NL8120270A - Self-supporting polymeric diffusion matrix contg. terbutaline - comprising polar plasticiser, polyvinyl alcohol and polyvinyl pyrrolidone - Google Patents

Abstract

Self-supporting polymeric diffusion matrix, for the sustained transdermal delivery of terbutaline (I), comprises 2-60% of a polar plasticiser, 6-20 wt.% of polyvinylalcohol, 2-10 wt.% of polyvinylpyrrolidone and an effective amt. of (I). Pref. the PVA has a mol.wt. of 50,000-150,000, esp. 100,000-150,000 the PVP has a mol.wt. of 15,000-85,000, esp. 20,000-60,000; and the plasticiser is polyethylene glycol (present in amt. 2-15 wt.%), or glycerol, or a mixt. of 1 wt.pt. glycerol and 1-5 wt.pts. polyethylene glycol. (I) is pref. present in amt. to provide sustained release of 1-20 mg/day. (I) is a bronchodilator.

Description

812 0116 'V.O.3151

Polymeric diffusion matrix for drug administration.

The invention relates to a polymeric diffusion matrix with one or more drugs suitable for transdermal administration to a patient. More in particular, the invention relates to a polymeric diffusion matrix with one or more of these types of drugs characterized by a delayed release of this kind medicines. Among the drugs suitable for administration via a polymeric diffusion matrix according to the invention may be mentioned terbutaline, 1 ephedrine, clonidine, phenylephrine, estradiol esters, phenylpropanolamine and chlorpheniramine maleate. A self-supporting polymeric diffusion matrix is contemplated for sustained release of a drug or drugs for transdermal delivery of this drug to a patient to achieve a therapeutic effect in such a patient. This matrix contains about 2 to 60% by weight of a polar plasticizer, about 6-20% by weight of polyvinyl alcohol, 15: about 2-10% by weight of polyvinylpyrrolidone, and a pharmaceutically effective amount of a drug, over a long period of time. to deliver.

In one embodiment, the polar plasticizer is glycerol and is present in an amount of about 2-60% by weight. In another embodiment, the polar plasticizer is polyethylene glycol and is present in an amount of about 2-15% by weight. A further embodiment comprises a mixture of glycerol and polyethylene glycol, the latter being present in an amount of about 1-5 parts by weight per part by weight of glycerol.

The self-supporting polymeric diffusion matrix usually contains a mixture of polyvinyl alcohol and polyvinylpyrrolidone, although other polymeric mixtures may also be used provided they result in the desired sustained release rate. For example, both polyvinyl alcohol and polyvinylpyrrolidone can be completely replaced by ca.

1-9% agar or agarose, and preferably about 1.5 to 3% agar or agarose, with 2% agar or agarose being especially preferred.

The polyvinyl alcohol used in the invention is preferably one with a molecular weight of about 50,000 to 150,000 and preferably 100,000 to 150,000, 115,000 of which has been the most successful.

8120270 -2-

The polyvinyl alcohol should usually be hydrolyzed to at least 90%, with a preferred degree of hydrolysis of at least 95%. The polyvinylpyrrolydone should have a molecular weight of about 15,000 to! 85,000 and preferably 20,000 to 60,000, with a molecular weight of 40,000 being especially preferred.

The amounts by weight of the ingredients other than the polar plasticizer should usually be within the following ranges: the polyvinyl alcohol is usually present in an amount of ca.

6-20 wt% with 10% being preferred; the polyvinylpyrrolidone is usually present in an amount of about 2-10% by weight. . '

The water-soluble polymer can be replaced, besides by agar, with gum arabic, gum tragacanth, polyacrylic acid, polymethacrylic acid, polyvinyloxazolidone, polyvinyl morpholinone and polyvinyl piperidone.

Polyalkylene glycols such as polyethylene glycol and polypropylene glycol can partially or completely replace the glycerol.

It is possible to replace the polyvinyl alcohol with polymers of: hydroxyethyl acrylate, polymers of hydroxyethyl methacrylate, polymers of hydroxypropyl acrylate, and polymers of hydroxypropyl methacrylate.

When forming the matrix, an excess of water is not necessary.

According to a preferred embodiment of the invention, about 2% by weight of one of the above-mentioned drugs is incorporated in the diffusion matrix. The resulting homogeneous mixture is then poured into molds, preferably of glass or stainless steel, and these molds produce a diffusion matrix with a thickness of about 1 to 3 mm according to a preferred embodiment of the invention. This diffusion matrix is either cast or cut into pieces of the desired size.

The following methods can be used to prepare the diffusion matrix of the invention.

In a first method, the matrix is formed at atmospheric pressure. Water and glycerol are first mixed together.

A polar plasticizer such as glycerol is a necessary component in the matrix. A matrix formed without a polar plasticizer is inflexible and has poor diffusion contact with the skin, causing an unreliable diffusion release.

The polyvinyl alcohol and the polyvinylpyrrolidone are then added to the mixture of polar plasticizer and water under stirring at room temperature. The mixture is then heated to a temperature between 90 and 95 ° C, at atmospheric pressure, whereby the polymers are plasticized. If desired, the mixture can be maintained at an elevated temperature for some time, based on the stability of the polymer, before adding the curative. Thus, the mixture is stable for quite a long time and can be used for such a; should be stored for a period of time before mixing with the medicinal product to be delivered to the patient. Then the mixture is finished! the desired temperature is brought and the medicament to be used is subsequently added to the mixture with good stirring. When once; a homogeneous mixture of polymer solution and drug is obtained,! the mixture is ready to be in the form of a drug container; diffusion matrix. After pouring, the mixture is soaked; cooled to such a temperature that gelation occurs. In a preferred 15; In the embodiment, the drug can be dissolved by stirring in a suitable solvent such as glycerol and water. The solution thus obtained can be kept at room temperature without decomposition for a relatively long time.

It has been found that curing is facilitated by immediately cooling the matrix to about -20 ° C after casting. This considerably shortens the clotting period.

Sodium dodecyl sulfate or sorbitan (Tween-20) or other detergents can be added in an amount of 0.1-10% by weight based on the matrix as dispersants if desired.

An absorption promoter to ensure skin penetration, such as dimethyl sulfoxide, decylmethyl sulfoxide or other penetration accelerators can also be added.

Thus, the present drug delivery form comprises a drug-containing diffusion matrix and means or means for applying and securing this matrix to the patient's skin. Such means or organs can take various forms, such as a confining backing layer, which creates a kind of bandage with which the diffusion matrix is pressed against the skin of a patient to be treated. A polyethylene or Mylar strip can be used as a retaining backing layer according to the invention. It can also be in the form of an elastic band, such as a textile band, a rubber band or a band of.

8120270 -4- other material. In this case, the diffusion matrix is applied directly to the skin and held in place by such an elastomer; tic band, which is usually placed over a patient's arm or wrist. An adhesive intermediate layer between the diffusion matrix and the skin permitting transdermal drug administration can also be used.

In any case, the amount of drug to be administered to a patient per day is usually less than the oral dose. This is because oral administration is expected to cause a large proportion of the drug to be lost through passage through the liver. To ensure that the desired amount of the drug is released, an excess of drug will preferably be incorporated into the matrix. When terbutaline is used for a bronchodilatory effect i, the daily dose is usually 1-20 mg, most preferably about 1 mg.

With ephedrine, a decongestid * effect is obtained with a daily amount of usually about 5-30 mg, preferably about 20 mg. With clonidine, a blood pressure lowering effect is obtained with a daily amount of usually about 0.2-0.6 mg, preferably about 0.4 mg, delivered daily. With phenylephrine, a decongestion effect is obtained by a daily release of usually 2-5 mg, most preferably 2.5 mg. Phenylpropanolamine as a bronchodilator and nasal liberator usually uses daily amounts of about 2-50 mg, preferably about 10 mg. With chloropheniramine maleate, an antihistamine effect is obtained by delivering a daily amount of usually 1-30 mg, most preferably about 3 mg. The estradiol esters used according to the invention protect the uterine wall.

The said drugs can be added to the said mixture not only in the form of the pure chemical compounds, but also mixed with other drugs which can be administered transdermally or together with other ingredients, which are not incompatible with the desired purpose of a transdermal administration of the drug to a patient. For example, simple pharmacologically suitable drug derivatives such as ehters, esters, amides, acetals, salts and the like can be used. In some drugs, derivatives may even be preferable.

The estradiol ester derivatives suitable for the invention 8120270-5 are pharmacologically suitable esters, especially the 3-benzoate and 3-valerate esters of estradiol. Estradiol diacetate and other esters of a pharmacologically active type which are small enough to pass through the skin may also be used. The esters suitable for this invention are a source of pharmacologically active estradiol in the bloodstream. It should also be recognized that the intended estradiol ester can be administered in admixture with other drugs which are compatible with the desired therapeutic purpose.

The invention is further illustrated by the following non-limiting Examples.

Example I

30 g of glycerol and 45 ml of water were mixed together. This mixture was heated to 90 ° C and 15 g of polyvinyl alcohol (PVA, 100% hydrolysed, MW 115,000) and 8 g of polyvinylpyrrolidone (mg 40,000) were slowly added after reaching at least 70 ° C. The resulting mixture was stirred at 90 ° C until everything was dissolved, which is approximately; Took 10 minutes. It will be understood that with larger quantities a considerably longer time may be required. 98 cm of this solution was then mixed with 2 g of terbutaline, stirring this mixture mechanically until homogeneous. This homogeneous mixture was then poured into glass or stainless steel molds that acted as templets to create a diffusion matrix about 2-3 mm thick. This diffusion matrix was then cut into pieces with a total surface area suitable for administration of a pharmaceutically active amount of terbutaline.

The diffusion matrix was applied to a patient's skin in need of a bronchodilator effect. The terbutaline was delivered transdermally to the patient's skin. Preferably, the diffusion matrix is applied to the patient's skin using a one-piece bandage where the diffusion matrix is centered underneath a confinement layer and the bandage is applied to the patient with a peelable coating approximately in the shape of an auxiliary belt.

Example II

Instead of the glycerol according to example I, 5 g of polyethylene glycol with a mol. of 1000 and 25 cm of water. The diffusion matrix obtained 8 1 2 0 2 7 0 -6 was stiffer than that of Example I.

Example III

! Instead of the glycerol according to example I, 5 g of polyethylene glycol with 1 mol. 1000.4 g of glycerol and 21 cm of water were used.

The diffusion matrix obtained had the improved stiffness of the diffusion matrix of Example II, while contact with the skin was good and characteristic of the glycerol in this type of diffusion matrix.

; Example IV

Instead of the polyvinyl alcohol and the ployvinylpyrrolidone 10 I according to example. I a 2 wt% agarose was used; this resulted in a diffusion matrix for a transdermal release of terbutaline. Examples V-XXIV

! Examples V-XXIV correspond to Examples I-IV but; instead of terbutaline, the same amounts of the following 15 medicines were used:

Examples Drug 1 V-VIII ephedrine IX-XII clonidine XIII-XVI phenylephrine 20 'XVII-XX phenylpropanolamine XXI-XXIV chlorophenyramine maleate

Each of these drugs showed the characteristic therapeutic effect when applied via a diffusion matrix.

Example XXV

20 g of glycerol and 55 ml of water were combined. This mixture was heated to 90 ° C while after reaching at least 70 ° C 15 g of polyvinyl alcohol (PVA, 100% hydrolysed, MW 115,000) and 8 g polyvinylpyrrolidone (MW 40,000) slowly became added.

The mixture was stirred at 90 ° C until everything had dissolved, which took about 10 minutes. Of course, larger quantities will require 3 longer mixing times. 98cm of the resulting solution was then mixed with 2g of estradiol diacetate and the resulting mixture was mechanically stirred until homogeneous. This homogeneous mixture was then poured into glass or stainless steel molds to give a diffusion matrix about 1-2 mm thick. This diffusion matrix 8120270 -7- was then cut into square pieces of about 2.5 cm on each 2 sides and a total area of about 6.5 cm.

The diffusion matrix was then applied to the skin of an ipatient whose uterine wall could be damaged; estradiol ester-5 derivative was released transdermally. The diffusion matrix is ideally applied to the patient's skin with a single bandage with a diffusion matrix in the center thereof under a barrier layer; this bandage is applied to the patient with a peelable adhesive layer, for example in the form of a plaster.

10 Example XXVI

Instead of pouring the liquid containing a drug homogeneously distributed therein into a 1-2 mm thick matrix as described in Example XXV, it was poured into 1 cm thick oval molds.

The hardened diffusion matrix was applied in the form of a vaginal insert into a patient whose uterine wall was at risk, the estradiol ester derivative being released in the vicinity of the patient's cervix.

Example XXVII

Instead of the glycerol according to example XXV, 10 g of polyethylene glycol with a mol. of 1000 and 10 cm of water. The diffusion matrix obtained was stiffer than that of Example XXV, making it easier to administer in the form of a vaginal insert.

Example XXVIII

Instead of the glycerol according to example XXV, 5 g of polyethylene glycol with molecular weight 1000, 4 g of glycerol and 11 cm of water were used. The resulting matrix had the same improved stiffness of the diffusion matrix of Example XXVII, while the improved skin contact was characteristic of glycerol. This type of diffusion matrix is particularly suitable for transdermal administration.

Example XXIX

Instead of the polyvinyl alcohol and plyvinylpyrrolidone according to Example XXV, 2 g of agarose and 21 cm of water were used, whereby a diffusion matrix was created for the release of oyster radiol ester derivatives.

8120270

Claims (21)

The polymeric diffusion matrix of claim 1 wherein the polar; plasticizer is glycerol. The polymeric diffusion matrix of claim 1, wherein said polyvinyl alcohol has a molecular weight. has between 50,000 and 150,000. The polymeric diffusion matrix of claim 1 wherein said polyvinyl alcohol has a molecular weight. of 100,000-150,000 possession. The polymeric diffusion matrix of claim 1, wherein said polyvinylpyrrolidone has a molecular weight. possession of approx. 15,000-85,000. The polymeric diffusion matrix according to claim 1, wherein said polyvinylpyrrolidone has a molecular weight. from about 20,000 to about 60,000. The polymeric diffusion matrix according to claim 1, wherein said polyvinylpyrrolidone has a molecular weight. of 40,000 and the said polyvinyl alcohol has a molecular weight. of 115,000. The polymeric diffusion matrix of claim 1 wherein the polar plasticizer is a polyethylene glycol in an amount of about 2-15 wt%. The polymeric diffusion matrix of claim 1 wherein the polar plasticizer is a mixture of glycerol and polyethylene glycol, said polyethylene glycol being present in an amount of 1-5 parts by weight per part by weight of glycerol. Method for transdermally delivering terbutaline to a patient to obtain a bronchodilator effect, characterized in that a self-supporting diffusion matrix is applied to this patient, containing about 2-60% by weight of a polar plasticizer, about 6 -20 wt% 8120270-9 polyvinyl alcohol, about 2-10 wt% polyvinylpyrrolidone and a pharmaceutically effective amount of terbutaline to obtain a retardant; the issue for an extended period. Method according to claim 10, characterized in that the terbutaline 5 is present in an amount sufficient for a delayed release of about 1-20 mg per day. 12. Method of transdermally administering ephedrine to a patient for a decongestant effect, characterized in that a self-supporting diffusion matrix containing about 2-60 wt% of a polar plasticizer, about 6-20 wt% is administered to the patient % polyvinyl alcohol, about 2-10% by weight: polyvinylpyrrolidone and a pharmaceutically effective amount of ephedrine for a sustained release of ephedrine over an extended period of time. The method of claim 12, wherein the ephedrine is present in an amount sufficient to achieve a sustained release of about 5-20 mg per day. 14. Method for transdermally administering clonidine to a patient to achieve a blood pressure lowering effect, characterized in that a self-supporting diffusion matrix containing 2-60 wt.% Of a polar plasticizer, approx. 6-20% by weight polyvinyl alcohol, about 2-10% by weight polyvinylpyrrolidone and a pharmaceutically effective amount of clonidine to obtain a sustained release of this clonidine over an extended period of time. The method of claim 14 wherein said clonidine is present in an amount that provides an extended release of about 0.2-0.4 mg 25 per. day. A method of transdermally administering phenylephrine to a patient for a decongestant effect, characterized in that a self-supporting diffusion matrix containing 2-60 wt.% Of one is applied to the patient. polar plasticizer # about 6-20% by weight polyvinyl alcohol, about 2-10% by weight polyvinylpyrrolidone and a pharmaceutically effective amount of phenylephrine to obtain a sustained release of this phenylephrine over an extended period of time. Method according to claim 16, characterized in that the phenylephrine is present in an amount that a delayed release of about 2 to 50 mg per day is achieved. 8120 270 k -10- Method for transdermally administering phenylpropanol-amine to a patient for a bronchodilator effect, characterized in that a self-supporting diffusion matrix is applied to this patient, containing about 2-60% by weight of a polar plasticizer, about 6-20% by weight % Polyphenyl alcohol, about 2-10% by weight polyphenylpyrrolidone and a pharmaceutically effective amount of phenylephrine for a sustained release of this phenylpropanolamine over an extended period of time. 19. A method according to claim 18, characterized in that the phenylpropanolamine is present in an amount that a delayed release of about 2-50 mg per day is achieved. A method of transdermally administering chlorpheniramine maleate to a patient for an antihistamine effect, characterized in that a self-supporting diffusion is applied to the patient containing about 2-60% by weight of a polar plasticizer, about 6-20 wt.% polyvinyl-15 alcohol, 2-10 wt.% polyvinylpyrrolidone and a pharmaceutically effective amount of chlorpheniramine maleate for a sustained release of this chlorpheniramine maleate over an extended period of time. 21. A method according to claim 20, characterized in that the chlorpheniramine maleate is present in an amount such that a delayed release of about 1-30 mg per day is achieved. 22. Method for the transdermal administration of estradiol esters suitable for transdermal administration to a patient for protection of the uterine wall, characterized in that a self-supporting diffusion matrix is applied to the patient, containing approximately 2-60% by weight of a polar plasticizer. about 6-20% by weight polyvinyl alcohol, about 2-10% by weight polyphenylpyrrolidone and a physiologically effective amount of an estradiol ester suitable for transdermal administration to achieve a sustained release of this estradiol ester over an extended period of time. 8120270