WO2003059221A1

WO2003059221A1 - Composition and method for inhibiting hypersensitivity

Info

Publication number: WO2003059221A1
Application number: PCT/US2003/000607
Authority: WO
Inventors: Stephen Francis Badylak; Kenneth Robert Morris
Original assignee: Purdue Research Foundation; Clarian Health Partners, Inc.
Priority date: 2002-01-11
Filing date: 2003-01-09
Publication date: 2003-07-24
Also published as: AU2003202264A1

Abstract

The present invention is directed to methods, compositions, and devices for preventing or inhibiting undesired sensitization reactions of the skin or mucosa caused by a component of a transdermal or transmucosal drug delivery system. A method is provided wherein an intestinal submucosa composition is administered to intact skin or mucosa of a vertebrate in combination with a transdermal or transmucosal drug delivery system to inhibit sensitization of the skin or mucosa by a component of the delivery system. The invention is also directed to a pharmaceutical composition comprising the transdermal or transmucosal drug delivery system, a therapeutically effective amount of a drug, and a therapeutically effective amount of a sensitization inhibitory composition comprising an intestinal submucosa composition, and to a device for administering such a composition.

Description

COMPOSITION AND METHOD FOR INHIBITING HYPERSENSITINITY

FIELD OF THE INVENTION

The present invention relates to methods, compositions, and devices for preventing or inhibiting undesired sensitization of the skin or mucosa caused by a component of a transdermal or transmucosal drug delivery system. More specifically, an intestinal submucosa composition is used to prevent or inhibit sensitization of the skin or mucosa by a component of a transdermal or transmucosal drug delivery system.

BACKGROUND AND SUMMARY OF THE INVENTION

The transdermal or transmucosal route of drug delivery provides many advantages over alternate routes of administration. For example, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs, and other inherent inconveniences (e.g., gastrointestinal irritation and the like) are also eliminated.

Transdermal or transmucosal delivery systems for delivery of drugs or other beneficial agents are well-known (see, for example, U.S. Pats. Nos. 3,598,122; 3,598,123; 4,286,592; 4,314,557; 4,379,454; 4,559,222; and 4,573,995, which are incorporated by reference herein). These drag delivery systems are generally composed of the following components: (a) basic components, such as a backing, a delivery matrix, and an adhesive layer; (b) the drag; and (c) additives, such as solubilizers, plasticizers and penetration enhancers.

Transdermal or transmucosal drug delivery systems provide conditions highly conducive for the induction of skin or mucosa allergic reactions known as hypersensitivity reactions. For example, psoriasis-like changes have been noted in skin from patients receiving propranolol and other beta blockers (Brigden, W. D. et al., Brit. J. Dermatol. 95:335 (1976); Gaylarde, P. M. et al., Clin. Exp. Dermatol. 3:157 (1978)). Allergic contact dermatitis has been reported for nitroglycerine in a transdermal drag delivery system (Transderm-Nitro) (Rosenfeld, A. S. et al., Am. Heart J. 108:1061 (1984); Fisher, A. A., Cutis 34:526 (1984)), where it was shown that the drug itself was the cause of the allergic response. Scopolamine delivery has been reported to induce delayed hypersensitivity reactions (Trozak, D. J., J. Am. Acad. Dermatol. 13:247-251 (1985); Nan der Willigen, A. H. et al., J. Am. Acad. Dermatol. 18:146-147 (1988)). Bircher, A. J. et al., Contact Derm. 25:230-236 (1991) reported contact sensitization to nicotine delivered in a transdermal drag delivery system. A number of approaches for avoiding undesired hypersensitivity reactions in the skin or mucosa have been tried including avoidance of sensitizing components, appropriate testing of allergenic drugs, and co-delivery of antihistamines, corticosteroids, or compounds that modulate metabolism of the drag to prevent generation of allergenic metabolites. Another approach is to inhibit the immunological processing of a transdermally or transmucosally sensitizing drag by co-administration of the sensitizing drag and an agent that inhibits antigen processing such as a lysosomal uptake inhibitor.

Sensitization reactions commonly occur where drugs are administered for sustained periods, and the skin inflammation or inflammation of mucosal tissues may persist well beyond the time that the drag delivery system is removed from the skin. Accordingly, the local inflaimiiation may be a source of discomfort and clinical complications in a patient suffering from such a reaction, and in some cases, drag administration must be stopped. Therefore, despite the development of the transdermal and transmucosal drug delivery art, there remains a continuing need for improved compositions and methods of overcoming sensitization reactions caused by transdermal or transmuco sal delivery of drags .

Sensitization is a two-phase process involving distinct immune responses. The first phase is called the induction phase and occurs when the skin of an individual is first exposed to the sensitizing drug or other component of a delivery system. In this phase, the sensitizing drag or antigen is presented to the T- lymphocytes by the Langerhans cells or dendritic cells of the epidermis, either in situ or in the draining lymph node. Consequently, T-lymphocytes which recognize the antigen proliferate, differentiate and upregulate production of T-cell components or factors that will accentuate or magnify responses to subsequent exposure to the same antigen. Following induction, the individual's T-lymphocytes are specifically sensitized to the drag and stand poised to respond to a future encounter with the same antigen.

The second phase of sensitization is called elicitation. Elicitation occurs when the individual is subsequently (i.e., after induction) exposed to the same sensitizing drug or other component of a delivery system. During elicitation, the antigen is once again presented mainly on the dendritic cells. The sensitized T- lymphocytes migrate to the treated site and cause local inflammation. Such a response, with a strong inflammatory component, is known by various names, including a sensitization reaction or a hypersensitivity reaction. Such a state of drug- specific immunity precludes further transdermal or transmucosal delivery of the same drug.

An individual animal can be rendered specifically unresponsive to an antigen for a prolonged period, a state known as immunological tolerance. It is known that tolerance to an antigen can be induced, for example, by first presenting the antigen in a tolero genie form, or by administering the antigen with compounds which suppress the individual's immune system. For example, presentation of an antigen following, or in conjunction with, a drag that suppresses the immune response may result in a state of prolonged or even permanent immunological tolerance. The present invention is based on the discovery that an intestinal submucosa composition that is administered to intact skin in combination with a transdermal or transmucosal drag delivery system is capable of inducing a state of immunological tolerance, which renders the immune system specifically unreactive, hyporeactive, or otherwise tolerant, to components of the delivery system. Such a composition induces a state of prolonged immunological tolerance. Accordingly, the methods and compositions of the present invention which employ an intestinal submucosa composition that is administered to intact skin to induce immunological tolerance are useful for prevention or inhibition of sensitization produced by transdermal or transmucosal delivery of known sensitizing drugs or by other components of transdermal or transmucosal delivery systems.

The present invention is directed to a method for preventing or inhibiting sensitization of the skin or mucosa by a component of a transdermal or transmucosal drag delivery system. The method comprises the steps of administering to a drag delivery locus of intact skin or mucosa of a vertebrate a transdermal or transmucosal drag delivery system comprising a therapeutically effective amount of a drag, and administering to a sensitization inhibitor delivery locus of intact skin or mucosa of the vertebrate a therapeutically effective amount of a sensitization inhibitory composition comprising an intestinal submucosa composition or extracts or hydrolyzates thereof to prevent or inhibit the sensitization of the skin or mucosa by the component of the delivery system. The sensitization inhibitory composition comprising an intestinal submucosa composition can be administered to intact skin before, together with, or after, the transdermally or transmucosally delivered drag and one or more presentations of the intestinal submucosa composition renders the vertebrate immunologically tolerant to the sensitizing component. The component causing sensitization of the skin or mucosa can be the transdermally or transmucosally delivered therapeutic drag or another component of the delivery system, or a combination thereof. In another embodiment a method is provided for inducing immunological tolerance in a vertebrate to a component of a transdermal or transmucosal drag delivery system that sensitizes skin or mucosa. The method comprises the steps of administering to a drug delivery locus of intact skin or mucosa of the vertebrate the transdermal or transmucosal drug delivery system comprising a therapeutically effective amount of a drag, and administering to a sensitization inhibitor delivery locus of intact skin or mucosa of the vertebrate a therapeutically effective amount of a sensitization inhibitory composition comprising an intestinal submucosa composition or extracts or hydrolysates thereof to induce immunological tolerance to the component of the sensitizing delivery system. In another embodiment, the present invention is directed to a pharmaceutical composition. The composition comprises a permeation enhancer and a therapeutically effective amount of a sensitization inhibitory composition comprising an intestinal submucosa composition or extracts or hydrolysates thereof. In still another embodiment a pharmaceutical composition is provided. The composition comprises a transdermal or transmucosal drug delivery system, a therapeutically effective amount of a drag, and a therapeutically effective amount of a sensitization inhibitory composition comprising an intestinal submucosa composition or extracts or hydrolysates thereof. hi yet another embodiment a drag delivery device is provided. The device comprises a delivery matrix for transdermal or transmucosal drug delivery, a detachable backing to hold the delivery matrix in transmitting relationship with skin or mucosa, a therapeutically effective amount of a drug incorporated in the delivery matrix, and a therapeutically effective amount of a sensitization inhibitory composition comprising an intestinal submucosa composition or extracts or hydrolysates thereof incorporated in the delivery matrix.

In another embodiment a transdermal or transmucosal drug delivery device is provided. The device includes a drag delivery matrix comprising a therapeutically effective amount of a drag for transdermal or transmucosal delivery, and a sensitization inhibitory composition comprising an intestinal submucosa composition or extracts or hydrolysates thereof, and a means for holding the drag and the intestinal submucosa composition in transmitting relationship with intact skin.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1 shows an exemplary drag delivery device with overlapping release liners.

Fig. 2 shows an exemplary drag delivery device with a single release liner.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compositions, methods, and devices useful for preventing or inhibiting the effects of a component of a transdermal drag delivery system that sensitizes skin or mucosa. An intestinal submucosa composition has been found by the present inventors to be useful in inducing immune tolerance, and, thus, acts as a counter-sensitizing agent that has the capacity to prevent or inhibit the development of sensitization of skin or mucosa in response to a component of a transdermal drag delivery system. The invention is applicable to any vertebrate, and, thus is applicable not only to humans, but can have veterinary applications (e.g., domestic, agricultural, zoo, or laboratory animals).

As used herein the term "drug" relates to a biologically active agent, compound or composition of matter which can be transdermally or transmucosally delivered to a vertebrate for the purpose of providing some beneficial or therapeutic effect. In accordance with this invention the term "drag" includes therapeutically effective proteins and polypeptides.

As used herein the terms "transdermal delivery" and "transdermal delivery system" mean, respectively, the delivery of a drag by passage through intact (i.e., unbroken) skin, and a system therefor. As used herein, the terms "transmucosal delivery" and "transmucosal delivery system" mean, respectively, the delivery of a drag by passage through intact mucosa, and a system therefor.

As used herein a "therapeutically effective amount" of the drug is an amount which prevents, reduces, or stabilizes one or more of the climcal symptoms of a disease state whether such improved condition is permanent or temporary.

As used herein a term "therapeutically effective amount" of the sensitization inhibitory composition comprising an intestinal submucosa composition is an amount which prevents, reduces, or stabilizes one or more of the clinical symptoms of a hypersensitivity reaction in a vertebrate suffering from a hypersensitivity reaction of the skin or mucosa whether such improved condition is permanent or temporary.

As used herein the term "inhibiting" means reducing, blocking or stabilizing.

The inclusion of the intestinal submucosa composition of the present invention prevents or inhibits sensitization of skin or mucosa induced by an immunogenic component of a transdermal or transmucosal drag delivery system. The transdermally or transmucosally delivered drug can induce sensitization when delivered at a therapeutically effective rate. Alternatively, another component of the delivery system can cause the sensitization, or a combination of components can cause the sensitizing effect. Thus, the intestinal submucosa composition acts to inhibit or prevent such sensitization, regardless of whether or not the drug administered or another component of the delivery system, or a combination thereof, causes the sensitization.

The above compositions and methods are useful for reducing or preventing skin or mucosa sensitization produced by one or more drugs selected from, but not limited to, the following groups: (a) an angiotensin converting enzyme inhibitor; (b) a beta adrenergic receptor blocker; (c) an anti-hypertensive drug other than an angiotensin converting enzyme inhibitor or a beta adrenergic receptor blocker; (d) an anti-histamine; (e) an anti-asthmatic; (f) a non-steroidal anti-inflammatory drag; (g) a central nervous system active drag; (h) a weight control drug; (i) an anticoagulant; (j) a potassium control drag; (k) an immunomodulatory drag; and (1) a decongestant. A large number of drugs are capable of producing hypersensitivity when they are delivered via the transdermal or transmucosal route, and this invention is applicable to drugs known to cause hypersensitivity such as clonidine, tetracaine, naloxone, naltrexone, nalbutaphine, and narcotic analgesics such as puprenorphine, hydroporphone and levorphanol.

This invention is also useful in connection with the delivery of any drags within the broad class normally delivered through the body surface and membranes, in particular through the skin or mucosa. This includes therapeutic agents in all of the major therapeutic areas, including, but not limited to, anti- infectives, such as antibiotics and antivirals; analgesics and analgesic combinations; anorexics; antiarthritics; anti-asthmatics (such as albuterol, metaproterenol, ketotifen and terbutaline); anticoagulants (such as urokinase); anticonvulsants; antidepressants; anti-diabetics; antidiarrheals; antihistamines (such as chlorpheniramine and diphenhydramine); anti-inflammatory agents (such as ketoprofen, prostaglandins, flurbiprofen, diclofenac, indomethacin, piroxicam and ibuprofen); antimigraine agents; anti-motion sickness preparations; antinauseants; antineoplastics; antiparkinsonism drags; antipraritics, antipsychotics; antipyretics; antispasmodics, including gastrointestinal and urinary; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular agents, including angiotensin converting enzyme inhibitors (such as captropril and fosinopril), calcium channel blockers, beta blockers (such as nadolol, timolol, propranolol and alprenolol), antiarrythmics, antihypertensives (such as clonidine), diuretics, vasodilators, including general, coronary, peripheral and cerebral; central nervous acting agents (such as fluphenazine, trifluperazine, haloperidol, Xanax®, Librium®, Valium®); cough and cold preparations; decongestants; diagnostics; hormones; hypnotics; muscle relaxants; parasympatholytics; parasympathomimetics; psychostimulants; sedatives; weight control and appetite suppressive drags (such as mazindol) and tranquilizers. The intestinal submucosa composition can also prevent or inhibit sensitization caused by therapeutically effective peptides and proteins used in accordance with the invention. In addition to the drag and the sensitization inhibitory composition comprising an intestinal submucosa composition, the transdermal or transmucosal drag delivery system includes other components such as a backing, a delivery matrix, an adhesive, a release liner, and additives such as permeation enhancers, plasticizers, solubilizers, excipients, and antioxidants known in the art. Any component of the delivery system, or a combination of components, can cause the sensitizing effect. The backing is detachable as a result of an adhesive present on one surface of the backing material, and holds the delivery matrix in transmitting relationship with the skin or mucosa. The backing can be made of any material known in the art to be suitable for use in a transdermal or transmucosal drug delivery system as long as the material is substantially impermeable to the drag and to the intestinal submucosa composition. For example, the backing material can comprise plastic films of polyethylene, vinyl acetate resins, ethylene/vinyl acetate copolymers, polyvinyl chloride, polyurethane, and the like, metal foils, non- woven fabric, cloth and commercially available laminates.

The drag and the sensitization inhibitory composition comprising an intestinal submucosa composition are dispersed in and released from a delivery matrix, (i.e., the delivery matrix serves as a reservoir for the drag and the sensitization inhibitory composition). The delivery matrix should be compatible with the drag, the sensitization inhibitory composition, and any carriers therefor. When using an aqueous based system, the delivery matrix is preferably a hydrophilic polymer (e.g., a hydrogel). When using a non-aqueous based system, the delivery matrix is preferably composed of a hydrophobic polymer. Suitable polymeric matrices are known in the transdermal or transmucosal drag delivery art and include, without limitation, natural and synthetic rubbers such as polybutylene, polyisobutylene, polybutadiene, polyethylene, styrenebutadiene copolymers, polyisoprene, polyurethane, ethylene/propylene copolymers, polyalkylacrylate polymers, copolyesters, ethylene/acrylic copolymers, silicones, butadiene/acrylonitrile copolymers, and ethylene vinyl acetate polymers as described in U.S. Pat. No. 4,144,317, the disclosure of which is incorporated herein by reference, polyvinylchloride, nylon, or the like. Other suitable materials include gelled or thickened mineral oil, petroleum jelly and various aqueous gels and cellulosic polymers. In an alternate embodiment, a pharmaceutically acceptable carrier known in the art is used to transdermally or transmucosally deliver the drag and the sensitization inhibitory composition comprising the intestinal submucosa composition in combination or individually.

The adhesive is preferably pressure sensitive and adheres effectively to the skin or mucosa to hold the backing in a transmitting relationship with the skin and mucosa. As a consequence, the delivery matrix is held in a transmitting relationship with the skin or mucosa so that the drag and the sensitization inhibitory composition comprising an intestinal submucosa composition can be delivered to the skin or mucosa. The pressure sensitive adhesive can be any such adhesive known in the art and preferably has desirable characteristics such as good adherence to skin or mucosa, ability to be peeled or otherwise detached from skin or mucosa without trauma to the skin or mucosa, retention of tack with aging, and the like.

Suitable protective release liners which seal and protect the adhesive layer and delivery matrix during residency of the drag delivery device within its package are also well known in the art and include the commercially available products of Dow Corning Corporation designated Bio-Release® liner and Syl-off® 7610 liner. The release liner must be compatible with the other components of the drag delivery system including the drug and the sensitization inhibitory composition comprising the intestinal submucosa composition. A major barrier to permeation of drags through the skin is the stratum corneum layer of the epidermis. Preferably, a component of the intestinal submucosa composition of the present invention is capable of permeating the epidermis. However, to augment the skin or mucosa permeation of drags or a component of the intestinal submucosa composition, certain other agents, called permeation enhancers can be added to the transdermal or transmucosal delivery system. Exemplary of compounds which can be added to enhance the permeation of the drug or a component of the intestinal submucosa composition include ethanol, oleyl alcohol, lauramidopropyl betaine, decylmethylsulfoxide, N-methylpyrrolidone, isopropyl alcohol, t-butanol, sodium lauryl sulfate, sucrose monolaurate, glycerol monooleate, nonionic surfactants, methylmethacrylate,dipropylene glycol, propylene glycol, and polyethylene glycol, oils such as olive oil, squalene, and lanolin, fatty ethers such as acetyl ether and oleyl ether, fatty acid esters such as isopropyl myristate, urea and urea derivatives such as allantoin, polar solvents such as dimethyldecylphosphoxide, methyloctyl-sulfoxide, dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethyl-acetonide, dimethylsulfoxide, decylmethyl-sulfoxide, and dimethylformamide, salicylic acid, amino acids which are penetration assistants, and higher molecular weight aliphatic surfactants such as lauryl sulfate salts, oleic and linoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate. Combinations of permeation enhancers can also be used to obtain the desired effect.

In certain embodiments a plasticizer is incorporated into the formulation to improve the adhesive characteristics of the composition. Suitable plasticizers are those known in the art including: (1) aliphatic hydrocarbons; (2) mixed aliphatic and aromatic hydrocarbons; (3) aromatic hydrocarbons; (4) substituted aromatic hydrocarbons; (5) hydrogenated esters; (6) polyterpenes; and (7) hydrogenated wood resins. The transdermal drag delivery system can further comprise various thickeners, fillers and other additives such as solubilizers, excipients, and antioxidants known for use with such systems.

In one embodiment the transdermal or transmucosal drag delivery system comprises a delivery matrix adapted to contain the drug and optionally the sensitization inhibitory composition comprising the intestinal submucosa composition. In another embodiment the drag and the sensitization inhibitory composition comprising the intestinal submucosa composition are in separate delivery matrices. In still another embodiment, the delivery matrix can be the sensitization inhibitory composition comprising the intestinal submucosa composition in a gel form. The delivery matrix is in transmitting relationship with the skin or mucosa. In accordance with this invention "transmitting relationship" does not mean that the delivery matrix is in direct contact with the skin or mucosa, but that the delivery matrix is situated to permit delivery of the drag or a component of the intestinal submucosa composition to the skin or mucosa. The delivery matrix contains sufficient amounts of the drag and the sensitization inhibitory composition to continuously deliver to the skin or mucosa site the drag, at a therapeutically effective rate and over a predetermined delivery period, and the intestinal submucosa composition at a rate and for a period of time sufficient to induce immune tolerance.

When a constant delivery rate is desired, the drag and/or the sensitization inhibitory composition comprising the intestinal submucosa composition is present in the delivery matrix or carrier at a concentration in excess of saturation, the amount of excess being a function of the desired length of the delivery period of the system. However, the drug or the sensitization inhibitory composition can be present at a level below saturation without departing from this invention as long as the drug or sensitization inhibitory composition is delivered to the skin or mucosa site at a rate and for a period of time sufficient to induce tolerance to the drag or other sensitizing component of the delivery system.

The precise formulation of the transdermally or transmucosally delivered drug and the sensitization inhibitory composition comprising an intestinal submucosa composition can be designed to deliver the drag and the intestinal submucosa composition at the desired fluxes and can be in numerous forms, including, without limitation, ointments, gels, and creams for use in a transdermal or transmucosal delivery device or for direct administration. The formulation can be aqueous or non-aqueous (e.g., oil) based. Aqueous formulations, in particular gels, typically comprise water and about 1-2% (w/w) of a gelling agent such as hydroxyethyl cellulose or hydroxypropyl cellulose. Typical non-aqueous gels comprise silicone fluid or mineral oil. The mineral oil can also have 1-2% (w/w) of a gelling agent such as colloidal silicon dioxide. The suitability of a particular gel composition depends on the compatibility of its constituents with the sensitizing drag (with or without a permeation enhancer) and the sensitization inhibitory composition. Examples of transdermal or transmucosal delivery systems are disclosed in Bodde, H. E. et al., Crit. Rev. Ther. Drag Carrier Syst. 6:87-115 (1989); and in U.S. Pats. Nos. 3,598,122; 3,598,123; 4,286,592; 4,314,557; 4,379,454; 4,559,222; and 4,573,995; which are incorporated herein by reference. Transdermal drag delivery systems include such devices as nicotine patches, nitroglycerine patches, tape, and bandages, for example.

Figs. 1 and 2 show exemplary drag delivery devices. In one embodiment the drag delivery device 10 includes a flexible backing 15. A pressure sensitive adhesive 14 is applied to the backing for securing the drag delivery device 10 to the skin. A drag delivery matrix 24 contains the drag and/or the intestinal submucosa composition. Release liners 17, 17a, and 17b seal and protect the adheisve layer 14 and delivery matrix 24 during the residency of the drag delivery device 10 in its package.

The drag and the sensitization inhibitory composition comprising the intestinal submucosa composition of the present invention are administered to intact (i.e., unbroken) skin or mucosa. The drag is delivered to a drag delivery locus of intact skin or mucosa and the sensitization inhibitory composition comprising an intestinal submucosa composition is delivered to a sensitization inhibitor delivery locus of intact skin or mucosa. In a preferred embodiment, the sensitization inhibitory composition comprising an intestinal submucosa composition is co-delivered in a transdermal or transmucosal drag delivery system with the drug. Accordingly, in this embodiment, the drag delivery locus and the sensitization inhibitor delivery locus are the same locus, and the drag and the sensitization inhibitory composition are delivered to the same locus. hi another embodiment, the drag and the sensitization inhibitory composition comprising an intestinal submucosa composition are contained in separate delivery devices and separate delivery matrices. In this embodiment, the drug delivery locus and the sensitization inhibitor delivery locus can be the same locus or can be different loci (i.e., the drag and the sensitization inhibitory composition can be delivered to the same or different loci).

In still another embodiment, the transdermal drag delivery system can comprise a formulation for direct administration to intact skin or mucosa. In this embodiment, the drug and the sensitization inliibitory composition comprising an intestinal submucosa composition are present, in combination or individually, in a formulation for direct administration to intact skin or mucosa. The formulation for direct administration can be a formulation such as a gel, ointment, cream, or the like, which is applied to intact skin or mucosa. Alternatively, the drug can be present in a delivery device and the sensitization inhibitory composition comprising an intestinal submucosa composition in a formulation for direct administration, or vice versa. The sensitization inhibitory composition comprising an intestinal submucosa composition can be delivered before, together with, or after the transdermally or transmucosally delivered drag to prevent or inhibit (i.e., reduce or stabilize) sensitization or to produce a state of immunological tolerance which is sustained and protects the patient from sensitization upon subsequent exposure to the sensitizing drug or other component of the delivery system. Such a state of tolerance is characterized by the fact that the initial treatment or treatments with the sensitization inhibitory composition comprising an intestinal submucosa composition, which can be co-delivered with the sensitizing component or delivered separately in transdermal or transmucosal delivery devices or a formulation for direct administration, is sufficient to prevent skin or mucosa sensitizing effects of any of a number of subsequent transdermal or transmucosal drag deliveries without further need to deliver the sensitization inhibitory composition.

Once immunological tolerance has been induced by application of the drug and the sensitization inhibitory composition comprising the intestinal submucosa composition, the sensitizing drag can be thereafter administered following a regimen which is sufficient to maintain the induced tolerance in the patient. Generally, continuous re-application of the sensitizing drag after the induction of sensitization will maintain the induced tolerance in the individual patient. However, in many instances continuous re-application of the drug is not necessary. Depending upon a number of factors including the particular drag being delivered and the patient, intermittent application of the sensitizing drug after tolerization is sufficient to maintain tolerance. Thus, once tolerance has been induced, the re-application of the sensitizing drug without the sensitization inhibitory composition comprising the intestinal submucosa composition for periods on the order of several weeks out of a period extending over about 6 to 12 months may be sufficient in many cases to maintain the induced tolerance.

As described above, in some cases, once immune tolerance to the drag or other component of the delivery system has been induced through delivery of the drug in combination with the sensitization inhibitory composition comprising an intestinal submucosa composition, the application of the sensitization inhibitory composition can be stopped and thereafter the sensitizing drag or other component of the delivery system delivered without danger of sensitizing the patient and causing adverse reactions of the skin or mucosa. Alternatively, multiple treatments with the sensitization inhibitory composition may be required. In one embodiment, a pharmaceutical composition is provided. The pharmaceutical composition comprises a transdermal or transmucosal drug delivery system, a therapeutically effective amount of a drag, and a therapeutically effective amount of a sensitization inhibitory composition comprising an intestinal submucosa composition or extracts or hydrolysates thereof. The pharmaceutical composition can be a transdermal or transmucosal drag delivery system comprising a delivery matrix, a backing, a drag, pigments, inert fillers, permeation enhancers, excipients, and other conventional components, and the sensitization inhibitory composition comprising the intestinal submucosa composition as described above. Alternatively, the pharmaceutical composition can be in other forms, including, without limitation, ointments, gels, and creams as described above.

In another embodiment, a pharmaceutical composition is provided. The composition comprises a permeation enhancer and a therapeutically effective amount of a sensitization inhibitory composition comprising an intestinal submucosa composition or extracts or hydrolysates thereof.

In still another embodiment a drag delivery device for delivery of the drug and the sensitization inhibitory composition comprising an intestinal submucosa composition is provided. The device comprises a delivery matrix for transdermal or transmucosal drag delivery, a detachable backing to hold the delivery matrix in transmitting relationship with skin or mucosa, a therapeutically effective amount of a drag incorporated in the delivery matrix, and a therapeutically effective amount of a sensitization inhibitory composition comprising an intestinal submucosa composition or extracts or hydrolysates thereof incorporated in the delivery matrix. In a related embodiment, a transdermal or transmucosal drag delivery device including a drag delivery matrix comprising a therapeutically effective amount of a drag for transdermal or transmucosal delivery, and a sensitization inhibitory composition comprising an intestinal submucosa composition or extracts or hydrolysates thereof, and a means for holding the drag and the intestinal submucosa composition in transmitting relationship with intact skin.

The dosage of the sensitization inhibitory composition comprising the intestinal submucosa composition will be dependent upon the age, health, and weight of the patient, kind of concurrent treatment, if any, and frequency of treatment. While individual needs vary, determination of optimal ranges of effective amounts of the sensitization inhibitory composition and other components of the transdermal or transmucosal delivery system is within the skill of the art. For transdermal or transmucosal delivery, typical effective dosages of the sensitization inhibitory composition to prevent sensitization by a sensitizing component of the delivery system will depend on permeation of the intestinal submucosa composition through skin or mucosa and its saturation level in the permeant. The sensitization inhibitory composition can be delivered one or more times and the requirement for multiple treatments may depend on dosage. The preparation of an intestinal submucosa useful in accordance with this invention is described in U.S. Pats. Nos. 4,902,508 and 5,554,389. To summarize, the intestinal submucosa tissues are prepared from vertebrate intestine, preferably harvested from porcine, ovine or bovine species, but not excluding other species. In this regard, the intestinal submucosa tissues are typically xenogeneic (i.e., from a different species) but also can be allogeneic (i.e., from a nonidentical member the same species) or autogeneic (i.e., from the same animal or individual).

In one method to prepare the intestinal submucosa tissues for use in the invention, the tissues are subjected to abrasion using a longitudinal wiping motion to remove the outer layers, comprising smooth muscle tissues, and the innermost layer, i.e., at least the luminal portion of the tunica mucosa. Thus, the intestinal submucosa tissue is delaminated from the tunica muscularis and at least the luminal portion of the tunica mucosa. The intestinal submucosa is rinsed with saline and optionally sterilized; it can be stored in a hydrated or dehydrated state. Lyophilized or air dried intestinal submucosa can be rehydrated and used in accordance with this invention without loss of biological activity. Native intestinal submucosa as a starting material is a relatively acellular collagenous matrix and the intestinal submucosa composition of the present invention is a collagenous matrix devoid of intact cells (i.e., the intestinal submucosa composition is acellular). To form multilayer sheets of intestinal submucosa, multiple layers of intestinal submucosa can be overlapped with each other. The individual layers can be fixed to one another using standard techniques known to those skilled in the art, including the use of sutures and biocompatible adhesives such as collagen binder pastes. Alternatively, layers can be fused together by compressing the overlapped regions under dehydrating conditions, optionally with the addition of heat as described in U.S. Pat. No. 5,711,969, the disclosure of which is expressly incorporated herein.

The intestinal submucosa can be sterilized using conventional sterilization techniques including glutaraldehyde tanning, formaldehyde tanning at acidic pH, ethylene oxide treatment, propylene oxide treatment, gas plasma sterilization, gamma radiation, electron beam and peracetic acid sterilization. Preferred sterilization techniques include exposing the intestinal submucosa tissue to peracetic acid, 1-4 Mrads gamma irradiation (more preferably 1-2.5 Mrads of gamma irradiation) or gas plasma sterilization; peracetic acid sterilization is the most preferred sterilization method. Typically, the intestinal submucosa is subjected to two or more sterilization processes. After the intestinal submucosa is sterilized, for example by chemical treatment, the tissue can be incorporated into the drag delivery device, packaged, and sterilized again using electron beam or gamma irradiation sterilization techniques. A sterilization technique such as that described in U.S. Pat. No. 6,206,931, incorporated herein by reference, may also be used.

It is also known that intestinal submucosa can be fluidized by comminuting and/or enzymatic digestion, without loss of its biological activity, for incorporation, for example, into the delivery matrix of the transdermal or transmucosal drug delivery system or for direct application in the form of a gel, for example. See U.S. Pat. No. 6,264,992 Bl the disclosure of which is expressly incorporated herein by reference. More particularly, the native or fluidized intestinal submucosa composition can be treated with an enzyme for a period of time sufficient to solubilize all or a major portion of the intestinal submucosa components.

Preferably the intestinal submucosa is digested with an enzyme that hydro lyzes the structural components of the intestinal submucosa to produce a suspension or homogenous solution of intestinal submucosa components. The intestinal submucosa can be enzymatically treated with proteases (for example, a collagenase or trypsin or pepsin), glycosaminoglycanases or a combination of proteases and glycosaminoglycanases. Optionally, other appropriate enzymes can be used alone or in combination with proteases and glycosaminoglycanases. The tissue digest can be optionally filtered to provide a homogenous solution of partially solubilized intestinal submucosa. The viscosity of fluidized intestinal submucosa for use in transdermal or transmucosal drug delivery in accordance with this invention can be manipulated by controlling the concentration of the intestinal submucosa component and the degree of hydration. The viscosity can be adjusted to a range of about 2 to about o

300,000 cps at 25 C. Higher viscosity formulations, for example, gels, can be prepared from the intestinal submucosa digest solutions by dialyzing the digested material and then adjusting the pH of such solutions to about 5.0 to about 9.0.

The preparation of extracts of intestinal submucosa tissue is described in PCT Application No. PCT/US97/22721, published as WO 98/25964 on June 18, 1998 incorporated herein by reference, and in Example 3. The fluidized and gel forms of the intestinal submucosa composition, and the extracts of intestinal submucosa may retain biologically active agents such as growth factors including transforming growth factor TGF β , TGF /3-related proteins, and fibroblast growth factor.

The present invention also contemplates the use of powder forms of intestinal submucosa. In one embodiment a powder form of intestinal submucosa is prepared by pulverizing the intestinal submucosa under liquid nitrogen to produce

2 particles ranging in size from 0.1 to 1 mm . The particulate composition is then lyophilized overnight and sterilized to form a solid substantially anhydrous particulate composite. Alternatively, a powder form of intestinal submucosa can be formed from fluidized intestinal submucosa by drying the suspensions or solutions of comminuted intestinal submucosa. A powder form of intestinal submucosa tissue could be mixed, for example, with gels, ointments, or creams for use in a transdermal or transmucosal drag delivery system or for direct application.

EXAMPLE 1

PREPARATION OF FLUIDIZED INTESTINAL SUBMUCOSA

Small intestinal submucosa was harvested and prepared from freshly euthanized pigs (Delphi Indiana) as previously described in U.S. Pats. Nos. 4,902,508 and 4,956,178 and as described above. Intestinal submucosa was powderized under liquid nitrogen and stored at -80°C prior to use. Partial digestion of the material was performed by adding 5 g powdered tissue to a 100 ml solution containing 0.1 % pepsin in 0.5 M acetic acid and digesting for 72 hours at 4°C. Following partial digestion, the suspension was centrifuged at 12,000 rpm for 20 minutes at 4°C and the insoluble pellet discarded. The supernatant was dialyzed against several changes of 0.01 M acetic acid at 4°C (MWCO 3500). The solution was sterilized by adding chloroform (5 ml chloroform to 900 ml of 0.01 M acetic acid) to the intestinal submucosa tissue hydrolysate. Dialysis of the intestinal submucosa tissue was continued with two additional changes of sterile 0.01 M acetic acid to eliminate the chloroform. The contents of the dialysis bag were then transferred aseptically to a sterile container. The resultant fluidized composition was stored at 4°C. The fluidized intestinal submucosa composition is used to inhibit the hypersensitivity response of skin to Nadolol (described below) by incorporating the fluidized composition into a transdermal drag delivery device or into a gel, ointment, or cream for transdermal delivery.

EXAMPLE 2

PREPARATION OF INTESTINAL SUBMUCOSAL GEL COMPOSITION

To prepare the gel form of the intestinal submucosa, 8 mis of fluidized intestinal submucosa was mixed with 1.2 ml lOx PBS buffer (lOx phosphate buffered saline containing 5 mg/L phenol red); 0.04 N HCl (approx 1.6 ml) was added to adjust the pH to between 6.6 and 7.4 and then 0.05 N NaOH (approx. 1.2 ml) was added to shift the pH to > 8. The final volume was adjusted to 12 ml with water. The resultant mixture is aliquoted in 100 μl aliquots onto the delivery matrix of a transdermal drag delivery device and incubated at 37°C for 0.5 to 1.5 hours to solidify the gel composition or is incorporated into a gel, ointment, or cream for transdermal delivery.

EXAMPLE 3

PREPARATION OF INTESTINAL SUBMUCOSAL EXTRACTS

Extraction buffers used for these studies included 4 M guanidine and 2M urea each prepared in 50 mM Tris-HCl, pH 7.4. The powder form of intestinal submucosa was suspended in the relevant extraction buffer (25% w/v) containing phenylmethyl sulphonyl fluoride, N-ethylmaleimide, and benzamidine (protease inhibitors) each at 1 mM and vigorously stirred for 24 hours at 4°C. The extraction mixture was then centrifuged at 12,000 x g for 30 minutes at 4°C and the supernatant collected. The insoluble material was washed briefly in the extraction buffer, centrifuged, and the wash combined with the original supernatant. The supernatant was dialyzed extensively in Spectrapor tubing (MWCO 3500, Spectrum Medical Industries, Los Angeles, CA) against 30 volumes of deionized water (9 changes over 72 hours). The dialysate was centrifuged at 12,000 x g to remove any insoluble material and the supernatant was used immediately or lyophilized for storage.

EXAMPLE 4

INHIBITION OF HYPERSENSITIVITY REACTIONS WITH INTESTINAL SUBMUCOSA COMPOSITIONS

A. Induction of Sensitization Ten rabbits are used per treatment group with four to five rabbits being maintained per pen. Rabbits are fed animal feed and water ad libitum. A 7% solution of Nadolol is prepared in distilled water. Previous studies have shown that Nadolol efficiently sensitizes rabbits when applied to skin. For induction, each rabbit receives epicutaneous application of 35 μg of Nadolol on the backs (dorsum) of the rabbits for 5 hours using a transdermal drag delivery device as described above. Alternatively, induction is achieved using the same protocol except that the rabbits receive epicutaneous application of Nadolol continuously for 2 weeks.

B. Elicitation of Responses A hypersensitivity response is elicited on day 5 for animals sensitized for 5 hours and after 2 weeks for animals continuously sensitized for this time period by exposing the rabbits on the dorsum of each rabbit to 35 μg of Nadolol in the same location in which the Nadolol was applied to induce sensitization. The site of sensitization is examined for redness at 24, 48, and 72 hours after exposure to Nadolol. Negative control rabbits are treated with PBS and exposed to Nadolol, as described above.

C. Pretreatment or Co-Administration of Intestinal Submucosa Compositions

For pretreatment, 100 μl of the intestinal submucosa composition as described above is applied to the dorsum of rabbits in the form of the fluidized or gel compositions or extracts described above. The composition is applied, in the same location in which Nadolol was applied to induce sensitization, to the dorsum of the rabbits for 24 hours prior to the induction of sensitization and is applied in a transdermal drug delivery device (for example, see Figs. 1 and 2) or is applied directly to the dorsum of the animals. Alternatively, an intestinal submucosa "patch" is applied directly to the dorsum of rabbits or is applied in a transdermal delivery device for 24 hours prior to induction, or the powder form of these compositions is applied in a gel, ointment, or cream or in a delivery device. The rabbits are epicutaneously sensitized with Nadolol on the dorsum of the rabbits and subsequently exposed to Nadolol as described above.

For co-administration, rabbits are treated with the fluidized or gel intestinal submucosa compositions, extracts, "patch," or powder form as described above at the time of induction with Nadolol and continuously thereafter. The rabbits are sensitized with Nadolol on the dorsum and are subsequently exposed to Nadolol as described above. During treatment with Nadolol the rabbits are concurrently treated with the intestinal submucosa composition on the dorsum in a transdermal drug delivery device or via direct application. The treatment with the intestinal submucosa composition continues until the last examination of the skin for redness at 72 hours after exposure to Nadolol. Alternatively, the rabbits are treated with Nadolol on the dorsum as described above and the intestinal submucosa composition is present in the same transdermal drug delivery device as Nadolol during sensitization.

In an alternative assay protocol, rabbits are treated with Nadolol as in the sensitization protocol described above, and no additional treatment with Nadolol is required to induce redness of the skin in response to Nadolol.

D. Results

The hypersensitivity reaction in response to Nadolol will be prevented or inhibited for rabbits treated with the intestinal submucosa tissue "patch," fluidized composition, gel composition, extract, or powder form.

Claims

CLAJMS:

1. A method for preventing or inhibiting sensitization of the skin or mucosa by a component of a transdermal or transmucosal drag delivery system, said method comprising the steps of administering to a drag delivery locus of intact skin or mucosa of a vertebrate the transdermal or transmucosal drug delivery system comprising a therapeutically effective amount of a drug; and administering to a sensitization inhibitor delivery locus of intact skin or mucosa of the vertebrate a therapeutically effective amount of a sensitization inhibitory composition comprising an intestinal submucosa composition or extracts or hydrolysates thereof to prevent or inhibit sensitization of the skin or mucosa by the component of the delivery system.

2. The method of claim 1 wherein the intestinal submucosa is delaminated from the tunica muscularis and at least the luminal portion of the tunica mucosa.

3. The method of claim 1 wherein the sensitization inliibitory composition comprises an extract of intestinal submucosa.

4. The method of claim 1 wherein the sensitization inliibitory composition comprises an hydrolyzate of intestinal submucosa.

5. The method of claim 1 wherein the sensitization inliibitory composition comprises intestinal submucosa in powder form.

6. The method of claim 1 wherein the sensitization inhibitory composition comprises a gelled hydrolysate of intestinal submucosa.

7. The method of claim 1 wherein the sensitization inliibitory composition is administered to the vertebrate before administration of the drag delivery system.

8. The method of claim 1 wherein the sensitization inhibitory composition is administered to the vertebrate together with the drag delivery system.

9. The method of claim 1 wherein the sensitization inhibitory composition is administered to the vertebrate after administration of the drug delivery system.

10. The method of claim 1 wherein the sensitizing component is selected from a group consisting of a drag, a backing, a delivery matrix, an adhesive, a release liner, a solubilizer, a plasticizer, an excipient, an antioxidant, a filler, a pigment, and a permeation enhancer.

11. The method of claim 1 wherein the sensitization inhibitory composition is administered to the vertebrate one or more times.

12. The method of claim 1 wherein the drag delivery locus and the sensitization inhibitor delivery locus are the same locus.

13. The method of claim 1 wherein the drag delivery locus and the sensitization inhibitor delivery locus are different loci.

14. A method for inducing in a vertebrate immunological tolerance to a component of a transdermal or transmucosal drag delivery system wherein said component sensitizes skin or mucosa, said method comprising the steps of administering to a drag delivery locus of intact skin or mucosa of the vertebrate the transdermal or transmucosal drag delivery system comprising a therapeutically effective amount of a drag; and administering to a sensitization inhibitor locus of intact skin or mucosa of the vertebrate a therapeutically effective amount of a sensitization inhibitory composition comprising intestinal submucosa or extracts or hydrolysates thereof to induce immunological tolerance to the sensitizing component of the delivery system.

15. A pharmaceutical composition comprising a permeation enhancer and a therapeutically effective amount of a sensitization inhibitory composition comprising intestinal submucosa or extracts or hydrolysates thereof.

16. A pharmaceutical composition comprising a transdermal or transmucosal drag delivery system, a therapeutically effective amount of a drag, and a therapeutically effective amount of a sensitization inhibitory composition comprising intestinal submucosa or extracts or hydrolysates thereof.

17. A drag delivery device comprising: a delivery matrix for transdermal or transmucosal drug delivery; a detachable backing to hold the delivery matrix in transmitting relationship with skin or mucosa; a therapeutically effective amount of a drag incorporated in the delivery matrix; and a therapeutically effective amount of a sensitization inhibitory composition comprising intestinal submucosa or extracts or hydrolysates thereof incorporated in the delivery matrix.

18. The drug delivery device of claim 17 wherein the delivery matrix is the intestinal submucosa in the form of a gel.

19. A transdermal or transmucosal drug delivery device including a drag delivery matrix comprising a therapeutically effective amount of a drug for transdermal or transmucosal delivery and a sensitization inhibitory composition comprising an intestinal submucosa composition or extracts or hydrolysates thereof, and a means for holding the drag and the sensitization inhibitory composition in transmitting relationship with intact skin.