslinking agent and a plasticizer, imparting adhesion to mixtures with PVP.

Examples 48-64

PSA compositions prepared by mixing various hydrophilic polymers with additional short-chain plasticizers

These examples show that not only PVP, but also many other hydrophilic polymers become adhesive when mixed with short-chain plasticizers having complementary reactive groups at the ends of the chains. Suitable hydrophilic polymers are poly (N-vinylamides) such as PVP (examples 1-47), poly (N-vinylcaprolactam) (PVCap) (examples 48-52) and poly (N-vinylacetamide) (PVAA, example 53), the poly (N-alkyl acrylamides) represented by poly (N-isopropyl acrylamide) (PNIPAM, example 54), polymethacrylic and polyacrylic acid (PMA, PAA, examples 55-60) and their copolymers are shown in table 4 (examples 61-64) materials Luviscol VAP®, commercially available from BASF. Luviscol VAP 37 is a copolymer of vinylpyrrolidone (VP, 30%) with 70% vinyl acetate (VA). Luviscol VAP 73 contains 70% VP and 30% VA.

Among the polymers shown in table 4, the best working properties were found in mixtures of PEG-400 with PVCap. Figures 9-11 show comparative hygroscopicity and adhesion of PVPCap-PEG-400 and PVP-PEG-400 mixtures. As shown in FIG. 10, PVPCap absorbs almost 4 times less water than PVP under comparable conditions. According to the above classification of the hydrophilicity of Zaikov-Jordan-Markin polymers, PVP is a hygroscopic substance, while PVCap is a moderately hydrophilic polymer. Compared to a mixture of PVP with 36 wt.% PEG-400, PVCap, plasticized with a similar amount of PEG-400, has much greater adhesion. The left side of the curves in FIG. 11 is characterized by an adhesive rupture mechanism, and the right side of the curves corresponds to the mixed and cohesive types of failure of the adhesive joint. As follows from examples 1, 10 and 11, an increase in the molecular weight of the polymer leads to a significant increase in cohesion resistance and adhesion. In this regard, the sorption and adhesive properties of PVCap-PEG hydrogels are very promising for pharmaceutical applications. It should also be noted that PVCap has a lower critical mixing temperature (NTCS) of approximately 35 ° C (see Kirsh Y.E., Water soluble poly (N-vinylamides), Wiley, N.Y., 1998). Below this temperature, PVCap readily dissolves in water and behaves like a moderately hydrophilic polymer, while above the temperature of the HCTS, PVCap becomes a water-insoluble hydrophobic polymer. This property is very useful for creating thermosensitive, or so-called “sensible” adhesive hydrogels.

In addition to pressure sensitive adhesion, hydrogels have a whole range of useful viscoelastic properties similar to those of weakly vulcanized rubbers (FIGS. 6-8). Adhesive hydrogels are in fact hydrophilic and water-soluble rubbers with high rubber-like elasticity as one of the main functional properties. Rubber-like elasticity and viscosity, complementary to the rheology of the adhesive hydrogels of the present invention, are illustrated by the data shown in Fig.6.

Under the action of a constant compressive force, the hydrogel is compressed, while the instant compliance (Hook's elasticity) of the PVP-PEG adhesive hydrogel is proportional to the magnitude of the applied compressive load (Fig.6). Hooke compression is accompanied by a compression flow (creep), which reflects the contribution of the viscous flow to the rheological properties of the hydrogel. As the compression deformation increases, the stress in the adhesive polymer gradually decreases, reaching a critical value of the yield strength at which the hydrogel spreading stops. The presence of a yield strength is a distinctive feature of crosslinked or highly ordered supramolecular structures characteristic of crosslinked polymers or liquid crystal polymers. Conventional polymers have no yield strength. The yield strength of the PVP-PEG adhesive hydrogel is determined by the critical value of the shear stress in the flow curve shown in Fig. 7, at which the apparent shear viscosity increases to infinity and the strain rate decreases, tending to zero. The yield strength is an integral measure of cohesive strength, which, as shown, is expressed by the value of σ _f in equation (2), and this determines the adhesive properties of the adhesive polymer (Feldstein et al. (2000), "Molecular insight into rheological and diffusion determinants of pressure- sensitive adhesion ", Proceed. 23 ^rd Annual Meeting Adhesion Soc., pp. 54-56).

After removal of the compressive load, the polymer deformation is relaxed, called "retardation", when the deformation changes its sign and the polymer recovers to a greater or lesser extent its original shape. Adhesive hydrogel is characterized (Fig.6) instant (Hooke) recovery of compression deformation with subsequent elastic rebound after creep. Gukovo elastic retardation is proportional to the compressive force (Fig.6), and the slope of the linear dependence determines the relaxation modulus of elasticity at shear of the adhesive hydrogel G = 2 · 10 ⁵ PA. It is well known that this value obtained for the PVP-PEG adhesion hydrogel is also inherent in various PSA polymers and weakly crosslinked rubbers.

After removing the compressive force, the adhesive hydrogel is left to relax, during which elastic recovery after creep occurs, accompanied by a gradual increase in compliance (Fig. 8). The kinetics of the elastic recovery of the PVP-PEG hydrogel after creep, determined by the elastic rebound function after creep S (t), corresponds to the Dickey-Ferry phenomenological equation (4), which is based on a model created to describe the relaxation of weakly crosslinked rubbers:

where S (t) means compliance with elastic rebound and S _е - compliance at equilibrium stress, t means time, τ is characteristic time (delay), n means Chasset-Thirion exponent. Computer modeling kinetic profiles rebound function 8 to determine that the equilibrium compliance with elastic rebound hydrogel PVP-PEG is S _e = 1.56 × 10 ^-5 Pa ^-1, the delay time is equal to τ = 1,8 · ¹⁰ March sec and the exponent Chasset-Thirion n = 0.99. The obtained value of S _e corresponds to the average molecular weight of the polymer chain between the grid nodes Ms ≈ 130,000 g / mol, which is characteristic of weakly crosslinked rubbers, while the value of n is characteristic of a very dense spatial structure. Thus obtained value S _e and τ likely relate to the structure formed by interlacing circuits PVP, while the exponent n refers to the much denser and faster relaxed hydrogen-bonded structure. The imposition of compliance profiles during elastic rebound for the PVP-PEG hydrogel and polybutadiene (PB) rubber (Fig. 8) shows that the hydrogel retardation properties are characteristic of elastomers. Thus, the adhesive hydrogels described in this invention are essentially water soluble rubbers.

Examples 65-82

Hydrophilic Matrix Therapy Systems PSA

Receiving. Drug substances are first dissolved in a mixture of PEG-400 (plasticizer) and ethyl alcohol (solvent). After complete dissolution of the drug substance, PVP or another hydrophilic polymer is dissolved in the previously obtained mixture, thereby obtaining an irrigation solution, which is applied to a 0.02 mm thick polyethylene terephthalate film used as a substrate and dried at a temperature of 20-60 ° C.

The in vitro transdermal drug delivery rate from water-soluble PSA matrices was determined using cadaver skin or a skin simulating Carbosil film to protect the matrices from dissolution in the receiving solution. The system was placed in the center of a carbosil film, the area of which is twice the area of the system. The edges of the film were bent around the sample, forming a packet. The back of the bag was firmly attached to the steel plate holder to prevent direct contact of the matrix with the receptor solution. Similarly, epidermis of cadaveric skin can be used instead of a carbosyl film. The holder with the wrapped sample was immersed in a glass with a receiving solution, and the subsequent determination was made according to the pharmacopeia by the "paddle mixer above the disk" method. The rate of appearance of the drug in the receptor solution (0.15 M NaCl solution) was determined spectrophotometrically at a temperature of 35.0 ± 0.5 ° C.

The drug permeability coefficients through the skin epidermis (P _s ) and the carbosyl film (P _m ) were measured by dividing the magnitude of the flow of drug substances from hydrophilic PSA matrices by the concentration of drug substance in the donor medium. The following results were obtained taking into account the density of the matrix (1.10 ± 0.12 g / cm ³ ).

results

The composition and properties of the resulting therapeutic systems are shown in table 5.

Table 5
Properties of hydrophilic drug-containing matrices Medicine Matrix composition The content of the drug in the matrix (%) In vitro delivery rate μg / cm ² hours after P _m (10 ⁴ ) cm / hour P _s (10 ⁴ ) cm / hour carbosil human skin 65. Anabazin PVP-PEG 1,6 150 ± 20 106.3 ± 12.0 66. Isosor-Biddinitrate PVP-PEG 9.6 384 ± 48 13.0 ± 4.3 44 ± 5 1.5 ± 0.5 67. Isosorobiddinitrate PVCap-PEG 9.6 411 ± 49 47.1 ± 5 68. Aminostigmine PVP-PEG 14.3 625 ± 20 33.7 ± 12.0 7.6 263 ± 10 4.0 65 ± 5 69. Glycerin- PVP-PEG 7.3 160 ± 40 12.4 ± 4.0 25.6 ± 1.4 1.9 ± 0.5 trinitrate 1.9 45 ± 12 70. Verapamil PVP-PEG 39.1 110 ± 20 21.4 ± 1.5 0.4 ± 0.1 24.3 110 ± 16 13.8 95 ± 19 6 ± 2 3.9 78 ± 6 71. Propranolol PVP-PEG 13.8 118 ± 25 26.0 ± 15.0 10.6 ± 1.1 2.1 ± 0.2 7.4 79 ± 6 72. Propranolol PVCap-PEG 13.8 145 ± 30 13.0 ± 1, 9 73. Silabolin PVP-PEG 13.9 131 ± 30 10.3 ± 0.5 10.8 107 ± 21 7.2 65 ± 14 74. Foridon PVP-PEG 13.8 37.3 ± 4.5 4.2 ± 1.5 10.8 34.1 ± 4.0 7.4 24.8 ± 3.0 3,1 20.6 ± 1.9 75. Clonidine PVP-PEG 7.7 26.8 ± 0.8 0.75 ± 0.04 4.0 ± 1.1 0.6 ± 0.2 1.4 5 ± 2 0.78 ± 0.1 76. Citizin PVP-PEG 7.4 21 ± 3 9.0 ± 4.0 3.0 ± 0.5 1.3 ± 0.5 77. Phenazepam PVP-PEG 7.4 11 ± 2 1.4 ± 0.3 6.8 7 ± 2 78. Nifedipine PVP-PEG 15.4 19 ± 3 1.3 ± 0.2 79. Fluoroacisin PVP-PEG 13.8 5 ± 1 6 ± 2 0.4 ± 0.1 0.4 ± 0.1 80. Salbutamol PVP-PEG 13.8 0.10 ± 0.04 0.003 81. Salbutamol PVCap-PEG 13.8 4.9 ± 1 0.4 ± 0.1 82. Quinozole PVP-PEG 3.0 no no no no

As can be seen from the data presented in Table 5, hydrophilic PSA matrices based on mixtures of PVP and PVCap with PEG-400 (36 wt.% Plasticizer in mixtures) are characterized by high delivery rates through the skin-simulating film of carbosil and epidermis of human skin. As the comparative data shown in table 6 show, the hydrophilic matrices of PSA can significantly increase the speed of drug delivery compared to known hydrophobic PSAs such as polyisobutylene (PIB), polydimethylsiloxane (PDMS) and styrene butadiene rubbers. The drug delivery rates from the PVCap-PEG matrices, in turn, are higher than the delivery rates from the PVP-PEG matrix (cf. examples 66 and 67, 71 and 72, 80 and 81).

Table 6 Comparative study of in vitro drug delivery rates (μg / cm ² h) from the hydrophilic matrix of PVP-PEG and known hydrophobic matrices Medicine Delivery rate from a hydrophilic matrix through carbosil The rate of release from hydrophobic matrices The composition of the hydrophobic matrix Aminostigmine 625 ± 20 8 ± 1 Styrene butadiene rubber Nitroglycerine 160 ± 40 80 ± 10 PDMS (Nitroderm® TTS) Silabolin 131 ± 30 16 ± 7 Styrene butadiene rubber Propanolol 118 ± 25 56 ± 4 Styrene butadiene rubber Clonidine 5 ± 2 1.6 ± 0.2 PIB (Catapress® TTS)

Targeted drug delivery is necessary not only in case of systemic transdermal administration, but also in case of local administration. Thus, the stratum corneum and epidermis are targets for the delivery of antifungal agents and antimicrobial agents. Ointments often turn out to be inconvenient for use and require repeated application to the affected area during the day, not to mention soiled clothing, which makes it difficult for patients to comply with the treatment regimen and treatment regimen. Topical medicinal plasters are more convenient to use and require two applications per week, which is much more convenient for the patient. Application of a local drug patch on human skin allows you to localize the concentration of the drug on the affected skin and does not affect the entire body. In addition, the constant contact of the drug substance with the affected tissue accelerates the healing of the affected tissue. For this, the application should not be occlusal (clogging the skin). The hydrophilic PSA matrix coated with a moisture-permeable fabric material used as a substrate best meets this requirement.

Example 82 illustrates a topical antifungal patch based on a PSA matrix containing PVP-PEG. Said patch consists of a permeable cotton fabric substrate located on one side of the drug-containing PVP-PEG adhesive matrix and a protective release layer on the other hand, which is removed before applying the sticker to the skin. The specified patch is intended for local targeted treatment of mycosis and contains 3% quinosole (8-hydroxyquinoline sulfate) as an antifungal agent. The use of a medicinal product in the form of salt inhibits its penetration through the skin into the central circulation. Due to this, the in vivo release rate of chinosol from a local drug patch on the skin of volunteers averages only 0.42 μg / cm ² , which is established by measuring the amount of drug remaining in the sticker removed from the skin. As shown by the results of clinical trials with the participation of volunteers, local antifungal monotherapy with a quinosol-containing patch significantly accelerates treatment compared with the control group that was treated with clotrimazole.

Thus, the hydrophilic PSA matrices described in the present invention have functional properties suitable for use in dosage forms intended for transdermal and dermal drug delivery.

Claims (58)

1. A method of obtaining an adhesive composition with an optimized degree of adhesion, including: (a) calculating whether the composition has an optimum degree of adhesion, by (i) obtaining a variety of compositions, each of which contains a hydrophilic polymer having a glass transition temperature T _{Art. floor} , mixed with a miscible plasticizer having a glass transition temperature T _{st. pl} and capable of covalently or non-covalently crosslinking a hydrophilic polymer, wherein the mass fraction of the hydrophilic polymer in each composition is w _floor , and the mass fraction of plasticizer in each composition is w _pl ; (ii) calculating the predicted glass transition temperature T _{art. pre} for each composition using the Fox equation (1)

and plotting T _{art. pre} depending on W _PL for each composition; (iii) determining the glass transition temperature T _{Art. fact} for each composition and plotting T _{st fact} , depending on w _PL for each composition; (iv) determining the area of graphs (ii) and (iii) in which T _{st fact is} less than T _{st. before} , so that there is a negative deviation from T _{Art. before} ; (v) in the region identified in paragraph (iv), determining the optimum mass fraction of plasticizer w _{pl. optim} , in which a negative deviation from T _{Art. pre} is maximum; and (b) selecting a composition defined in (a) as having a mass fraction of plasticizer w _{pl. optim} and (c) mixing the monomeric precursor of the hydrophilic polymer and the plasticizer under polymerization conditions to obtain an adhesive composition with an optimized degree of adhesion, wherein the mass fraction of plasticizer in the composition is w _{pl. optim} and the mass fraction of the hydrophilic polymer in the composition is 1 - w _{pl. optim} 2. A method of obtaining an adhesive composition with an optimized degree of adhesion, including: (a) calculating whether the composition has an optimum degree of adhesion, by (i) obtaining a variety of compositions, each of which contains a hydrophilic polymer having a glass transition temperature T _{Art. floor} mixed with a miscible plasticizer having a glass transition temperature T _{st. pl} and capable of covalently or non-covalently crosslinking the hydrophilic polymer, wherein the mass fraction of the hydrophilic polymer in each composition is w _floor and the mass fraction of plasticizer in each composition is w _pl , so that w _floor is 1 - w _pl ; (ii) calculating the predicted glass transition temperature T _{art. pre} for each composition using the Fox equation (1)

and plotting T _{art. pre} depending on w _PL for each composition; (iii) determining the glass transition temperature T _st.fact for each composition and plotting T _st.fact as a function of w _pl for each composition; (iv) determining the area of graphs (ii) and (iii) in which T _{st fact} has a predetermined deviation from T _{st pre} ; and (b) selecting a composition as defined in (a) as having a predetermined deviation from T _{Art. before} ; and (c) mixing the monomeric precursor of the hydrophilic polymer and the plasticizer under polymerization conditions to obtain an adhesive composition with an optimized degree of adhesion, wherein the mass fraction of plasticizer in the composition corresponds to the value characteristic of the region identified in (iv). 3. The method according to claim 1 or 2, in which the plasticizer is capable of covalently crosslinking a hydrophilic polymer. 4. The method according to claim 3, in which the plasticizer is capable of non-covalently crosslinking a hydrophilic polymer. 5. The method according to claim 4, in which the plasticizer is capable of crosslinking the hydrophilic polymer through the formation of hydrogen bonds. 6. The method according to claim 1 or 2, in which the difference between T _{Art. sex} and T _{Art. pl} is at least about 50 ° C, so that T _{st fact} for each composition is determined only by the value of T _{st. pl} . 7. The method according to claim 1 or 2, wherein the hydrophilic polymer is selected from the group consisting of poly (N-vinyl lactams), poly (N-vinyl amides), poly (N-alkyl acrylamides), polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, polyvinylamine , their copolymers and mixtures. 8. The method according to claim 7, in which the hydrophilic polymer is selected from the group comprising poly (N-vinyl lactams), poly (N-vinyl amides), poly (N-alkyl acrylamides), their copolymers and mixtures. 9. The method of claim 8, in which the hydrophilic polymer is poly (N-vinyl lactam). 10. The method according to claim 9, in which the hydrophilic polymer is a homopolymer of poly (N-vinyl lactam). 11. The method of claim 10, wherein the poly (N-vinyl lactam) is selected from the group consisting of polyvinylpyrrolidone, polyvinylcaprolactam, and mixtures thereof. 12. The method according to claim 11, in which poly (N-vinyl lactam) is polyvinylpyrrolidone. 13. The method of claim 11, wherein the poly (N-vinyl lactam) is polyvinylcaprolactam. 14. The method according to claim 1 or 2, in which the hydrophilic polymer has a weight average molecular weight in the range of from about 100,000 to 2,000,000. 15. The method according to 14, in which the hydrophilic polymer has a weight average molecular weight in the range from about 500,000 to 1,500,000. 16. The method according to claim 1 or 2, in which T _{Art. pl} is in the range from about -100 to -30 ° C. 17. The method according to claim 1 or 2, in which the melting temperature of the plasticizer is below about 50 ° C. 18. The method according to claim 1 and 2, in which the plasticizer has a molecular weight in the range from about 45 to 800. 19. The method according to p, in which the plasticizer has a molecular weight in the range from about 45 to 600. 20. The method according to claim 19, in which the plasticizer has a molecular weight in the range from about 300 to 600. 21. The method according to claim 1 or 2, in which the plasticizer is selected from the group consisting of polyhydric alcohols, monomeric and oligomeric alkylene glycols, polyalkylene glycols, polyalkylene glycols with terminal carboxyl groups, polyalkylene glycols with terminal amino groups, ethers of alcohols, alkanediols and dicarboxylic acids. 22. The method according to item 21, in which the plasticizer is selected from the group comprising polyalkylene glycols and polyalkylene glycols with terminal carboxyl groups. 23. The method according to item 22, in which the plasticizer is selected from the group comprising polyethylene glycol and polyethylene glycol with terminal carboxyl group. 24. The method according to item 23, in which the plasticizer is polyethylene glycol. 25. The method according to claim 1 or 2, in which the adhesive composition further comprises a photoinitiator, and after step (v), the adhesive composition is crosslinked by the radiation method. 26. The method according to claim 1 or 2, in which stage (v) further comprises mixing the hydrophilic polymer and the plasticizer with at least one chemical crosslinking agent that covalently crosslinks the adhesive composition. 27. The method according to p, in which at least one chemical crosslinking agent is selected from the group comprising dipentaerythritol pentaacrylate, ethylene glycol dimethacrylate and triethylene glycol dimethacrylate. 28. The method according to item 27, in which the mass ratio of the chemical crosslinking agent to the hydrophilic polymer is less than 5%. 29. The method according to claim 1, in which, after the stage of mixing the monomeric precursor with a hydrophilic polymer and a plasticizer under polymerization conditions, the obtained adhesive composition is thermally crosslinked. 30. The method according to any one of claims 25 to 29, wherein the crosslink frequency of the crosslinked adhesive composition provides a degree of swelling in the range of about 20 to about 60. 31. Hydrophilic adhesive composition, pressure-sensitive, obtained by the method according to claim 1 or 2. 32. The composition according to p, in which the predetermined deviation is the maximum negative deviation. 33. The composition according to p or 32, which is mainly non-aqueous. 34. The composition according to p, in which the difference between T _{Art. sex} and T _{Art. pl} is at least about 50 ° C, so that T _{st fact} for each composition is determined only by T _{st. pl} . 35. The composition of claim 31, wherein the hydrophilic polymer is selected from the group consisting of poly (N-vinyl lactams), poly (N-vinyl amides), poly (N-alkyl acrylamides), polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, polyvinylamine, and copolymers and mixtures. 36. The composition according to clause 35, in which the hydrophilic polymer is selected from the group comprising poly (N-vinyl lactams), poly (N-vinyl amides), poly (N-alkyl acrylamides), as well as their copolymers and mixtures. 37. The composition of claim 36, wherein the hydrophilic polymer is poly (N-vinyl lactam). 38. The composition according to clause 37, in which the hydrophilic polymer is a homopolymer of poly (N-vinyl lactam). 39. The composition of claim 38, wherein the poly (N-vinyl lactam) is selected from the group consisting of polyvinylpyrrolidone, polyvinylcaprolactam, and mixtures thereof. 40. The composition of claim 39, wherein the poly (N-vinyl lactam) is polyvinylpyrrolidone. 41. The composition of claim 39, wherein the poly (N-vinyl lactam) is polyvinylcaprolactone. 42. The composition according to p, in which the hydrophilic polymer has a weight average molecular weight in the range from about 100,000 to 2,000,000. 43. The composition according to § 42, in which the hydrophilic polymer has a weight average molecular weight in the range from about 500,000 to 1,500,000. 44. The composition according to p, in which T _{art. pl} is in the range from about -100 to -30 ° C. 45. The composition according to p, in which the melting temperature of the plasticizer is below about 50 ° C. 46. The composition according to p, in which the plasticizer has a molecular weight in the range from about 45 to 800. 47. The composition according to item 46, in which the plasticizer has a molecular weight in the range from about 45 to 600. 48. The composition according to clause 47, in which the plasticizer has a molecular weight in the range from about 300 to 600. 49. The composition according to p, in which the plasticizer is selected from the group consisting of polyhydric alcohols, monomeric and oligomeric alkylene glycols, polyalkylene glycols, polyalkylene glycols with terminal carboxyl groups, polyalkylene glycols with terminal amino groups, partial ethers of polyhydric alcohols, and alkanediols. 50. The composition according to 49, in which the plasticizer is selected from the group consisting of polyalkylene glycols and polyalkylene glycols with terminal carboxyl groups. 51. The composition of claim 50, wherein the plasticizer is selected from the group consisting of polyethylene glycol and polyethylene glycol with a terminal carboxyl group. 52. The composition according to 51, in which the plasticizer is polyethylene glycol. 53. The composition according to p, which is a covalently cross-linked composition. 54. The composition according to item 53, in which the frequency of cross-links of the crosslinked adhesive composition provides a degree of swelling in the range from about 20 to about 60. 55. The hydrophilic, pressure-sensitive adhesive composition of claim 31, which is substantially non-aqueous, in which the hydrophilic polymer and plasticizer are crosslinked to a predetermined degree, and furthermore, in which the degree of crosslinking and the ratio of the hydrophilic polymer to the plasticizing agent are selected with in such a way as to optimize the hydrophilicity, adhesive and cohesive strength of the composition. 56. A therapeutic system for topical or transdermal administration of a pharmacologically active substance, which includes: (A) a drug reservoir containing an adhesive composition according to any one of claims 31-50; and (B) a substrate forming a layered structure with a reservoir for a medicinal substance, which serves as the outer surface of the specified device during use, 57. The system of claim 56, wherein the substrate is non-occlusive. 58. The system of claim 56, wherein the substrate is occlusal.

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