A DRUG DELIVERY DEVICE AND A METHOD OF PRODUCING IT TECHNICAL FIELD The invention relates to a drug delivery device, in particular a drug delivery device for slow release of drugs, such as analgesic. The invention also relates to a method of its productions and to particular applications thereof BACKGROUND ART Slow release of pharmaceuticals, or release in certain areas within the body, such as in the intestinal area or subcutaneously, is common practice. It is achieved using two methods, (i) coating of pharmaceuticals (using e. g. acid- resistant molecules which protect a potentially unstable substance during passage through the stomach, ) or conversion of active pharmaceuticals into less active derivatives which split due to a different pH into a more potent substance upon arrival in the desired target area, e. g. affected cancer cells, or (ii) immersion or mixing of the pharmaceutical active substance into an basically inert carrier from which the substance diffuses out into the body, e. g. through the skin in the case of patches.

Related prior art can be described in the following manner: US 2003/0141268A1 describes the synthesis of relatively clean polyisoprenen rubber by using novel Neodymium catalysts.

US 6027745 describes a process for producing a drug-release contact lens.

The patent highlights some of the difficulties in using the prior art.

US 5322031 teaches the production and application of coloured nipples whereby the discolouration of the nipple indicates wear and successive degradation.

US 4341728 teaches the production of an intra-uterine device containing slow release agents.

As mentioned above the prior art drug delivery devices are based on one of two production methods.

(A) Coating: Coating of pharmaceutical is not the most desired solution because non-active coating substances have to be digested by e. g. a human already suffering from a condition. The coating process itself may involve solvents whose removal cannot be guaranteed to 100%. The coating process may involve elevated temperatures at which a partial decomposition of the often complex chemical pharmaceuticals is possible. The same arguments are valid for chemical derivatisation to render the substances temporarily less potent.

(B) Immersion and mixing into a matrix: These preparative processes involve typically organic solvents whose removal after the process cannot be guaranteed to 100%. Also, the process may involve elevated temperature as well as mechanical shear, both conditions at which partial decomposition of the pharmaceutical substances is a risk.

DISCLOSURE OF INVENTION The objective of the present invention is to provide an improved drug delivery devise, and preferably a drug delivery device which is improved with respect to one or more of the drawbacks mentioned above.

A particular objective of the invention is also to provide a method of producing a drug delivery device which method does not leave remainings of undesired solvents, in particular organic solvents for the drugs in the drug delivery device. Preferably the method does not require the use of organic solvents at all.

Another objective is to provide a method which, does not require undesired high processing temperatures and is furthermore relatively simple and inexpensive to produce.

These objectives of the invention are achieved by the invention as it is defined in the claims and as described in the following.

According to the invention, drugs (also called pharmaceuticals) are impregnated into a polymer matrix material such as silicone or other rubber, or synthetic thermoplastics using high pressure gas or liquid, the pressure preferably being above 1 bar, and for process speed reasons preferably being above 5 bars, and technically most preferably above 20 bars, such as at least 35 bars, such as at least 50 bars A particularly suitable medium or high pressure fluid is carbon dioxide in liquid or supercritical form.

The process may be carried out at very low temperatures, such as below 0 degree Celsius, but technically preferably the process is carried out at ambient temperature or above, such as at 25 degree Celsius.

Thus, in one embodiment the drug is incorporated into the polymer matrix using one or more solvents at a pressure of above 1, such as above 10 bars or preferably between 25 and 200 bars, and a temperature of between 0 and 30 degree Celsius, such as between 5 and 20 degree Celsius.

In addition to the pharmaceuticals, more carrier substances may be impregnated simultaneously, or before or after the impregnation process, this in order to influence the migration and diffusion speed, i. e. the release kinetics. As an example, glycols or waxes of specific melting points may be added in order to activate and accelerate the release process once a certain temperature is reached within the body or on the skin. This temperature may e. g. be 38 or 38.5 or 39 degree Celsius.

The polymeric matrix also called a reservoir material, into which the pharmaceuticals (drugs) are impregnated, may have any form and size and shape and function as long as it serves the purpose of controlled and slow

release of pharmaceuticals for the treatment of conditions in humans and animals. Examples (non-limiting regarding the scope of the invention) can be (i) baby nipples for adding pharmaceutical during feeding, teething devices (ii) catheters and shunts for any body fluid (urine, blood, excess water) containing e. g. anti-inflammatory substances or salts, (iii) drug delivery patches containing moderate or strong pain killers such as morphines and opiates (iv) nicotine patches (v) wound care products (vi) surgical films (vii) condoms and prophylactic devices, gloves, intravenous bags (viii) other products for professional use or self-care, such as contact lenses and other ophthalmologic devices, passive or active implants, diagnostic devices The drug delivery device according to the invention is preferably a) a trans dermal drug delivery device suitably for delivering a drug onto the skin for transdermal drug administration, b) a trans mucous membrane drug delivery device for delivering a drug onto a mucous membrane for trans mucous membrane drug administration or c) a wound or implant drug delivery device for delivering drug directly into a wound or from an implant. Such drug devices are particularly useful in the combination with administration of pain killers. Preferred drug delivery devises thus includes wound dressings with pain killers, catheters with pain killers and baby nippels with pain killers.

In one embodiment the drug delivery device is a wound care product with growth factors for chronic wounds.

In one embodiment the drug delivery device is a nicotine patch e. g. as disclosed in US 6682757 and US 5603947 wherein the nicotine has been loaded as drug loading disclosed herein.

The main different between the 3 drug delivery device types is the release profile, as the amount released directly into a wound should in general be

less than the amount delivered onto a mucous membrane, which yet again should in general be less than the drug amount delivered onto the skin.

In one embodiment the polymeric matrix comprises silicone e. g. in the form of a silicone matrix, a layered matrix comprising a silicone layer or is an IPN comprising a silicone matrix, e. g. as the basic matrix. A drug delivery device comprising silicone has several advantages: First of all it is non-toxic. It is simple to load, and relatively large drug molecules may be able to be incorporated into the silicone and released there from again. The silicone matrix may be very soft and comfortable to wear against the skin. Silicone may also be used for implants.

In one embodiment the polymeric matrix is PTFE matrix, preferably a porous PTFE. The PTFE matrixes used as drug delivery device and loaded with drug e. g. as herein described, may e. g. be as the PTFE materials disclosed in any one of US 6027779, US 6075,108 and US 5814405 which are hereby incorporated by reference.

In one embodiment the drug delivery devise is in the form of an implant comprising a polymeric matrix loaded with a drug, preferably a drug such as antibiotics, antimicrobials, growth factors, differentiations factors, cell attachment factors, heparin or other drugs, for stimulating the body to accept the implant in its new environments. It is particularly preferred that this implant comprises silicone and or PTFE as disclosed above, e. g. the PTFE sold under the trademark Gore-Tex@, which has been loaded with a drug according to the present invention.

The implant may e. g. be in the form of a patch e. g. of drug loaded Gore- Tex@ which is used in the surgical treatment of atrial septal defect (ASD), which is an abnormal opening in the wall (septum) that divides the two upper chambers of the heart (atria). The patch is sutured into place to close the defect.

In one embodiment the implant is a drug loaded tubular implant for e. g. as disclosed in US 6027779 further loaded with a drug.

In one embodiment the implant is a drug loaded implant for plastic and reconstructive surgery, e. g. as disclosed in US 6075180 further loaded with a drug.

In one embodiment the drug device of the invention comprises a polymeric matrix which is of bioabsorbable material, preferably selected from the group consisting of polycaprolactone, poly-p-dioxanon, polymers of trimethylene carbonate, polyglycolic acid (PGA), polyactic acid (PLA), copolymers and mixtures thereof.

Bioabsorbable materials are herein defined as those materials of either synthetic or natural origin which when placed into a living body are degraded through either enzymatic, hydrolytic or other chemical reactions, into by- products which are either integrated into or expelled from the body.

Other suitable bioabsorble matrixes which may be used in the invention and loaded with drug according to the invention are e. g. as disclosed in US 6031148.

The method for impregnating the polymeric matrix may be as the method for deposition of a primer deposition as disclosed in WO 03068846 with the difference that the deposition material is a drug. WO 03068846 is hereby incorporated by reference.

The polymeric matrix may in principle be any type of polymer or mixture but it includes preferably the polymeric matrix specified in the claims.

The polymeric matrix may in principle be a pure polymer or it may be a mixture comprising two or more polymers and additives e. g. as disclosed below. In one embodiment, the polymeric matrix includes an adhesive. In one embodiment, the polymeric matrix includes a gel.

Examples of useful matrix compositions include one or more of the following :

i: Thermoplastic elastomer selected from the group consisting of a block copolymer, more preferably TPE, even more preferably selected from the group consisting of SEBS, SBS, SIS, TPE-polyether-amide, TPE-polyether- ester, TPE-urethanes, TPE PP/NBR, TPE-PP/EPDM, TPE-vulcanisates and TPE-PP/I I R. ii: Rubber selected from the group consisting of butadiene rubber, isoprene rubber, nitril rubber, styrene-butadiene rubber, latex and urethane rubber. iii: Polyolefin selected from the group consisting of polyvinyl such as polyvinylpyrrolidone, polyethylene, polypropylene, polybutylene including its isomers. iv: Silicone polymers selected from the group consisting of dimethyl polysiloxan, methylphenyl polysiloxane, fluorosilicone rubber, silicone esters, polysiloxanes, polysilanes, chlorosilanes, alkoxysilanes, aminosilanes, polysilanes polydialkylsiloxanes, polysiloxanes containing phenyl substituents, said polymers of the silicone polymer composition optionally being vinyl-functionalized and/or optionally being partially or fully fluorinated.

In one embodiment the polymeric matrix is an interpenetrating polymer network (IPN). IPNs are defined as macromolecular assemblies comprising two or more polymers wherein at least one is in the form of a network; the polymers are at least partially interlaced on a molecular scale but not covalently bonded to each other.

Because there is no chemical bonding between the networks (or polymer/network), each network may retain its individual properties independently of its individual proportion in the blend. As a result, an improvement can be attained compared to the individual polymers in properties such as mechanical strength, impact resistance, and toughness and other. There are two main types of IPNs, viz semi-IPN where at least one component is not in network form, and full IPN where all species are in network form.

The polymer matrix may be a semi-lPN or preferably a full IPN.

In one preferred embodiment the polymeric matrix includes an IPN gradient, that means that the polymeric matrix comprises a first basis polymer preferably in the form of a network, e. g. a cross linked polymer, and a secondary polymer which is penetrated partly into the first polymer, to form a stepwise or continuous gradient of the second polymer in the basis polymer.

The second polymer may be in the form of a network, e. g. a cross linked polymer.

Such IPN may be produced as disclosed in the co pending Patent applications PA 2003 001027 DK and PA 2003 001330 DK which are hereby incorporated by reference.

By using such IPN with a gradient, the gradient may have a release control function. Thus, in one embodiment the drug delivery device is produced by providing a first polymer basis material, incorporating a monomer into the first polymer basis material using as solvent (e. g. CO2) having a surface tension at the exposing step of about 15 mN/m or less, such as about 10 mN/m or less, such as about 8 mN/m or less, such as about 6 mN/m or less, such as about 5 mN/m or less, such as about 0 mN/m so that the monomer forms a concentration gradient into the polymer basis material.. The treatment may preferably be as disclosed in one of the co pending Patent applications PA 2003 001027 DK and PA 2003 001330. The monomer may be subjected to a cross linking step. Thereafter a drug is incorporated in the IPN polymeric matrix.

The production may be carried out in the same pressure chamber comprising the steps of first subjecting the first polymer basis material to CO2 preferably in supercritical state. Thereafter the monomer is introduced to the reaction chamber and the treatment using CO2 as solvent is continued, and finally the addition of monomer is terminated and addition of drug is initiated and continued for a desired time.

By the selection of the first polymer basis material and the monomer of the IPN polymeric matrix, the release profile of the drug delivery device may be controlled. Thus in one embodiment the first polymer basis material is more hydrophilic than the monomer. In this embodiment the transfer of a hydrophilic drug may go fast in the area of the IPN polymeric matrix with no or low concentration of the monomer, whereas it may be slower in the surface areas where the concentration of the monomer is higher. Thereby the surface area of the polymeric matrix may form a drug release barrier, whereas the areas below the surface of the polymeric matrix with no or low concentration of monomer may form a drug reservoir.

In one variation of the above embodiment the first polymer basis material is less hydrophilic than the monomer.

In another variation of the above embodiment the first polymer basis material has a higher pH value than the monomer.

In another variation of the above embodiment the first polymer basis material has a lower pH value than the monomer.

In a further variation of the above embodiment the first polymer basis material has a higher swellability of liquid (preferably aqueous liquid) than the monomer or the cross-linked monomer, the release of drug may then be controlled by contacting the drug delivery device with moisture e. g. exudates, sweat or other body moistures.

In yet a further variation of the above embodiment the first polymer basis material has a lower swellability of or solubility in liquid (preferably aqueous liquid) than the monomer or the cross-linked monomer the release of drug may then be controlled by contacting the drug delivery device with moisture e. g. exudates, sweat or other body moistures.

In yet a further variation of the above embodiment the first polymer basis material has a lower molting temperature than the monomer or the cross-

linked monomer, the release of drug may then be controlled by adjusting the temperature e. g. essentially no release at a low temperature such as 10 degree Celsius or less, such as 0 degree Celsius or less, and release at a higher temperature e. g. skin temperature (around 30 degree Celsius).

In yet a further variation of the above embodiment the first polymer basis material has a higher molting temperature than the monomer or the cross- linked monomer, the release of drug may then be controlled by adjusting the temperature e. g. essentially no release at a low temperature such as 10 degree Celsius or less, such as 0 degree Celsius or less, and release at a higher temperature e. g. skin temperature (around 30 degree Celsius).

The matrix may include fillers and additives. e. g. particles or fibres e. g. in the form of minerals or organic fillers, preferably selected from the group consisting of silica, metals, metal oxides, mixed metal oxides, glass beads or glass fibers. Other examples of fillers are those that are disclosed in US 5,968, 652, US 2001/00366617, US 5,861, 445 and US 4,740, 538, and in the co pending application filed simultaneously with this application by the same applicant.

The drug may in principle be any type of drug which can be carried into the polymeric matrix using the drug carrier. The drugs that can be used according to the present invention include inorganic and organic drugs without limitation and include drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles, blood circulatory system, synaptic sites, neuro-effector junctional sites, endocrine system, hormone systems, immunological system, reproductive system, skeletal system, autocoid systems, alimentary and excretory systems, histamine systems, and the like. The active drug that can be delivered for acting on these recipients includes, but is not limited to, anticonvulsants, analgesics, antiparkinsons, antiinflammatories, calcium antagonists, anesthetics, antimicrobials, antimalarials, antiparasitics, antihypertensives, antihistamines, antipyretics, alpha-adrenergic agonists, alpha-blockers, biocides, bactericides, bronchial dilators, beta-adrenergic blocking drugs,

contraceptives, cardiovascular drugs, calcium channel inhibitors, depressants, diagnostics, diuretics, electrolytes, enzymes, hypnotics, hormones, hypoglycemics, hyperglycemics, muscle contractants, muscle relaxants, neoplastics, glycoproteins, nucleoproteins, lipoproteins, ophthalmics, psychic energizers, sedatives, steroids sympathomimetics, parasympathomimetics, tranquilizers, urinary tract drugs, vaccines, vaginal drugs, vitamins, collagen, hyaluronic acid, nonsteroidal anti-inflammatory drugs, angiotensin converting enzymes, penicillins polynucleotides, polypeptides, polysaccharides, vaccines and the like.

The present invention is particularly suitable for delivering polypeptide drugs which are water soluble. Exemplary drugs include, but are not limited to, insulin ; growth factors, such as epidermal growth factor (EGF), insulin-like growth factor (IGF), transforming growth factor (TGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), bone morphogenic protein (BMP), fibroblast growth factor and the like ; nicotine; somatostatin; somatotropin; somatropin; somatrem; calcitonin ; parathyroid hormone; colony stimulating factors (CSF); clotting factors; tumor necrosis factors; interferons; interleukins ; gastrointestinal peptides, such as vasoactive intestinal peptide (VIP), cholecytokinin (CCK), gastrin, secretin, and the like ; erythropoietins; growth hormone and GRF; vasopressins; octreotide; pancreatic enzymes; dismutases such as superoxide dismutase; thyrotropin releasing hormone (TRH); thyroid stimulating hormone; luteinizing hormone; LHRH; GHRH; tissue plasminogen activators; macrophage activator; chorionic gonadotropin; heparin; atrial natriuretic peptide; hemoglobin; retroviral vectors; relaxin ; cyclosporin ; oxytocin; and peptide or polypeptide vaccines. Other particularly suitable drugs include polysaccharide including, but not limited to, hyaluronic acid.

Other drugs can be used e. g. such as the drugs disclosed in US 2003/0141268, US 6027745, US 5322031 and US 4341728.

The drug carrier at the processing parameters is a gas, a supercritical or a dense gas-like fluid, where the dense gas-like fluid preferably is a medium

which becomes a gas, or a supercritical fluid by lowering the pressure about 10%.

In one embodiment, the drug carrier and the impregnation conditions should be selected such that the drug carrier has a surface tension at the exposing step of about 15 mN/m or less, such as about 10 mN/m or less, such as about 8 mN/m or less, such as about 6 mN/m or less, such as about 5 mN/m or less, such as about 0 mN/m.

Irrespective of the state of the drug carrier during the exposing step, it is in one embodiment desired that the drug carrier has a surface tension in liquid form of about 15 mN/m or less, such as about 10 mN/m or less, such as about 8 mN/m or less, such as about 6 mN/m or less, such as about 5 mN/m or less. Thereby the drug may be dissolved or dispersed in the drug carrier in its liquid step prior to the impregnation step.

The drug carrier may at the impregnation step be in any of its states gas state, liquid state and supercritical state.

In one embodiment, the drug carrier is one or more hydrocarbons or carbon- containing compounds or a composition comprising hydrocarbons or carbon- containing compounds with a Hildebrand solubility of below 11, preferably 8 or less. In this embodiment, the polymeric matrix composition may preferably be impregnated with the drug using the drug carrier in its supercritical state or near its supercritical state, where the term"near its supercritical state" means that the total pressure is at least 10 bars.

In one embodiment, the drug carrier is CO2 and this02 is in its liquid state during the impregnation step. This method is particularly preferred since the pressure need not be extremely high as when using supercritical drug carrier. Thereby both the reaction chamber and the method may be much cheaper.

In one embodiment, the drug carrier comprises one or more compounds from the group of Cl-Cl2 hydrocarbons or carbon-containing compounds,

preferably Cr-C4 hydrocarbons, more preferably selected from the group consisting of methane, ethane, propane, propene, isobutane, butane, butene, isobutene, methanol, and acetone.

In one desired embodiment, the drug carrier comprises one or both of the compounds N20 and CO2. The most preferred solvent is a solvent comprising C02.

In one embodiment, the drug carrier comprises at least 50 %, such as at least 75%, such as at least 90% by weight of one or more of the components selected from the group consisting of CO2, and N20, and C,-C5 hydrocarbons, the solvent preferably comprising at least 50 %, such as at least 90% of CO2.

The drug carrier may also comprise a surfactant for reducing surface tension.

In one embodiment, the drug carrier comprises a surfactant preferably selected from the group of anionic, cationic, non-ionic and amphoteric surfactants, said drug carrier preferably comprising up to 5% by weight, such as between 0.001-50 grams of surfactant per kg drug carrier.

The amount of drug in the drug delivery device may vary or it may be evenly distributed. By varying the amount a desired release profile may de obtained.

The amount of a drug in a drug delivery device depends on the type of drug, the size of the device and etc. The skilled person will easily be able to find an appropriate amount of drug concentration for a given combination of polymeric matrix and drug.

The drug delivery device according to the invention may in one embodiment comprise a polymeric matrix containing the drug in combination with one or more additional polymer units e. g. in layered or agglomerated forms. In one embodiment the drug delivery device according to the invention comprises a first and a second polymeric matrix's, the polymeric matrixes comprises a different concentration of the same drug or alternatively the polymeric

matrix's comprises different drugs. In this embodiment the two polymeric matrixes may e. g. totally or partly separated from each other by a polymer film, acting as a drug barrier. E. g. as disclosed in WO 03/024431, wherein a cup shaped barrier layer is separating a first component, namely a first polymeric matrix contains one drug, from a second component, namely a second polymeric matrix containing a second drug.

In one embodiment the drug delivery device is a self-adhesive product comprising a pressure sensitive adhesive where the pressure sensitive adhesive is in the form of the polymeric matrix containing the drug. The pressure sensitive adhesive may e. g. be a hot melt pressure sensitive adhesive e. g. comprising at least one water-soluble or water-swellable polymer e. g. as disclosed in US 6190689. In one embodiment the polymeric matrix is a hydrogel, a hydrocolloid containing matrix and/or an alginate containing dressing.

A trans dermal drug delivery device In a particular preferred embodiment of the invention the drug delivery device is a trans dermal drug delivery device.

Desired types of trans dermal drug delivery devices includes breast and skin care products e. g. products that are suitably for being in contact with the skin for long periods, e. g. breast prosthesis or adhesives therefore. The drug for use in such products may in principle be any of the above mentioned drugs.

In preferred breast and skin care products according to the invention the drug includes antifungal drug.

Another desired type of trans dermal drug delivery devices includes drug delivery patches e. g. products that are used for transdermal drug delivery to local treatment or non-local treatment. The drug for use in such products may in principle be any of the above mentioned drugs. In preferred drug delivery patches according to the invention the drug includes psycopharma, hormones, vitamins, vaccine and/or nicotine.

A trans mucous membrane drug delivery device In a particular preferred embodiment of the invention the drug delivery device is a trans mucous membrane drug delivery device.

Desired types of trans mucous membrane drug delivery devices includes catheters e. g. for incontinence use, condoms, diaphragms, contact lenses and similar products e. g. products that are suitably for being in contact with a mucous membrane for longer or shorter periods. The drug for use in such products may in principle be any of the above mentioned drugs. In preferred trans mucous membrane drug delivery devices according to the invention the drug includes antibiotics, metals e. g. silver, hormones and contraceptive drug.

A wound or implant drug delivery device In a particular preferred embodiment of the invention the drug delivery device is a wound drug delivery device.

Desired types of wound drug delivery devices include adhesive dressings, such as hydrocolloid or hydrogel dressings. E. g. , wound dressing comprising adhesives as disclosed in WO 89/05619 or in WO 94/15562. The drug for use in such products may in principle be any of the above mentioned drugs.

In preferred wound drug delivery devices according to the invention the drug includes polylactan, kreatin, polyhydroxyeste, antibacterial drugs (bactericidal and/or bacteriostatic compounds), cytokine, growth hormones, polypeptide growth factors, pectins, silver, silver compounds, zinc or salts thereof, steroids, pain relieving agents and similar drugs.

In a particular preferred embodiment of the invention the drug delivery device is an implant.

Desired types of implants includes bone implants, stents and similar. The drug for use in such products may in principle be any of the above mentioned drugs. In preferred implants according to the invention the drug

includes, antibacterial drugs (bactericidal and/or bacteriostatic compounds), penicillin, heparins and drugs that increases the biocompatibility of the surfaces of the implant.

EXAMPLE Apparatus: pressure reactor of suitable volume, such as 0. 5 I, 5 I, 50 I, 250 1 or larger, suitable for impregnations involving high pressure gases and fluids, the pressure being higher than 2 bar, such as 10 bar, such as 50 bar, such as 300 bar, the fluid consisting of at least 10% carbon dioxide, such as 50%, such as 90% or such as 100%.

Feeding system for antibiotics, either by pumps for liquids, or pre-dissolved in carbon dioxide, or dissolving during the impregnation, e. g. by feeding part of the fluid constantly through a reservoir of pharmaceutical substance, the latter thus dissolving gradually and precipitating within the article to be impregnated by way of an equilibrium reaction.

Process control and safety systems in line with current GMP and FDA regulations.

A typical impregnation process in supercritical carbon dioxide will thus take less than one hour for articles of thicknesses not exceeding 5 mm. Silicone is particularly preferred in this invention due to its excellent gas permeability, however, many other rubbers and plastics are also suitable.