ENHANCED PHARMACEUTICAL COMPOSITIONS FOR SKIN PENETRATION FOR PIROXICAM

Description

[0001] The present invention is directed to a transdermal (or percutaneous) delivery system for piroxicam. This delivery system is a drug-containing adhesive device which has a constant release rate over a period of time.

[0002] Piroxicam is a non-steroidal anti-inflammatory drug and used as an effective analgesic and anti-inflammatory agent in rheumatoid arthritis, osteoarthritis and acute pain in musculoskeletal disorders and acute gout. It has been known to be an effective analgesic in fracture, dental, postoperative and postpartum pain. It is about equal in potency to indomethacin as an inhibitor of prostaglandin biosynthesis in vitro.

[0003] Piroxicam is used generally orally. Although piroxicam has a strong therapeutic effect, it causes side effects such as gastro-intestinal trouble, peptic ulcer. Orally administered piroxicam is metabolized at the first pass route. Less than 5% of the drug is excreted in the urine unchanged. The metabolite is at least 1000 times less active than piroxicam inhibiting prostaglandin synthesis.

[0004] The potential advantage of delivering piroxicam transdermally is that gut wall and hepatic metabolism and the gastrointestinal reaction may be avoided.

[0005] Transdermal delivery system eliminates the first pass effects and allows a controlled amount of the active substance piroxicam to be continuously administered over a sustained period of time.

[0006] Patent Abstracts of Japan, no. 3-251534, page 65 C 908, 1992, discloses a transdermal delivery system for piroxicam. Polyvinylpyrrolidone is added to a copolymer of N-vinyl-2-pyrrolidone with (meth)acrylic acid ester. Then a polyoxyethylene alkyl ether and/or a fatty acid alkylolamide and piroxicam are added.

[0007] EP-A-0328806 shows a transdermal delivery system for an estrogen or derivative thereof. A matrix comprises an adhesive polymer, a solvent, a skin penetration enhancer and the active substance.

[0008] EP-A-0271983 discloses a transdermal flux enhancing pharmaceutical composition comprising an active compound, an aqueous alcohol solvent and a penetration enhancer selected from a 1-alkylazacycloheptan-2-one and a cis-olefin. EP-A-0356382 mentions that the permeability of systemic active compounds is enhanced by means of dimethyl sulfoxide or dimethyl formamide.

[0009] US-A-925,641 discloses topical compositions of amlodipine, doxazosin, glipizide, piroxicam and other drugs containing aqueous solution of ethanol, 1-alkylazacycloheptane-2-one and oleic acid. However, this method is impossible to make a thin patch and is only possible to make gel, ointment and liquid compositions.

[0010] In JP-A-91-251534, there are disclosed patch compositions for increased dermal penetration of piroxicam by adding penetration enhancer, selected from polyoxyethylenealkyl ethers or alkanolamides, and dissolving assistant agent of polyvinylpyrrolidone to pressure-sensitive adhesives of copolymer of vinylpyrrolidone and methacrylic ester. However, this composition is also inferior in percutaneous absorption because polyvinylpyrrolidone acts only a dissolving assistant role and does not assist the absorption of drug.

[0011] For the reasons mentioned above, as result of concentrative researches about the improvement of percutaneous absorption and high content of drug in patch, the present inventors found that, in case of using certain absorption assistants, the excessively dissolved piroxicam is included in matrix and simultaneously the percutaneous absorbability is surprisingly enhanced.

[0012] The present invention is related to transdermal drug delivery system which is preferably used to administer piroxicam for the treatment of rheumatoid arthritis, osteoarthritis, acute pain in musculoskeletal disorder and acute gout.

[0013] This transdermal delivery system improves percutaneous absorbability by absorption assistants, which remarkably increase permeation and dissolution of piroxicam, and penetration enhancers. A further surprising feature of the present invention resides in the fact that absorption assistant which assists penetration enhancer is able to include the active substance excessively in adhesive matrix as solvent of the active substance. The transdermal delivery system is composed as shown by patent claim 1. Preferably the matrix consists of one or several laminated layers.

[0014] In the drawing

Figure 1 is an isometric view of a preferred embodiment of the present invention,

Figure 2 is a sectional view taken generally along lines A-A in Figure 1, and

Figure 3 is a graph illustrating the results of inhibition ratio on carrageenin-induced paw edema in rats.

[0015] In the drawing, the transdermal delivery system comprises an impermeable backing membrane (1), a polymeric diffusion matrix (3) which preferably is composed by one or more thin layer (illustrated in phantom) and a release liner (2). The impermeable backing membrane is well known in the art and is not limiting on the instant invention.

[0016] The matrix is compounded on a weight percentage basis, from 35 to 90% of an adhesive polymer, from 9 to 40% of one or more absorption assistants which maintain the piroxicam in a solubilized state, from 0.5 to 10% of penetration enhancer and from about 0.5 to about 25% of the active substance piroxicam.

[0017] The adhesive polymer is a pressure sensitive adhesive and is acceptable for medical use. Of these type of polymer, either water base or solvent base materials may be used. These polymers have two functions in the instant invention. First, they are adhesive to the skin and securely hold the matrix on and in good diffusion contact with the skin. Second, they are the carrier of the active substance or storage of the active substance.

[0018] Preferably, the adhesive polymer is a vinylacetate-acrylate multipolymer. Such a multipolymer is commercially available from the Monsanto Company, St. Louise 70. under the name of GELVA®, GELVA® 737,788 and 2484 may be used. Specifically, GELVA® 737 comprises up to 1.1% of 2-ethylhexyl acrylate and the balance vinyl acetate.

[0019] To produce a synergistic effect locally; from about 0.5 to about 15.0% of a corticosteroid may be added to the polymer matrix. Such a corticosteroid is one or more selected from the group of cortisone, hydrocortisone, prednisolone, dexamethasone and their derivatives.

[0020] The absorption assistant dissolves the active substance. It is one or more selected from the group of dimethyl sulfoxide, alkanolamine, alkylamine, N-alkyl pyrrolidone and diethylene glycol mono ethyl ether. The skin penetration enhancer is one or more selected from the group of alkylene glycol derivatives, propylene glycol, oleic acid, lauric diethanolamide and polyethylene glycol derivatives such as polyethylene glycol 200 mono laurate, polyethylene glycol 300 mono laurate, polyethylene glycol 400 mono laurate and so on.

[0021] In operation, the system is applied to the skin where the adhesive polymer affixes the system on the skin. The active substance which is dissolved by the solvent, is dispersed throughout the matrix. The active substance diffuses from the matrix with the enhancer. At the stratum corneum, the enhancer facilitates the transdermal diffusion therethrough and into the systemic circulation.

[0022] The preparation of the transdermal delivery system according to the present invention is accomplished as follows. The active substance is dissolved in the solvent and enhancer to form a solution or a suspension. This solution or suspension is added to the polymer and mixed for about 20 to 30 minutes and then allowed to stand for about 20 to 60 minutes to eliminate the air bubbles. This mixture is cast on the impermeable membrane, a polyethylene film or aluminized polyethylene film made by 3M Company (e.g. 3M-Scotchpak 1006 or 3M 1012) and dried at about 40°C to 50°C for about 30 to 60 minutes. After drying the coated matrix, a release liner, such as a silicon release paper, or the like which are well known, is placed over the exposed surface of the matrix. Then the system is die-cut into an optimum size. If multiple matrix layers are required, each subsequent layer is cast over or overlaps on the previous layer. The finished system is put into a pouch and hermetically sealed.

EXAMPLE 1

[0023] To prepare the matrix, 0.4g of piroxicam is dissolved in 1.0g of dimethyl sulfoxide and 0.3g of triethanol amine. 0.3g of poly ethylene glycol 400 monolaurate are added to the solution and mixed well. This solution is added to 10g of polymer solution (Monsanto GELVA® 737) and then mixed for 20 to 30 minutes. After mixing, the mixture is settled for about 20 minutes to remove air bubbles and is cast onto the backing material (3M-Scotchpak 1006 or 1012). The cast mixture is dried for 30 minutes at 45°C. To make a triple layer matrix, the 2nd and 3rd layer are sequentially cast over the prior layer after the prior layer is settled and dried or cast" the mixture on the release liner and overlay on the prior layer. This formation is then cut into 10cm² shapes.

EXAMPLE 2

[0024] 0.3g of piroxicam is dissolved in 1.8g of diethyleneglycol monoethyl ether. 0.5g of polyethylene glycol 300 monolaurate and 0.2g of diethanolamine are added to the solution and then mixed well. This solution is mixed with 25g of polymer solution (Monsanto GELVA® 2484) for 20 minutes. The remaining steps are set forth in Example 1.

EXAMPLE 3

[0025] 0.1g of piroxicam is dissolved in 1.5g of diethyleneglycol monoethylether. 0.4g of polyethylene glycol 200 monolaurate, 0.3g of lauric diethanolamide and 0.2g of polysorbate 60 are added to the solution and then mixed well. This solution is mixed with 10g of polymer solution (Monsanto GELVA® 737) for 25 minutes. The remaining steps are the same as set forth in Example 1.

EXAMPLE 4

[0026] Piroxicam 0.7g is dissolved in 2.2g of dimethylsulfoxide and 1.0g of diethyleneglycol mono ethylether. 0.3g of lauric diethanolamide and 0.2g of polysorbate 20 are added to the solution and then mixed thoroughly. This solution is mixed with 15g of polymer solution (Monsanto GELVA® 737) for 30 minutes. After settling for 20 minutes, the remaining steps are set forth in Example 1.

EXAMPLE 5

[0027] 0.35g of piroxicam is dissolved in 1.2g of dimethylsulfoxide, 0.3g of N-octylpyrrolidone and 0.7g of diethyleneglycol mono ethylether. 0.4g of oleic acid, 0.05g of polysorbate 80 and 0.2g of lauric diethanolamide are added to the solution and then mixed well. This solution is mixed well with 10g of polymer solution (Monsanto, GELVA® 737), and then this mixture is cast to 0.6mm thick onto the backing material - aluminized polyethylene film (3M-Scotchpak 1009) after settled to remove the air bubbles. The casting material is dried for 60 minutes at 45°C. To make a double layer matrix, the second layer is cast over the prior dried layer or cast the mixture on the release liner and overlay on the prior layer. This information is then cut into 20cm² shape.

EXAMPLE 6

[0028] 0.4g of piroxicam is dissolved in 1.8g of dimethylsulfoxide and 1.5g of diethyleneglycol mono ethylether. 0.3g of lauric diethanolamide and 0.5g of polyethyleneglycol 200 monolaurate are added to above solution and is mixed well. This solution is mixed well with 11g of polymer solution (Monsanto GELVA® 737), and then this mixture is settled to remove the air bubbles. The remaining steps are the same as set forth in Example 5.

EXAMPLE 7

[0029] 1.0g of piroxicam is dissolved in 1.8g of dimethylsulfoxide and 0.5g of diethylenglycol mono ethylether. 0.4g of oleic acid are added to above solution and this solution is mixed well. This solution is mixed well with 15g of polymer solution (Monsanto, GELVA® 737), and then this mixture is cast to 0.6mm thick onto the backing material - polyethylene film (3M-CoTran 9720) after settled to remove the air bubbles. The casting material is dried for 60 minutes at 45°C and then the release liner is covered over the dried matrix. This formation is then cut into 20cm² shape.

EXAMPLE 8

[0030] 1.6g of piroxicam is dissolved in 2.0g of dimethylsulfoxide and 0.7g of diethyleneglycol mono ethylether. 0.4g of oleic acid and 0.1g of propyleneglycol are added to above solution and this solution is mixed well. This solution is mixed well with 15g of polymer solution (Monsanto, GELVA® 737), and then this mixture is settled to remove the air bubbles. The remaining steps are the same as set forth in Example 7.

EXAMPLE 9

[0031] 2.0g of piroxicam is dissolved in 2.0g of dimethylsulfoxide and 0.7g of diethyleneglycol mono ethylether. 0.4g of oleic acid and 0.4g of triethanolamine are added to above solution and this solution is mixed well. This solution is mixed well with 15g of polymer solution (Monsanto, GELVA® 737), and then this mixture is settled to remove the air bubbles. The remaining steps are the same as set forth in Example 7.

EXAMPLE 10

[0032] 1.2g of piroxicam is dissolved in 1.8g of dimethylsulfoxide and 0.5g of diethyleneglycol mono ethylether. 0.4g of oleic acid are added to above solution and this solution is mixed well. This solution is mixed well with 15g of polymer solution (Monsanto, GELVA® 737), and then this mixture is settled to remove the air bubbles. The remaining steps are the same as set forth in Example 7.

EXPERIMENT 1

Anti-inflammatory activity on carrageenin-induced paw edema in rats.

[0033] Male rats of Wister strain, weighing 287±11g (7 to 9 weeks old), were depilated and allowed to stand overnight for use in the experiment (Topical applied: 5mg/kg, systemical applied: 30mg/kg). Then, 0.1ml of 1% carrageenin solution was hypodermally injected into left hind leg after 3 hours of applying patch. The swelling inhibition ratio is measured by plethysmometer (UGO BASILE TYPE 7150) at intervals of 1 hour for a 6 hours period after injection. The results are presented in Figure 3.

EXPERIMENT 2

[0034] The flux of piroxicam through human skin is measured as following methods. In generally, the percutaneous flux is measured on nude mouse skin in vitro, but the flux on nude mouse skin is higher about 10 to 50 times than that of human skin. Thereof, it is impossible that the absolute value is calculated for the use of animal skin and in case of using human skin that is also different between in vitro and vivo.

[0035] In the present invention, in vitro test, human cadaver skin was obtained from Ohio Valley Tissue and Skin Center and hydrated for 24 hours with phosphate buffer (pH 6.0 Standard buffer solution in U.S. Pharmacopoeia) before experiments. The hydrated skin was mounted in Frantz cell. The upper side of skin, having an available diffusion area of 1.0cm², was exposed to ambient conditions. The lower side was filled by the receptor medium (5.0ml, pH 6.0 Standard buffer solution in U.S. Pharmacopoeia) being stirred and kept at 32°C. Piroxicam patch directed in the present invention was adhered to upper side of skin and fixed with clamp. For 72 hours samples were withdrawn and replaced by fresh receptor medium keeping an infinite sink. The flux of piroxicam penetrating the skin was determined by measuring the concentration by HPLC system.

[0036] In vivo test, fifty male volunteers were subjected to residual test of patch.

[0037] Piroxicam patches, directed in the present invention, of which content was known were adhered to the outer side of volunteer's upper arm and maintained there for 72 hours, and then removed. The absorbed amount of piroxicam was determined by measuring the residual amount of piroxicam in removed patch by HPLC system.

<Measuring condition>

[0038] 

Column: µ Bondapak C₁₈ 3.9mm (ID) 30cm (L)

Mobile phase: 0.01 M 1-heptane sulfonic acid, sodium salt/Acetonitrile/Methanol (3:5:1) adjusted pH 3.0 with phosphoric acid

Detector: UV (340nm)

Injection volume: 10 µl

Flow rate: 1.0 ml/min

The results-are presented in Table 1.

Table 1.

The Flux of Piroxicam through Human Skin.
	In vitro (µg/cm2 · hr)	In vivo (µg/cm2 · hr)
Example 5	6.10	0.82
Example 6	15.79	2.55
Example 8	34.52	5.20
Example 10	30.23	4.58

[0039] As is seen from the above results, the flux of in vitro disclosed in US-A-925641 was a high value of 24.0 µg/cm² · hr in case of nude mouse skin but in case of human cadaver skin was a low value of 0.43 µg/cm² · hr, while in the present invention was very higher 8 to 80 times than that in case of human cadaver skin. Also, the result in JP-A-91-251534 was shown very lower value of 3.7 µg/cm² · hr than in US-A-925641 in case of nude mouse skin.

EXPERIMENT 3

[0040] Fifty patients (30 male/20 female) were subjected to the systemical remedial effect test on patch in the present invention. The adhesion site of patch was same as that in Experiment 2. The results are presented in Table 2.

EXPERIMENT 4

[0041] Thirty male people were subjected to skin irritation test on effect of the existence of corticosteroid in piroxicam patch.

[0042] The patch was applied to te back of volunteers for 48 hours and the skin was evaluated for evidence of erythma, edema or more severe skin changes occurring 24, 48 and 72 hours after removal of patch. The results are presented in Table 3.

Claims

1. A transdermal delivery system comprising a matrix which consists of 0.5 to 25 wt.% piroxicam as active substance, 35 to 90 wt.% of an adhesive polymer, 9 to 40 wt.% of one or more absorption assistants selected from the group of dimethylsulfoxide, alkanolamines, alkylamines, diethyleneglycol monoethylether and N-alkylpyrrolidone, and 0.5 to 10.0 wt.% of one or more penetration enhancers selected from the group of alkyleneglycol derivatives, propyleneglycol, lauric diethanolamide, oleic acid and polyethyleneglycol derivatives.

2. The system as defined in claim 1, wherein said matrix consists of one or several laminated layers.

Ansprüche

1. Ein Transdermalzuführungssystem mit einer Matrix, welche aus 0,5 bis 25 Gew.-% Piroxicam als aktive Substanz, 35 bis 90 Gew.-% eines Haftpolymers, 9 bis 40 Gew.-% eines oder mehrerer Absorptionshilfsmittel, ausgewählt aus der Gruppe Dimethylsulfoxid, Alkanolamine, Alkylamine, Diethylenglykol-Monoethylether und N-Alkylpyrrolidon,und 0,5 bis 10,0 Gew.-% eines oder mehrerer Durchdringungsverbesserer, ausgewählt aus der Gruppe von Alkylenglykolderivaten, Propylenglykol, Lauryldiethanolamid, Ölsäure und Polyethylenglykolderivaten, besteht.

2. System nach Anspruch 1, bei dem die Matrix aus einer oder mehreren geschichteten Lagen besteht.

Revendications

1. Système de délivrance transdermique comprenant une matrice constituée de 0,5 à 25% en poids de piroxicam comme substance active, 35 à 90% en poids d'un polymère adhésif, 9 à 40% en poids d'un ou plusieurs assistants d'absorption choisis dans le groupe constitué par le diméthylsulfoxyde, les alcanolamines, les alkylamines, l'éther monoéthylique de diéthylèneglycol et une N-alkylpyrrolidone, et 0,5 à 10,0% en poids d'un ou plusieurs renforçateurs de pénétration choisis dans le groupe constitué par les dérivés d'alkylèneglycol, le propylèneglycol, le diéthanolamide laurique, l'acide oléique et les dérivés de polyéthylèneglycol.

2. Système selon la revendication 1, dans lequel ladite matrice est constituée d'une ou plusieurs couches stratifiées.

Drawing