MXPA01000527A - Transdermal patch and topical compositions comprising propylnorapomorphine - Google Patents

Abstract

Pharmaceutical composition comprising R(-)-propylnorapomorphine hydrochloride or S(+)-propylnorapomorphine hydrochloride and/or derivatives thereof, together with antioxidants, solubilizers and permeation activators to facilitate the passage of the active principle through the skin. The pharmaceutical composition is used in matrix (3, 3', 3") of a transdermal patch (1, 1', 1"), for the treatment of disorders of the Central Nervous System and in particular for the treatment of sexual impotence, hemicrania, Parkinson's disease and psychotic disorders. The release of the active principle can be modified by varying the concentrations of the solubilizers or of the permeation activators, or by providing a permeable membrane (4).

Description

TRANSDERMAL PATCH AND TOPICAL COMPOSITIONS CONTAINING PROPYLNORAPOMORPHINE DESCRIPTION OF THE INVENTION "Transdermal patch and pharmaceutical compositions containing R (-) - propylnorapomorphine hydrochloride and / or S (+) - propylnorapomorphine hydrochloride and / or derivatives thereof, in the treatment of sexual impotence, migraine, Parkinson's disease and psychotic disorders" .

TECHNICAL FIELD The present invention relates to the use of substances such as R (-) - propylnorapomorphine hydrochloride [hereinafter abbreviated to R (-) - NPA-HCl, or compound (1)] and S (+) - hydrochloride propylnorapomorphine or compound (2)] and derivatives thereof, for the treatment of Parkinson's, migraine, sexual impotence and psychotic disorders. More particularly, the invention also relates to a "device" (transdermal patch) for the slow release of said substances through the skin.

PREVIOUS TECHNIQUE Apomorphine (11 B-13B) has been used successfully as a drug and, especially in the veterinary field, as an emetic. Recently it has been found that apomorphine (abbreviated to APO), in adequate doses, can have beneficial effects in patients with Parkinson's disease, since in smaller doses it is useful in the treatment of migraine, sexual impotence and psychotic disorders (4B, 5B, 6B, 7B). In the aforementioned therapeutic indications APO is a powerful dopamine agonist drug, which is administered intravenously (i.v.), subcutaneously (s.c.), intramuscularly (i.m.), rectally, sublingually or intranasally. The substance is characterized by rapid absorption, correlated with a rapid attack (latent period around 15 ') and an equally rapid elimination (half-life around 33') (8B). The apomorphine molecule is unstable when exposed to air and light, oxidizing rapidly. In fact, when exposed to air, the preparations based on apomorphine change color, turn green, thus giving rise to a product that can no longer be used clinically for a long time. For this reason, in order to ensure that the patient meets their needs pharmacologically, with therapeutically effective blood levels that are sufficient and constant for more than 24 hours, a large number of daily administrations are needed, with limited doses, of the order of 5 mg / hour of the active substance. Exceeding said dose even for a minimal amount would cause serious side effects, such as vomiting, depression of the Central Nervous System (CNS) and, in some cases, even the death of the patient. Recently, it has been proposed and carried out in the medical practice the administration of apomorphine by continuous subcutaneous infusion, by means of small insulin pumps that could guarantee drug coverage with the infusion hour by hour of small doses, without causing side effects. But even this alternative mode of administration is not without disadvantages: already in doses of 2-5 mg / hour, there is a tendency for subcutaneous granulomas to form around the infusion site, which require the suspension of the treatment. This is due to the fact that the drug is concentrated in almost a single point: around the point of the needle.

DESCRIPTION OF THE INVENTION It is an object of the present invention to use a pharmaceutical composition based on R (-) - NPA-HCI (compound (1)) or S (+) - NPA-HCl (compound 2) and / or derivatives thereof, which can be administer to the patient in therapeutically effective doses of active principle, in a continuous manner, without causing the incidence of serious side effects, such as vomiting and depression of the Central Nervous System (CNS), due to a high dose of active ingredient, or even granulomas around the infusion site (when the dose is lower), as found with the use of APO. The activity of compounds (1) and (2) is 10 times greater than that of APO, and therefore their toxicity is lower. further, the average life is higher than that of APO. For this reason, when said components are provided in adequate doses for more than 24 hours, effects are obtained that are far more beneficial than those of APO. Another objective of the present invention is to produce a transdermal patch for the slow release of the compounds (1) and (2), and / or derivatives thereof, hereinafter referred to as PATCH-TDDS (TDDS, for short English = Transdermal Drug Delivery System). The transdermal patch of the invention will guarantee a therapeutically effective level of the compounds (1) or (2) and / or the derivatives thereof (active ingredient) for more than 24 hours, without presenting the disadvantages of traditional techniques. This is because, since the patch has relatively larger dimensions (for example: 40 cm2), the active principle can penetrate the epidermis through the 40 cm2 without any possibility of producing accumulation sites. In addition, the greater therapeutic activity allows the dose to be reduced almost 10 times. A higher solubility in water allows the release and penetration rate in vivo to be adequately modified by the addition of suitable penetration activators.

BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be described in greater detail with reference to some preferred embodiments thereof which are shown in the accompanying drawings, in which: Figure 1 is a first type of transdermal patch according to the invention, with a permeable membrane; Figure 2 is a second type of transdermal patch according to the invention without a permeable membrane; Figure 3 is a third type of transdermal patch, according to the invention with an adhesive matrix; Figure 4 is a diagram of the penetration of compound (1) in vitro on guinea pig skin (accumulation); Figure 5 is a diagram of the penetration of compound (1) in vitro on guinea pig skin (flow per unit of time): Figure 6 is a diagram showing the approximate curve representing the levels of human plasma at the time indicated (in hours (h)) referring to the active principle (1).

PREFERRED MODALITIES OF THE INVENTION Figure 1 shows a first type of transdermal patch 1 which includes an impermeable support film 2 in which a matrix 3 is placed. The active substance, (1), (2), and / or the derivatives thereof, they dissolve and / or disperse in matrix 3 which serves as a deposit. The matrix 3, on the side opposite the impermeable support 2, is covered by a membrane 4 permeable to the active substance, which regulates the cross flow. This membrane will not be necessary if the degree of penetration of the active substance into the skin does not exceed the values that can cause side effects (see Figures 2 and 3 where this membrane is not provided). The degree of diffusion of the active substance will also depend on the penetration activators, solubilizers, etc. On the free side of the permeable membrane 4 there is a layer of a contact adhesive 5 (adhesive layer), protected by a release strip 6. During the use of the transdermal patch the release strip 6 is removed and the patch is placed on the desired part of the patient's body, exerting slight pressure. After the "start" phase the flow reaches a constant "saturation" value. The release curves of the active substances (see Figure 4, 5) and the plasmatic concentration based on the computer model will be discussed below, with reference to the type III transdermal patch. In the case of patch V of type II (Figure 2), a matrix or "tank" 3, in which the active substance dissolves and / or disperses is applied to a waterproof support film 2 '. In the present case, the membrane permeable to the active substance, which is used to modify the cross-flow, is lost. Therefore, the 3 'matrix comes into direct contact with the epidermis. The glue 5 'is located around the edge of the patch, like an adhesive ring. Everything is protected on the free side by an individual release strip 6 ', which can be removed, like the type I. The use of the "device" is as follows: the release strip 6' is removed, the device is placed in the desired part of the patient's body, exerting a slight pressure. This solution (type II) can be adopted in particular if the active principle interacts in an undesired way with the adhesive, as a result of which it is not possible to mix the 5 'adhesive and the active ingredients in the 3' matrix. The type III patch is of the type related to the "drug in an adhesive matrix". In this "device" the pharmacological dose is directly placed, dissolved or dispersed in a glue, which in this way becomes a 3"" reservoir "matrix which is placed in a layer on a permeable support film 2 '. The adhesive matrix 3"is protected on one side by a support 2" (back) and the other by a release strip 6". The use of the device is as follows: the release strip 6"is removed and the device is placed in the desired part of the patient's body, exerting slight pressure, depending on the particular application, the first, second and third patch will be used. However, it is obvious that a person skilled in the art will be able to modify the shape and / or structure of the patch as desired, obtaining the best results based on the selected therapy and the place of application, or on other factors. Therefore, the three configurations shown in Figures 1, 2 and 3 are examples and are not limited. The differences in the structure and shape of the patch (regular or anatomical) must be: to the interactions that may exist between the active principle, the glue (different types of adhesive can be used simultaneously), the support material, and other materials such as excipients, stabilizers, etc.; by improving the stability in the chosen place of application; at the dose (the area of the patch should also be increased for a larger dose). For purposes of illustration, the manufacturing method of the type III patch will be discussed in the following description, and in addition the components of the pharmaceutical composition constituting the matrix will be indicated. Next, the three particular non-limiting examples of the pharmaceutical composition used to form the type III patch matrix will be illustrated (Figure 3). The type III patch, which contains a matrix made with these three types of formulations, will then be "tested" on guinea pig skin, to analyze the penetration of the active principle, to consider both the accumulation of the active ingredient for more than 48 hours (figure 4), as the flow (also for more than 48 hours, figure 5).

Method of manufacture of the transdermal patch of type III 1. The active principle (1) or (2) or a derivative thereof is incorporated simultaneously with other components (stabilizer, penetration activators, etc.,) in a hot adhesive solution and homogenized by stirring, until the matrix or "tank" of liquid adhesive is obtained; 2. The liquid matrix cools, and acquires a "viscous" consistency; 3. The process for forming layers of the adhesive matrix on the support is carried out using a machine for layering that is continuously connected to a drying machine, in the following phases: the blade of a knife is mounted across the width of the conveyor belt of the layer forming machine where the release strip is securely placed; the "viscous" adhesive matrix is emptied in front of the blade, which, as the conveyor belt advances, distributes a uniform layer (layering) of an adhesive matrix on the release strip; the thickness of the layer is determined primarily by the distance between the edge of the blade of the knife and the release strip running behind it; the release strip, which carries the adhesive matrix, rotates on the inside of the drying machine, in which the adhesive matrix is solidified by evaporation of the solvent that is achieved by gradually increasing the temperature and "ventilation", as shown in the following table 1.

TABLE 1 Drying phase Time (in minutes) T ° C Vent. (rpm) 1 15 40 700 2 20 55 1000 3 25 70 1200 The described procedure allows the elimination of the solvent preventing it from being occluded by the rapid formation of a crust on the surface. When the adhesive matrix has dried, the support film (backing) is applied. This phase called "lamination" ends the procedure. The procedure is described in the literature (9B, 10B, 11 B) and gives rise to a TDDS patch in which the adhesive matrix remains protected both by the "backing" and by the release strip that can be removed. It is very important to use an adhesive that is inert and permeable to (1) or (2) and to the derivatives thereof, and the properties of the adhesive which (cohesion, adhesion and interlacing) do not adversely affect by themselves the principle active and / or excipients or by any other added material.

COMPOSITION OF THE PATCH-TDDS OF TYPE 3 Adhesive matrix: formulation Active principle: (1) or (2) or derivatives thereof; antioxidant: sodium metabisulfite, disodium salt of EDTA, solubilizing agent: a glycol; Penetration activator: fatty acids; acrylic resin to improve the cohesive strength: cationic copolymers based on methacrylic esters and dimethylaminoethyl methacrylate; cellulose derivatives to improve the cohesion strength: ethyl cellulose; Surfactant: SDS (sodium dodecylsulfate); Pressure contact adhesive: mixture of two adhesives, A and B, in which A is a non-self-adhesive acrylic contact adhesive of medium molecular weight with a high interlacing index, with a skin irritation index of 0.20, classified as "minimal irritation", using 100% ethyl acetate as a solvent; and B is a self-adhesive acrylic adhesive with a high molecular weight, with moderate interlacing, with a skin irritation index of 0, classified as "non-irritable", using a mixture of ethylacetate, isopropanol, hexane and toluene as solvent.

T Release strip The release strip is a polyester film laminated with silicone on one of its sides (which is opposite the adhesive matrix). The thickness is approximately 125 μm.

"Backing" The "backing" is a laminated polyester film which is transparent and occlusive with a thermally weldable layer. The total thickness is approximately 51 μm.

Amount of active ingredient The amount of (1) or (2) or derivatives thereof, which is expressed as (1) or (2), is 5% by weight of the adhesive matrix and corresponds to 5 mg / cm2 in the PATCH-TDDS. The main part of the drug is dispersed in the matrix. A smaller part dissolves in the matrix. The drug dispersed in the matrix acts as a "reservoir", since the drug available for release and penetration is the dissolved drug. Three examples of the application efficacy of the type III transdermal patch based on (1) or (2) and / or derivatives thereof are given below. Three batches of patches of differentiated formulation containing (1) and (2) and / or derivatives thereof were prepared for this purpose. Using the in vitro cell penetration technique recommended by the FDA in E.U.A. (1B, 2B, 3B), the following results were obtained, for example, with the three different formulations given below, wherein compound (1) was used as the active ingredient, ie, the most pharmacologically active molecule: EXAMPLE A Lot R (-) - NPA-HCI / A, with the addition of penetration inducers: 1) Compound (1) 2.00% 2) Sodium metabisulfite 0.20% 3) Solubilizing agent 4.00% 4) Acrylic resin 29.00% 5) Fatty acid 1 3.20% 6) Fatty acid 2 1.60% 7) Pressure sensitive adhesive 60.0% EXAMPLE B Lot R (-) - NPA-HCI / B, with addition of penetration inductors, 4. 5% of product dispersed in the matrix 0.5% of active principle dissolved in the matrix. 1) Compound (1) 4.99% 2) Sodium metabisulphite 0.50% 3) EDTA 0.025% 4) Solventizing agent 9.96% 5) Fatty acid 1 7.96% 6) Fatty acid 2 3.97% 7) Acrylic resin 1.99% 8) Derivative of cellulose 0.25% 9) Surfactant 19.90% 10) Pressure sensitive adhesive 50.455% EXAMPLE C Lot R (-) NPA-HCI / C, with the addition of penetration inductors, with 0.5% active ingredient in the matrix (all the drug dissolves): 1) Compound (1) 0.50% 2) Sodium metabisulfite 0.50% 3) EDTA 0.025% 4) Solventizing agent 9.96% 5) Fatty acid 1 7.96% 6) Fatty acid 2 3.97% 7) Acrylic resin 1.99% 8) Derivative of cellulose 0.25% 9) Surfactant 19.90% 10) Pressure sensitive adhesive 50.945% Results of the experiment The in vitro penetration study with guinea pig skin that was carried out with the established procedures showed a percentage of penetration equal to the values given in figure 4 (total amount) in figure 5 (flow), for the three examples A, B, C, at different times. It can be seen that in the case of example C the values almost reached zero, that is, all the black boxes are located virtually on the abscissa axis (time in hours).

This shows that an amount of active substance at 0.5% dissolves in the matrix, in the absence of a certain amount of dispersed active principle, does not produce an appreciable penetration of active principle through the skin that allows the contemplated use.

Therefore, it will be necessary to disperse a certain quantity of active principle in the matrix, in such a way that a concentration gradient is produced which facilitates the diffusion of active principle, as well as constituting a "deposit", in order to obtain a Slow release. When processing the in vitro penetration data reported previously with one of the most appropriate pharmacokinetic models for the transdermal administration of drugs (10B, 11 B) and considering a patch of 40 cm2 (5 x 8 cm) with the following constants: molecular weight of: propylnorapomorphine hydrochloride 331.8 Water / alcohol distribution coefficient 0.0005 Half-life 45 Volume of distribution 132 The approximate curve shown in figure 6 is obtained, representing the levels of human plasma at the indicated times, in the case of the application of an NPA / B patch of a single lot (ordered: unit ng / ml, abscissa: time in hours). From figures 4 to 6, it is possible to conclude that the penetration of the compound (1) into the skin is by itself sufficient and can be increased or decreased by using different penetration activators such as fatty acids or alcohols. All the in vitro penetration studies that were carried out using models that use guinea pig skin, which are known to have a comparable penetration with human skin and provide more reproducible results than later ones. The chemical stability of the compound (1) in the patch formulation is achieved by the addition of an antioxidant (sodium metabisulfite) and it is demonstrated that an accelerated stability test of 15 days at 40 ° C and 75% RH (relative humidity) . The surfactant (SDS) is added with the aid of a solubilizing agent in a larger amount of the compound (1), as only the solubilized substance (1) is available to be released and to penetrate. The patches also have good physical and chemical properties exhibited that can be optimized by the person skilled in the art with respect to the adhesiveness of the place of application and the tolerability by the subject under treatment without modifying the penetration percentage of the active principle. As mentioned above, the most appropriate configuration of the transdermal patch varies depending on the circumstances.

For example, the type III patch can be cut from a large tape, to obtain a transdermal patch of the appropriate size for the application site. The type II patch, on the other hand, will have to have the final dimensions, and can not be cut, as the 3 'matrix is not adhesive and the glue is limited to the 5' annular region.

BIBLIOGRAPHY 1 B. Gummer LC, Chapter 9, "The in vitro Evaluation of Transdermal Delivery". In "Transdermal Drug Delivery Developmental Issues and Research Initiatives", published by Hadgraft J e Guy RH. Marcel Dekker, Inc., New York (1989). 2B. Tojo K, Chapter 6, "Design and Calibration of in vitro Permeation Apparatus". In "Transdermal controlled Systemic Medications", published by Chien YW. Marcel Dekker, Inc., New York. (1987). 3B. Priborski j e Muhulbachova E, "Evaluation of in vitro Percutaneous Absorption across Human Skin and in Animal Models ", J. Pharm, Pharmacol 42; 468-472 (1990), 4B, T. VAN LAAR and ENH JANSEN," Rectal apomorphine: a new treatment modality in Parkinson's disease. "J of Neurology, Neurosurgery and Psychiatry 55; 737-737 (1992) .5B. VAN LAAR et al .: "Intranasal Apomorphine in Parkinsonian on-off fluctuations." Arch. Neurol. Vol. 49, 482-484, May (1992) 6B. W. Poewe et al. "Continuous Subcutaneous Apomorphine Infusions for Fluctuating Parkinson's Disease". "Advances in Neurology", vol. 60, 656-659. Reven Press Ltd. New York (1993). 7B. E. Nicolle et al. "Pharmacokinetics of apomorphine in parkinsonian patients". "Fundam Clin Clincol." 7: 245-252 (1993). 8B. That M. et al. "Stability of apomorphine in plasma and its determination by high-performance liquid chromatography with electrochemical detection". J. of Chromatography B, 658: 311-317 (1994). 9B. Satas D. Chapter 34, "Coating equipment". In Handbook of Pressure Sensitive Adhesive Technology. "Donatas Satas, eds. New York, Van Nostrand Reinhold 809-830 (1989), 10B, Grand OW and Satas D, Chapter 4, Other Knife and Roll Coaters. In "Web Processing and Coverting Technology and Equipment". Donatas Satas eds. New York, Van Nostrand Reinhold 60-80 (1984). 11 B. Elias JJ, Chapter 1, "The Microscopic Structure of the epidermis and its Derivatives". In Percutaneous Absorption, "published by Bronaugh RL and Maibach Hl. Marcel Dekker, Inc. New York (1989) 12B Nora S. Kula, Ross J. Baldessarini et al." Effects of Isomers of Apomorphines on dopamine receptors in striatal and limbic tissue of rat brain "." Life Sciences ", vol 37, pp. 1051-1057 13B John L. Neumeyer et al." Aporpines. 48. Emantioselectivity of (R) - (-) - and (S) - (+) - Nn- Propylnorapomorphine on Dopamine Receptors. "J. Med. Chem. 1983, 26, 516-521, 14B. Richard F. Cox and Al. "Effects of Nn- Propylnorapomorphine Enantiomers on Single Unit Activity of Substantia Nigra Pars Compact and Ventral Tegmental Area Dopamine Neurons".

Journal of Pharmacology and Experimental Therapeutics "; 1988, 7, pages 355-362.

Claims (12)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A pharmaceutical composition characterized in that it comprises R (-) - propylnorapomorphine hydrochloride and / or S (+) - propylnorapomorphine hydrochloride and / or derivatives thereof, and pharmaceutically acceptable and effective doses and further comprising stabilizers, solubilizers, and activators of penetration to facilitate the passage of the active principle through the skin. 2,. A pharmaceutical composition according to claim 1, further characterized in that said derivatives of R (-) - propylnorapomorphine and S (+) - propylnorapomorphine hydrochloride are salts or organic derivatives. 3. A pharmaceutical composition according to claim 1, further characterized in that said stabilizers are antioxidant substances. 4. A pharmaceutical composition according to claim 1, further characterized in that a glycol is used as a solubilizer. 5. A pharmaceutical composition according to claim 1, further characterized in that fatty acids or alcohols are used as penetration activators. 6. A pharmaceutical composition according to claim 3, further characterized in that the oxidant is sodium metabisulfite and EDTA. 7. A pharmaceutical composition according to any of the preceding claims, which additionally comprises a surfactant (SDS). 8. A pharmaceutical composition according to any of the preceding claims, comprising an acrylic resin to improve the cohesive force, the cellulose derivatives to improve the cohesive force, and a mixture of pressure contact adhesives. 9. A transdermal patch (1; 1 '; 1") characterized in that it comprises at least one support film called" backing "(2; 2'; 2"), an intermediate matrix (3; 3 '; 3") containing the pharmaceutical composition referred to in claims 1 to 8, and a protective release strip (6; 6'; 6"). transdermal (1) according to claim 9, further characterized in that the matrix (3) does not include adhesives and on its lower side has a layer (4) made of a permeable membrane 11.- A transdermal patch in accordance with the claim 10, further characterized in that the permeable membrane (4) that modifies the release of the active ingredient is itself made of an adhesive layer to conform to the skin. 12. - A transdermal patch according to claim 10, further characterized in that the permeable membrane (4) is non-adhesive and has an adhesive layer (5) below it to conform to the skin. 13. A transdermal patch according to claim 9, wherein an adhesive layer (5 ') is applied on the sides of the matrix (3') that does not contain adhesives. 14. A transdermal patch according to claim 9, characterized in that it comprises an adhesive matrix (3") and contains an acrylic resin and cellulose derivatives to improve the cohesive force, as well as a mixture of pressure contact adhesives. 15. The use of the pharmaceutical composition referred to in claim 1 to 8 to obtain a slow release of the principle or active ingredients through the skin, in the treatment of Parkinson's disease, migraine, sexual impotence and psychotic disorders. The use of the transdermal patch, referred to in claims 9 to 14, to obtain a slow release of active principle or principles through the skin, in the treatment of Parkinson's disease, migraine, sexual impotence and psychotic disorders. The use of the transdermal patch according to claim 16, wherein part of the active principle is immediately available for penetration through the skin and another part thereof is dispersed in the matrix (3; 3'; 3") that acts as" deposit ".