MXPA00000408A - Block copolymer - Google Patents

Abstract

The present invention provides a block copolymer capable of retaining drugs, there being chemical cross-linking between the soft segments, such block copolymers providing improved cohesion and drug storage capacity. Transdermal patches having such copolymers, especially as adhesives, are also provided.

Description

BLOCK COPOLYMER The present invention relates to block copolymers useful in transdermal patches such as adhesives and / or drug retention means, as well as transdermal patches comprising said block copolymers. Transdermal patches are well known in the pharmaceutical industry and are used to deliver drugs to the patient's skin. The delivery of the drug through the use of the transdermal patch has a number of advantages over oral delivery methods. For example, the drug can be continuously supplied over a long period, rather than in separate higher doses, and the patches are easily applied and used.

The patch also has an adhesive portion, which allows the patch to adhere to the skin. An adhesive suitable for use in a transdermal patch should have certain properties including adhesion, tackiness and cohesion. Adhesion refers to the force with which the adhesive is glued to a surface. "Stickiness" refers to the speed at which the adhesive can form a bond with the surface, while cohesion refers to the internal strength of an adhesive and its ability to resist separation when placed under external stress. Good cohesion, in particular, if necessary to clean the removal of the transdermal patch.

A use of the adhesive can be to fix a patch to the skin. However, it is preferable that the drug to be delivered can be incorporated into the adhesive, when possible, in order to reduce the amount of the components and, therefore, the expenses necessary to form the patch. A certain number of adhesives is available for use in transdermal patches. Acrylic polymers are commonly used, since they have adhesive properties that can be easily modulated by changing the polymer composition. In connection with transdermal patches, US-A-5413776 discloses the use of a copolymer adhesive consisting of a polymeric portion of acrylic acid ester in combination with a polymeric portion of N-vinyl-2-pyrrolidone. EP-A-450986 describes the use of an alkyl methacrylate (co) polymer in combination with silicic acid anhydride, specifically for the supply of nicotine. Both adhesives are acrylic copolymer. EP-A-0450986 further discloses that a multi-functional monomer can be included as a copolymer, to provide chemical entanglement between the copolymer filaments. The chemical entanglement is through an increase in the degree of polymerization and, therefore, the cohesion of the adhesive. Block copolymers have also been used as adhesives for transdermal patches. A block copolymer consists of a mixture of "hard" (A) and "soft" segments (B), which may be combined in a structure of type A-B-A or (A-B) n (c.f.

Block Copolymers, Overview and Critical Survey, Norhay and McGrath, 1977). The association of the hard segments is thought to provide a degree of physical entanglement, which improves the cohesive properties of the adhesive. An example of a block copolymer adhesive is a polystyrene-polyisopropene-polystyrene (SIS) which is a type A-B-A block copolymer adhesive made by Shell, for example. This adhesive requires the use of an additional glue to provide adequate tack in the adhesive. US 5,066,728 describes a multi-block copolymer comprising ends of phenylbutadiene blocks and an elastomeric middle block of a conjugated diene such as isoprene or butadiene. The copolymer is crosslinkable by electron beam radiation, so that the entanglements are ly confined to the dos of the end blocks in the polymer. With a minimum entanglement carried out in the rubber-like matrix. Blends of the copolymer with the glue resins provide curable pressure sensitive adhesives. JP-62036412A discloses vinyl chloride resins, produced by a graft copolymerization of vinyl chloride and a block copolymer, wherein the copolymer contains a smooth segment that is entangled. Reportedly, the resins have excellent impact resistance, weathering properties and flexural elasticity.

WO-97/01589 also discloses graft copolymers, suitable for use in the influence of optical quality, coloration ability, stability to weathering or impact cracking and stress cracking in molding compositions. The graft copolymers comprise a soft segment with at least one acrylate monomer, and a hard segment comprising at least one aromatic vinyl monomer. The soft segment is intertwined, and the hard and soft segments are placed. While a number of adhesives are available for use in transdermal patches, there is still a need for transdermal patch adhesives that have excellent tackiness, cohesion and improve the storage capacity of the drug. We have surprisingly found that a degree of chemical entanglement between the smooth segments of a block copolymer can cause the polymer to have improved properties, particularly with respect to the cohesion and storage properties of the drug. Therefore, in a first aspect, the present invention provides an interlaced block copolymer having drug retention properties, the block copolymer having the hard and soft segments, characterized in that they are intertwined between the segments. Preferably, the block copolymer is an acrylic block copolymer, it is also preferred that the block copolymer be capable of acting as an adhesive, preferably on its own, but also in conjunction with one or more substances, such as those normally used in the manufacture of transdermal patches. Therefore, in a preferred aspect, a block copolymer, preferably an acrylic block copolymer, comprising the soft and hard segments, which are suitable for use as an adhesive, can be provided. Characterized because it is a degree of chemical entanglement between the soft segments. It should be appreciated that the term "drug", as used herein, refers to any substance or compound suitable for administration via a transdermal patch. A substance that has the properties of drug retention is adapted in the present being a substance capable of absorption or absorption of a drug. In the example where the substance is loaded with the drug to be dispensed via a transdermal patch, then it should be appreciated that said absorbance and / or absorbance should be at least partially reversible. The block copolymers of the present invention are simple for manufacturing in an inexpensive manner, and can be selected for drug retention and / or adhesive / cohesive properties. Accordingly, it is possible to provide an adhesive for use with a transdermal patch that allows the delivery of a greater amount of drug than is currently possible using known adhesives, as well as to provide cleaning removal of used patches.

The term "block copolymer", as used herein, refers to a macromolecule comprising two, or more, chemically distinct polymer structures, terminally connected together (Block Copolymers: Overview and Critical Survey, Noshay and MacGrath, 1977) . These dissimilar polymer structures, sections or segments, represent the "blocks" of the block copolymer. The blocks may generally be arranged in a structure A-B, a structure A-B-A, or a system of (A-B) n of multiple blocks, wherein A and B are the polymer segments chemically distinct from the block copolymer. It is generally preferred that the block copolymer of the present invention be one of structure A-B-A, especially wherein one of A and B is an acrylic type polymer unit. It should be appreciated that the present invention is also applicable to block copolymers having three, or more, different "blocks," such as a block copolymer A-B-C. However, for convenience, the reference hereinafter for block copolymers should be assumed to be only subunits A and B, but it should be appreciated that said reference also covers block copolymers having more than two different subunits, unless is specified otherwise. It should be appreciated that the block copolymer properties are largely determined by the nature of the blocks a and B, the block copolymers commonly have both "hard" and "soft" segments.A "hard" segment is a polymer having a glass transition temperature (Tg) and / or a melting temperature (TM) that is above ambient temperature, while a soft segment is a polymer that has a Tg (and possibly a T) below the ambient temperature The different segments are through the different properties imparted in the block copolymer Without being constructed by theory, they are made through the association of the hard segments of the block copolymer units separated into the physical entanglement within the copolymer of block, so they promote the cohesive properties of the block copolymer.It is particularly preferred that the hard segments of the block copolymers of the block This invention forms said closed physical associations. The present invention preferably relates to acrylic block copolymers. In acrylic block copolymers, at least the hard block blocks of the block copolymer is an acrylic acid polymer, or a polymer of an acrylic acid derivative. The polymer can be composed of just one kind of repeating monomer. However, it should be appreciated that a mixture of monomeric species can be used to form each of the blocks, so that the block can, by itself, be a copolymer. The use of a combination of different monomers I can affect various properties of the resulting block copolymer. In particular, the variation in the ratio or nature of the monomers used that allow properties such as adhesion, tackiness and cohesion can be modulated, so that it is generally advantageous for the block copolymer segments composed of more than one species of monomers. It is preferred that the alkyl acrylates and alkyl methacrylates are polymerized to form the smooth portion of the block copolymer. The alkyl acrylates and alkyl methacrylates are provided through the tack and adhesion properties. Suitable alkyl acrylates and alkyl methacrylates include n-butyl acrylate, n-butyl methacrylate, hexyl acrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate and tridecyl methacrylate, through other suitable acrylates and methacrylates are readily apparent to those skilled in the art. It is preferred that the acrylic block copolymer comprises at least 505 by weight of alkyl acrylate or (co) polymer of alkyl methacrylate. A polar monomer is advantageously copolymerized with alkyl acrylate alkyl methacrylate where it is desired to improve the drug solubility of certain drugs, especially hydrophilic ones. Suitable polar monomers can be copolymerized with alkyl acrylates or alkyl methacrylates including hydroxyethyl acrylate, hydroxypropyl acrylate, vinyl pyrrolidone, acrylamide, dimethacrylamide, acrylonitrile, diacetone acrylamide and vinyl acetate, although others will be apparent to those skilled in the art. matter. The diacetone acrylamide, or a combination of diacetone acrylamide or vinyl acetate, are useful in the present invention. The diacetone acrylamide component allows the polymerization regime, which is of commercial importance. In this case, where the two polar monomers are used in an adhesive, it should be appreciated that the levels of each monomer can be manipulated in such a manner to provide optimal drug retention and delivery. As stated above, the variation in the components of the soft segments affects the overall properties of the block copolymer, through the essential aspect that allows the interleaving of the soft segments. For example, the soft segments essentially consist of diacetone acrylamide with butyl acrylate and / or 2-ethylhexyl acrylate, in about equal portions, well worked and a weight ratio of about 3: 4: 4 which provide good results. It is preferred that the diacetone acrylamide, or other polar monomer, such as hydroxyethyl methacrylate or vinyl acetate, may be present in not more than 50% w / w of soft segment monomer mixture, so that they can be charged to reduce the adhesion, for example. However, where adhesion is not important, good levels of drug loading can be obtained with an excess of polar monomer. The acrylate component can generally vary more freely, with good results observed with 2-ethylhexyl acrylate and butyl acrylate together or individually, through the more hydrophobic side chain size, there is a slight decrease in drug loading, both for the hydrophobic drugs as hydrophilic. As noted above, the ratios of several monomers are generally preferred to be approximately equal. For adhesives, it is preferred that they can be with a polar component of 50% or less of the soft segment, with the apolar portion forming up to about 85% w / w, but preferably between about 50 and 70% w / w. In the previous example, this is about 72% (4 + 4) apolar to about 18% (3) polar. In general, it is preferred that the combination of the chosen monomers produce an adhesive, and that the adhesive have a combination of good drug loading, cohesion and adhesion, so that they are suitable for use with a transdermal patches. When the variation of the monomers and their different ratios, it is preferred that they retain the loading properties of the drug. The adhesives of the prior art are generally capable of loading the drug of up to about 5% w / w of adhesive.

The block copolymers of the present invention, depending on the composition, are often loaded in excess of 15%, but the load of between 5 and 10% is easily obtainable. The drug loading of less than 5% is occasionally observed, depending on the constitution and method of the block copolymer preparation, worse is acceptable, especially where other properties are important, such as cohesion. It should be appreciated that compounds with superior drug retention properties but also reduced adhesion may also be suitable as an adhesive for use with a medical patch. Said adhesives may be suitable for use in a transdermal patch which needs only to be applied for a short time or, alternatively, the adhesive may be used in combination with an additional agent, such as an improver, for example polyethylene glycol, Azone (Trade Mark). ), vitamin E or liquid paraffin, to increase its adhesive properties. As described above, suitable polymers, for use in the hard portion of the block copolymers have transition temperatures above room temperature. Suitable monomers for use in forming the hard segment polymer include styrene, α-methylstyrene, methyl methacrylate and vinyl pyrrolidone, through other suitable monomers which will be readily apparent to those skilled in the art. It has been found that styrene and polymethyl methacrylate are suitable for use in forming the hard segment of the block copolymers of the present invention.

It is preferred that the hard portion of the block copolymer be formed of 3-30% w / w of the total block copolymer, particularly preferably 5-15% w / w. The block copolymers of the present invention are characterized in that the soft portions contain a degree of chemical entanglement. Said entanglement can be affected by any entanglement agent. It is particularly preferable that the entanglement agent be in the form of a monomer suitable for incorporation into the soft segment during polymerization. Preferably the crosslinking agent has two, or more, radically polymerizable groups, such as a vinyl group, per molecule of the monomer, at least one tends to remain unchanged during the initial polymerization, thereby allowing the interlacing of the copolymer of resulting block. Suitable crosslinking agents for use in the present invention include divinylbenzene, methylene bis-acrylamide, ethylene glycol dimethacrylate, ethylene glycol tetramethacrylate, propylene glycol dimethacrylate, butylene glycol dimethacrylate or trimethylolpropane trimethacrylate, through of other entanglement agents will be readily apparent to those skilled in the art. The preferred entanglement agent is tetraethylene glycol dimethacrylate. It is preferred that the crosslinking agent comprises about 0.01-0.6% by weight of the block copolymer, with 0.1-0.4% by weight being particularly preferred. The methods for the production of the block copolymers of their monomeric constituents are well known. The block copolymer portions of the present invention can be produced by any suitable method, such as the passage of development methods, anionics, cations and free radicals (Block Copolymers, supra). Free radical methods are generally preferred over other methods, such as anionic polymerization, so that the solvent and the monomer do not have to be purified. Suitable initiators for polymerization include polymeric peroxides with more than one peroxide moiety per molecule. Another suitable initiator has been found to be "Perhexa MC" (1, 1'-di-tert-butyl-peroxy-2-methyl cyclohexane, Nihon Yusi C.C.). This compound contains two tertiary butyl peroxy groups which allow the polymerization in this way of the hard and soft segments of the block copolymer. The initiator CH-50-AL (Peroxid-Chemie GmbH) has also been found to be suitable in the manufacture of the compounds of the present invention. The choice of reaction conditions is within one's skin in matter, once a suitable initiator has been chosen. The initiator is preferably used in an amount of 0.005-0.1% by weight of the block copolymer, with 0.01-0.05% by weight being particularly preferred, although it should be appreciated that the chosen amount is, again, within the skin of one in the matter. In particular, it is preferred that the amount is not so much that it causes the instantaneous gelation of the mixture, nor so low that polymerization decreases and leaves residual monomers in excess. A preferred level of residual monomers is below 2000 ppm. It should also be appreciated that the amount of the initiator may vary substantially, depending on such considerations so that the initiator itself and the nature of the monomers. The block copolymers of the present invention are preferably adhesives, particularly preferably pressure sensitive adhesives. Pressure sensitive adhesives can be applied to a surface by manual pressure and do not require activation by heat, water, or solvent. As such, they are particularly suitable for use with transdermal patches. The block copolymer adhesives of the present invention are particularly suitable for use in combination with a transdermal patch. A number of adhesives currently used in transdermal patches require the use of a glue, to provide improved tack. The block copolymers of the present invention are suitable for use without a glue and, thus, are particularly advantageous. However, it should be appreciated that the block copolymers of the present invention are also suitable for use in combination with a glue, as required or desired. Suitable adhesives are well known and will be readily apparent to those skilled in the art. Without being restricted by any theory, it is thought that the combination of chemical entanglement between the soft segments of the combined copolymer generally with the hydrophobic interaction, or physical entanglement, between the hard portions results in a "matrix-like" structure. Copolymers that only have physical entanglement of the hard segments are less able to form said matrix. It is thought that the combination of both entanglement forms of the block copolymers of the present invention provides both the reduced internal resistance (cohesion) and the significantly improved storage capacity of the drug that was observed. Essentially, it is thought that the hard segments associated to form islands or nodes, with the radiation of the soft segments of and between these nodes. Where the soft segment is segment B and an ABA structure, then it is necessary that they be as long as possible to allow the entry of the drug. In the block copolymers of the present invention, there is a physical structure defined on the "sea" between the islands, where the soft segments are intertwined, so that they are not necessary for the extensive intermixing of soft segments. This results in a greater cohesion than the total block copolymer, at the same time, allowing the shorter soft segment length and still having large or large distances between the islands. This allows greater storage capacity of the drug. Even if the length of the soft segment is reduced to 50% or less than that of the material, the adhesives still have a greater cohesion and can also be manufactured more easily (infra). It is thought that the ability of a copolymer adhesive retains a drug that is released to the length of the copolymer chains and the degree of entanglement. The ability to store the improved drug of the block copolymer of the present invention allows the reduction in length of the polymer chains compared to other copolymers that are used as adhesives., while still improved drug storage is provided. In addition, shorter polymer chains reduce the viscosity of the block copolymer, which is particularly advantageous in the manufacture of the adhesive. Therefore, in addition a transdermal patch comprising a block copolymer of the present invention is provided, the block copolymer preferably being an adhesive. The term "transdermal patch," as used herein, is used to describe any means that can be applied to the skin and that can be used to deliver a drug or pharmaceutical preparation in, and preferably through, the skin layer. , usually the dermis. The transdermal patch generally comprises a backing portion impervious to the drug and an adhesive. The adhesive serves to stick the patch on the skin and can also serve to contain and deliver the drug. The transdermal patch can be any patch that is suitable for use in combination with the block copolymer adhesive of the present invention. It should be appreciated that the improved storage capacity of the block copolymer of the present invention allows for improvements in the design of the transdermal patches. For example, patches that are smaller are those currently available that can be made and that can still deliver a therapeutically effective amount of the drug by themselves at the highest storage capacity of the drug and provide the block copolymers of the present invention. The block copolymers of the present invention also allow the manufacture with greater forward strength of the transdermal patches. Acrylic adhesives that can be used in transdermal patches are commonly interlaced to harden them by the use of isocyanates. However, the entanglement of isocyanate should be carried out just before the coating of a transdermal patch, because the entanglement reaction is immediately. If the adhesive is left to interlock for too long, then it can no longer be coated on the patch. However, the block copolymer of the present invention is entangled so that the solvent is removed, so that entanglement can occur after the coating, this being the preferred method. Consequently, not only can the block copolymer be easily applied to the patch, but also the entire solution can be stored for a period before the coating. Consequently, the manufacture of an interlaced block copolymer having drug retention properties, the block copolymer having hard and soft segments, being interleaved between the soft segments, is also provided, the process comprising the polymerization of the monomeric constituents of each soft segment in solution, then they added the constituents to the hard segment to each resulting solution and polymerized the resulting mixture, followed by entanglement by removing any solvent. Such a complete solution is also provided, which provides the interlaced block copolymer of the present invention by removing the solvent or solvent system, such as evaporation. If the solution can be stored for any length of time, it may be necessary to preserve the polymer from precipitation, and this can be achieved by known means, suspending or agitating the agents. It may also be necessary to select the type of polymers that should not be subjected substantially to some entanglement until the solvent evaporates. Suitable examples of drug-impermeable reinforcements that can be used for transdermal patches include films or sheets of polyolefins, polyesters, polyurethanes, polyvinyl alcohols, polyvinyl chlorides, polyvinylidene chloride, polyamides, ethylene-vinyl acetate copolymer (EVA), ethylene-ethyl acrylate copolymer (EEA), vinyl acetate-vinyl chloride copolymer, cellulose acetate, ethyl cellulose, metallic vapor deposited films or sheets thereof, sheets or films of rubber, sheets or films of expanded synthetic resin, non-woven fabrics, fabrics, fabrics knitted, paper and metal sheets. Other reinforcements will be readily apparent to those skilled in the art. Suitable drugs are usually biologically active compounds or mixtures of compounds which have therapeutic, prophylactic or other beneficial pharmacological or physiological effects. Examples of the drugs that can be used in combination with the block copolymers of the present invention include anti-arithmetic, anticoagulant, antidiabetic, antiepileptic, antifungal, anti-drop, antimalarial, antimuscarinic agents, antineoplastic agents, antiprotozoal agents, thyroid agents and anti-thyroid, anxiolytic and neuroleptic sedatives, beta-support agents, drugs that affect the metabolism of bones, cardiac inotropic agents, chelating agents, antidotes and antagonists, corticosteroids, cough suppressants, espectorants and mucolytics, dermatological agents, diuretics, gastrointestinal, general and local anesthetic agents, histamine H1 receptor antagonists, nitrates, vitamins, opioid analgesics, parasympathomimetics, anti-asthmatic agents, muscle relaxants, simultaneous and anorexic agents, sympathomimetics, thyroid agents, xanthines, regulatory agents pills, anti-inflammatory drugs, analgesics, antiarrhythmic drugs, antispasmodics, antidepressants, antipsychotic drugs, tranquilizers, narcotic antagonists, antiparkinsonism agents, cholinergic agonists, anti-carcinogenic drugs, immunosuppressive agents, antiviral agents, antibiotic agents, appetite suppressants , antiemetics, anticholinergics, antihistamines, antimigraine agents, coronary vasodilators, cerebral or peripheral, hormonal agents, contraceptive agents, antithrombotic agents, diuretics, antihypertensive agents and cardiovascular drugs. Other drugs will be readily apparent to those skilled in the art. Examples of specific drugs include steroids such as estradiol, levonorgestrol, noretristerone, testosterone and their esters; nitro compounds such as nitroglycerin and isosorbide nitrates; nicotine, scopolamine; oxikam derivatives such as lornoxicam, ketoprofen, fentanyl, salbutamol, terbutaline, selegiline and clonidine, as well as pharmaceutically acceptable equivalents thereof and pharmaceutically acceptable esters and salts of said compounds with pharmaceutically acceptable acids and bases as appropriate. It should be appreciated that the above classes of drug, or specific drugs, are contemplated individually for use with a transdermal patch of the present invention.

It should be appreciated that while several drugs have been exemplified before, some drugs are more suitable for use in transdermal delivery systems than others. While a transdermal delivery system can deliver an amount of drug, this amount can not be the optimal therapeutic dose. Essentially, any drug that can be released by a patch and that is not substantially crystalline at low levels can be useful so that they are expected to be useful in the patches of the present invention. It should be appreciated that the present invention also provides for the use of permeation enhancers that allow greater permeation of the drug into the skin. Suitable compounds for use as permeation agents include compounds that contain at least one amide bond, lactic acid esters, lactic acids, lactic acid salts, dicarboxylic acids, dicarboxylic acid salts, citric acid and citric acid salts , O-alkyl (polyoxyethyl) phosphates and esters of higher fatty acids, glycerin carboxylic acids and polyoxyethylene ethers and monoalcohols. Suitable builders include lauryl di-methanol amide, glycerin monolaurate, glycerin triacetate, and polyoxyethylene lauryl ether. Other specific examples of permeation enhancers include PEG (polyethylene glycol), liquid paraffin, Azone and vitamin E. Furthermore, said improvers can improve the adhesion qualities of the block copolymers of the invention and, when used, may be convenient. to select an adhesive with inferior adhesive properties. Alternatively, said enhancers can be used to supplement a block copolymer having lower adhesive qualities. The present invention also provides for the use of suitable agents to inhibit the crystallization of the drug in the adhesive. Many agents will be apparent to those skilled in the art, and polyethylene glycol is generally particularly effective. However, it has been found that a further advantage of the adhesives of the present invention is that the compounds can generally be released in a less similar manner to crystallize them in the systems of the prior art. The present invention is now further illustrated with reference to the following Examples without linkage. Example 1 Drug saturation The ability of the block copolymer of the present invention to store the drugs was compared to a polystyrene-polyisoprene-polystyrene-based adhesive (hereinafter referred to as "SIS") used in transdermal patches (KratonD-110 ™ , Shell Chemicals). For the purpose of the comparative studies, the SIS block copolymer was mixed with the glue (Arkon P-100, Arakawa Chemicals, Osaka, Japan) and paraffin in the ratio 1: 1.6: 1.2 by weight, respectively. This mixture provides optimal adhesive properties. Three drugs, isosorbide mononitrate (ISMN), indomethacin and ketoprofen, were used in the present example. Each of the drugs was mixed with each of the adhesives, as in the scale of the drug concentrations were obtained in each adhesive. Each adhesive / drug mixture was applied to a backing film, and the film was allowed to dry. After drying, the films were tested for crystallization of the drug. More specifically, the compound of the present invention was dissolved in ethyl acetate to form 39% by weight of the final solution. The SIS adhesive was dissolved in chloroform, at a final concentration of 19% by weight of the final solution. Each drug was dissolved in methanol at a final concentration of 5% by weight. The adhesives and drug solutions were mixed together in suitable proportions so that a scale of different drug concentrations was produced. The mixture was then applied to a polyethylene terephthalate film (abbreviated herein as "PET"). The solvents were evaporated at 60 ° C, so that the thin films of adhesives containing the drug were allowed to stand. The films were allowed to stand at 50 ° C for 48 hours, then at room temperature for 48 hours. Crystal formation was evaluated.

The following scale of drug concentrations was chosen: SIS Adhesive: 1%, 2%, 3%, 5%, 7.5%, 10% (w / w of adhesive) Adhesive of the invention: 10%, 12.5%, 15 %, 17.5%, 20% (p / p / adhesive). It was not possible to obtain drug concentrations above 10% in the SIS adhesive. The saturation concentration of each drug was determined, which was defined as the maximum concentration of the drug at which the formation without crystal was observed. The results of the experiment are shown in the following Table 1.

Table 1 Drug Saturation Concentration (% w / w of adhesive) Adhesive of the SIS invention ISMN > 20% 5% Cetoprofen 17.5% 1 Indomethacin 15 < 1% It was observed from the above Table that the drug crystallized in the SIS adhesive at substantially lower concentrations than in the compounds of the invention, both ketoprofen and indomycin are essentially unusual in SIS.

Therefore, the compound of the present invention is capable of incorporating larger amounts of SIS adhesive drug before crystal formation occurs. Example 2 Drug delivery The ability of an adhesive compound of the present invention to deliver ISMN was compared to the SIS adhesive. The transdermal patches were manufactured, each containing the adhesives in combination with ISMN. The test patches were applied to two volunteers for 24 hours. After this time, the test patches were removed, and the residual drug levels were measured. The amount of ISMN in a normal patch (control) was measured, to obtain a reference value. Compared to the residual drug content of the test patches with the total drug content of the control patch allowed the total amount of the drug supply of the patch to be determined. More specifically, a 20% w / w solution of ISMN in methanol was prepared. The ISMN solution was mixed with an amount of the SIS adhesive or the adhesive of the present invention, sufficient to obtain the desired final drug concentration. Each adhesive drug mixture was coated on a 30 μm PET film (linear supply). Therefore, after drying, the adhesive layer was observed laminated on a PET backing film.

The films were then cut to form circular patches of 3 cm in diameter. After they were used in the patients for 24 hours, the patches containing the SIS adhesive were placed in 15 cm3 of chloroform for 24 hours to dissolve the ISMN. Then methanol was used to precipitate the ISMNs from the chloroform solution. The ISMN levels were then determined by High Pressure Liquid Chromatography (CLAP). The patches containing the adhesive of the present invention are placed directly in 30 cm3 of methanol for 24 hours, in order to dissolve the remaining ISMN. The concentration of ISMN was determined by CLAP in accordance with the foregoing. In the latter case, methanol alone is sufficient to supply the drug of the adhesive of the present invention, and a chloroform step is not required. For comparative purposes, an extraction of chloroform-methanol from ISMN of the adhesive of the present invention has been shown. Therefore, the following results are directly comparable and are not affected by the different extraction techniques used. The drug supply of the following patches was valued, and the results are shown in the following Table 2.

Table 2 It is not possible to provide more than 5% p / p of ISMN in the SIS adhesive. Therefore, the relative drug delivery of the different adhesive is not directly comparable. However, there is the absolute amount of the drug supply that is important in this case. Table 3 below shows the maximum effective levels of drug delivery to the volunteers of each adhesive. Table 3 Residual drug content (mg) From the above table, it was observed that the total drug that can be released from the patch is much larger when the adhesive of the present invention is used. This is released for the ability of the adhesive of the present invention to contain a larger initial amount of drug. In addition, drug delivery continues from the patches of the invention after the 24-hour trial period.

Example 3 Preparation of the Adhesive Compounds of the Present Invention The adhesive composition used in Examples 1 and 2 were made in a two step synthesis: Step 1: 115 g of 2-ethylhexyl acrylate, 84 g of diacetone acrylamide, 115 g of butyl acrylate and 0.72 of dimethacrylate were mixed. of tetraethylene glycol, in order to obtain a homogeneous solution. The solution was placed in a flask, and 200 cm3 of ethyl acetate was added together with 200 cm3 of toluene. The solution was heated to 80 ° C under nitrogen, then 0.05 g of 1, 1'-di-ferf-butylperoxy-2-methyl cyclohexane dissolved in 10 cm 3 of ethyl acetate was added. The polymerization was allowed to proceed for 24 hours. This step produced the soft segments. Step 2: After 24 hours, 45 mg of methyl methacrylate and 300 cm3 of toluene were added to the mixture from Step 1. The solution was then heated to 99 ° C in order to start the second stage of the polymerization step, which continued for 12 hours. After this time, the polymerization was transferred to a can for cooling. The resulting solution represented by a pre-interlaced polymer, used in subsequent experiments. The average molecular weight of the polymer produced in this form was calculated to be 358,000 Da by a process according to claim 30, wherein of gel permeation. Example 4 Comparative Cohesion Studies There are no standard industry tests for cohesion measurement. The bond strength of the adhesives was analyzed in the following manner. The polymer solution of Example 3 was applied to a backing strip, evaporation of the solvent resulted in an interlaced adhesive compound. One end of the strip was then glued to the glass plate, angled at 20 ° C from the vertical. The rest of the strip was left hanging vertically. A weight was then suspended from the free end of the strip. The adaptation time for the strip to be separated from the plate (ie, for the strip and the weight to begin the development) were measured. More specifically, in this example, the SIS adhesive was compared with the adhesive composition of the present invention. The SIS adhesive containing 5% by weight of ISMN, while the adhesive of the present invention containing 10% by weight of ISMN Strips of length 5 cm and width 0.6 cm were each coated with the adhesive drug mixture, attached to the glass plate. The total adhesion area in each case was 0.36 cm3. It was used in weight of 80 g. The measurements were taken at ° C. The adaptation time for each strip was again separated from the plate shown in the following Table 4. Table 4 It can be seen from the above table that the adhesive of the present invention takes significantly longer to be re-separated from the glass plate, compared to the SIS adhesive under the same conditions. Therefore, the adhesive of the present invention has significantly improved cohesive properties with respect to the SIS adhesive. Example 5 Effects of Variation in the Monomeric Composition A number of variations of the adhesive of the invention were prepared, in order to determine the effect of variation in the composition. 5.1 The initial variants were tested for cohesion. The tested compositions are shown in the following Table 5. Table 5 Data not available In all the above cases, the solvents used were toluene (500 ml) and ethyl acetate (200 ml). The strong initiator Perhexa MC (0.05 mg) in all cases. From the above, it was observed that the composition A represents an adhesive with excellent cohesion. The results obtained with B and C indicate some of the variations that can be made and a suitable composition obtained. Composition D contains the comparatively lower levels of glycol dimethacrylate of tetraethylene and methyl methacrylate. This adhesive has lower cohesion compared to B or C, each of which only have these two amounts reduced. Compositions E and F produce gel-like polymers, which are not preferred as a suitable adhesive for use with a transdermal patch, while X and Y have lower levels of each of which are diacetone acrylamide, tetraethylene glycol dimethacrylate and methyl methacrylate and produce a sticky polymer with weak cohesion. 5.2 A number of additional adhesives are made, with different compositions. These were tested for cohesion and retention of the drug. These compositions and properties are presented in the following Table 6. cn N > or cn cn TABLE 6 Composition GHIJKLMNOP Monomer 1 2-ethylhexyl acrylate 110 110 55 55 55 55 Butyl acrylate 110 110 55 55 110 55 55 110 Hydroxyethyl methacrylate 75 Diacetone acrylamide 110 55 75 75 75 75 75 100 Vinyl acetate 75 37.5 37.5 40 Dimethacrylate of tetraethylene glycol 0.35 0.35 0.35 0.5 0.35 0.35 0.35 0.35 0.35 0.35 Methacrylate of methyl 25 15 15 15 15 - 15 15 15 15 Styrene 15 Primer1 - or Perhexa MC 0.09 0.14 0.14 0.14 0.14 0.14 0.14 0.14 0.21 0.14? Solvent2 Ethyl acetate 200 200 200 200 200 200 200 300 300 300 Toluene 250 250 250 250 250 250 250 350 350 350 Adhesive properties Lightweight Bonding Good Good N / D5 Lightweight Good Light Good N / D5 No adhesion Cohesion 5 10 > 15 N / D5 10 > 15 10 > 15 N / D5 0 Drug loading property Piroxicam 5 5 8 N / D5 5 6 4 8 N / D5 10 Oestradiol 8 8 15 N / D5 6 10 < 4 15 N / D5 > 15 1 units = grams 3 units = minutes 2 units = ml 4 units = grams per 100 g of adhesive 5 Not available From the foregoing, it can be seen that the compositions G, H, I, K, L, M and N show good retention properties to the drug, in combination with suitable cohesives and adhesive properties. These adhesives are suitable for use in combination with transdermal patches. Compounds J and O, which have high levels of glycol dimethacrylate of tetraethylene and Perhexa MC, produce a product that gels in the first stage of polymerization.

Such compounds are not suitable for use as adhesives for transdermal patches. Compound P, with a high level of hydrophilic monomers, produces a produce with, or without adhesion. This compound is unsuitable for use as an adhesive for transdermal patches, with no less adhesion generally in the presence of an improver. In any case, this compound may be suitable for use with transdermal patches as a drug retention agent, even if an extra adhesive is necessary, it is due to its greater drug retention. Comparative Example 1 Cohesion and Loading Capacity of the Commercially Available Adhesive Drug Two commercially available adhesives used in transdermal patches were tested for drug loading capacity, using the piroxicam and estradiol drugs. The adhesives were National Starch 837-2516 and National Starch 387-2052. Each drug showed cohesion of more than 15 minutes. The National Starch 837-2616 was able to heat 4 g of piroxicam and 4 g of estradiol per 100 g of adhesive. The National Starch 837-2052 was able to heat 4 g of piroxicam and 2 g of estradiol, per 100 mg of adhesive. Therefore, by comparison with Table 6 above, the National Starch adhesives show equivalent drug loading properties compared to M, while other compounds of Table 6 for which the drug face was tested show drug loading. improved with respect to commercially available products. Example 6 Use of the CH-50-AL Initiator The experiments were carried out using the CH-50-AL initiators, instead of Perhexa MC. CH-60-AL is 1, 1 -di (fery-butylperoxy) cyclohexane and is available from Peroxid-Chemie GmbH. The compositions listed in the following Table 7 were tested.

Table 7 1 units = grams 2 units = ml.

Claims (42)

1. CLAIMS 1. An interlaced block copolymer having drug retention properties, the block copolymer having hard and soft segments, characterized in that they are entangled between the soft segments.
2. 2. A block copolymer, according to claim 1, which is an acrylic block copolymer.
3. 3. A block copolymer, according to claim 1 or 2, wherein the block copolymer is an adhesive.
4. 4. A block copolymer, according to the claim 3, wherein the block copolymer is an adhesive when in conjunction with one or more improvers.
5. 5. A block copolymer according to any of the preceding claims, having a structure A-B-A.
6. 6. A block copolymer according to the claim 5, wherein one of A and B are a polymer unit of acrylic type.
7. 7. A block copolymer according to any of the preceding claims, wherein the soft portion of the block copolymer comprises monomer units selected from alkyl acrylates and alkyl methacrylates.
8. 8. A block copolymer according to claim 7, wherein the monomer units are selected from n-butyl acrylate, n-butyl methacrylate, hexyl acrylate, 2-ethyl butyl acrylate, isooctyl acrylate, sodium acrylate, 2-ethylhexyl, 2-ethylhexyl methacrylates, decyl acrylate, decyl methacrylate, dodecyl acrylic, dodecyl methacrylate, tridecyl acrylate and tridecyl methacrylate and mixtures thereof.
9. 9. A block copolymer according to claim 7 or 8, wherein the acrylic block copolymer comprises at least 59% by weight of alkyl acrylate or (co) polymer of alkyl methacrylate.
10. 10. A block copolymer according to claims 7 to 9, wherein a polar monomer is copolymerized with the alkyl acrylate or alkyl methacrylate.
11. 11. A block copolymer according to the claim 10, wherein the polar monomer is selected from hydroxyethyl acrylate, hydroxypropyl acrylate, vinyl pyrrolidone, acrylamide, dimethacrylamide, acrylonitrile, diacetone acrylamide, vinyl acetate and mixtures thereof.
12. 12. A block copolymer according to any of the preceding claims, wherein the diacetone acrylamide is an ingredient of at least a mild portion.
13. 13. A block copolymer according to any of the preceding claims, which is an adhesive, wherein the adhesive properties were improved by an additional agent.
14. 14. A block copolymer according to claim 13, wherein the improver is polyethylene glycol, Azone, vitamin E or liquid paraffin.
15. 15. A block copolymer according to claim 13, wherein the enhancer is lauryl di-methanol amide, glycerin monolaurate, glycerin triacetate or polyoxyethylene lauryl ether.
16. 16. A block copolymer according to any of the preceding claims, wherein the hard segment polymer is formed of styrene, α-methylstyrene, methyl methacrylate, vinyl pyrrolidone or mixtures thereof.
17. 17. A block copolymer according to claim 16, wherein the hard segment polymer is formed from styrene and / or polymethyl methacrylate.
18. 18. A block copolymer according to any of the preceding claims, wherein the hard portion of the block copolymer is formed of 3-30% w / w of the total block copolymer.
19. 19. A block copolymer according to the claim 18, wherein the hard portion of the block copolymer is formed from 5-15% w / w of the total block copolymer.
20. 20. A block copolymer according to any of the preceding claims, which is a pressure sensitive adhesive.
21. 21. A transdermal patch comprising a block copolymer according to any preceding claim.
22. 22. A patch according to claim 21, loaded with a drug selected from anti-arrhythmic drugs, anticoagulants, antidiabetics, antiepileptics, antifungals, anti-gout, antimalarials, antimuscarinic agents, antineoplastic agents, antiprotozoal agents, thyroid and anti-thyroid agents, anxiolytic and neuroleptic sedatives, backup agents beta, drugs that affect bone metabolism, cardiac inotropic agents, chelating agents, anti-gout and antagonists, corticosteroids, cough suppressants, expectorants and mucolytics, dermatological agents, diuretics, gastrointestinal agents, general and local anesthetics, receptor antagonists H1 of histamine, nitrates, vitamins, opioid analgesics, parasympathomimetics, anti-asthmatic agents, muscle relaxants, simultaneous and anorexic agents, sympathomimetics, thyroid agents, xanthines, lipid regulating agents, anti-inflammatory drugs, analgesics, drugs antiarrhythmic os, antispasmodics, antidepressants, antipsychotic drugs, tranquilizers, narcotic antagonists, antiparkinson agents, cholinergic agonists, anti-carcinogenic drugs, immunosuppressive agents, antiviral agents, antibiotic agents, appetite suppressants, antiemetics, anticholinergics, antihistamines, antimigraine agents, coronary, cerebral or peripheral vasodilators, hormonal agents, contraceptive agents, antithrombotic agents, diuretics, antihypertensive agents and cardiovascular drugs.
23. 23. A patch according to claim 22, wherein the drug is a steroid, or a salt or ester thereof.
24. 24. A patch according to claim 23, wherein the drug is an estradiol, levonorgestrol, norethisterone, testosterone or a salt or ester thereof.
25. 25. A patch according to claim 22, wherein the drug is a nitro compound or a salt or ester thereof.
26. 26. A patch according to claim 25, wherein the drug is nitroglycerin or an isosorbide nitrate or an ester salt thereof.
27. 27. A patch according to claim 25, wherein the drug is nicotine or scopolamine or a salt or ester thereof.
28. 28. A patch according to claim 22, wherein the drug is an oxicam derivative or a salt or ester thereof.
29. 29. A patch according to claim 28, wherein the drug is lornoxicam, ketoprofen, fentanyl, salbutamol, terbutaline, selegiline or clonidine or a salt ester thereof.
30. 30. A process for the manufacture of an interlaced block copolymer having drug retention properties, the block copolymer having hard and soft segments, with interleaved between the soft segments, the process comprising the polymerization of the monomeric constituents of each soft segment in solution said constituents including at least one entanglement agent, then added the constituents of the hard segment to each resulting solution and the polymerization of the resulting mixture, followed by entanglement by removal of any solvent, an initiator being added before the aggregation of the hard segment constituents.
31. 31. A process according to claim 30, wherein the block copolymer is produced in a manner having properties of a block copolymer according to any of claims 1 to 20.
32. 32. A process according to claim 30 or 31, wherein the entanglement agent is in the form of at least one monomer suitable for incorporation into the soft segment during polymerization.
33. 33. A process according to claim 32, wherein at least one entanglement agent has two, or more, radically polymerizable groups.
34. 34. A process according to claim 32 or 33, wherein at least one interlacing agent is selected from divinyl benzene, methylene bis-acrylamide, ethylene glycol dimethacrylate, ethylene glycol tetramethacrylate, propylene glycol dimethacrylate. , butylene glycol dimethacrylate and trimethylolpropane trimethacrylate.
35. 35. A process according to any one of claims 32 to 34, wherein at least one entanglement agent is tetraethylene glycol dimethacrylate.
36. 36. A process according to any of claims 32 to 35, wherein at least one entanglement agent comprises 0.01-0.6% by weight of the block copolymer.
37. 37. A process according to claim 32, wherein the entanglement agent comprises 0.1-0.4% by weight of the block copolymer.
38. 38. A process according to any of claims 30 to 37, wherein the initiator is 1,1'-di-re-butylperoxy-2-methylcyclohexane.
39. 39. A process according to claims 30 to 38, wherein the initiator is used in an amount of 0.005-0.1% by weight of the block copolymer.
40. 40. A process according to claim 39, wherein the initiator is used in an amount of 0.01-0.05% by weight.
41. 41. A process according to any of claims 30 to 40, wherein the polar monomer comprises up to 50% w / w of the monomers of any soft segment.
42. 42. A process according to claim 41, wherein the polar monomer comprises an excess of 15% w / w of the monomers of any soft segment.