PHARMACEUTICAL COMPOSITIONS COMPRISING APOCODEINE AND/OR ITS DERIVATIVES

Abstract: Three pharmaceutical compositions are described: slow-release transdermal patches, sublingual/chewable tablets, and sprays based on apocodeine (APC) and/or its derivatives, for the treatment of male impotence and for the stimulation of male and female libido.

Description: PHARMACEUTICAL COMPOSITIONS COMPRISING APOCODEINE AND/OR ITS DERIVATIVES 10 Disorders associated with reduced sexual potency and a fall in sexual desire are the most common problems for which adults currently resort to alternative medical practices rather than conventional medicine, one reason being that a confident diagnosis 15 cannot be met with an adequate pharmacological remedy. Besides bringing together diverse activity, the drugs currently commercially available show the greatest and most significant differences with regard to the side effects, the duration of action and the ease of use. These differences are the most important factor to take into consideration when choosing a drug, since they determine both the safety and the patient compliance. In addition, the safety of use and the compliance make the difference all the more perceptible in drugs for which indications are given which improve the quality of life and which are not "lifesaving" drugs . Important considerations regarding the choice of drug for the treatment of male sexual impotence and for the stimulation of male and female libido concern the side effects liable to be induced and the safety of use in a self-administration regime. The current limitations in the treatment of impotence and in the stimulation of desire are due to the fact that effective drugs exist, but they can only be used with extreme caution on account of the numerous and extremely serious side effects which can be induced, and equally effective drugs exist which, although not exhibiting side effects, require highly sophisticated production technology, as a result of which the marketed product is penalized by a high cost, thus restricting its use. The present invention, which relates to the use of apocodeine (APC) and/or its derivatives for the preparation of various medicinal forms (patches, tablets, sprays), overcomes the current limitations of the treatment in use for treating the pathologies under consideration, since, in the forms and doses proposed, APC is effective, is free of side effects and requires only simple and cost-effective technology for its preparation. Transdermal patch Description in support of a patent application entitled: Pharmaceutical compositions (transdermal patches, chewable/sublingual tablets, sprays) comprising apocodeine (APC) and/or its derivatives, for the treatment of male impotence and for the stimulation of male and female libido. The molecule APC and its derivatives are stable with respect to air and light. In the abovementioned therapeutic indications, APC is a powerful drug which can be administered transdermally. The active principle (APC) is rapidly absorbed, becomes effective rapidly (latency time 8 ' -18 ' ) and is equally rapidly eliminated (half-life 30'). Thus, in order to ensure that the patient has the required pharmacological cover with effective, sufficient and constant levels in the blood, it will be necessary to make the individual take the drug at the physiological dose via the transdermal route for the time required to satisfy the expectations. For transdermal administration, it will be sufficient to apply a slow-release patch (TDDS = transdermal drug delivery system) , referred to hereinbelow as a TDDS patch, based on APC in order to provide pharmacological cover for about 8 hours . Three basic types of TDDS patch can be prepared, as represented schematically in the drawings below: TYPE I DESCRIPTION impermeable support film (backing) matrix or reservoir permeable membrane adhesive protective release strip TYPE II ble support film (backing) adhesive release strip TYPE III impermeable support film (backing) <ss y /ss s s</z adhesive matrix protective release strip A subject of the present invention is thus a pharmaceutical composition comprising, in pharmaceutically acceptable and effective doses, APC and/or its derivatives. A further subject of the invention is a transdermal patch comprising, as active principle, APC and/or its derivatives, this patch having a type I, type II or type III structure, and its shape and size being suitably sized in relation to the site of application and the desired dosage. A further subject of the invention is the use of APC and/or its derivatives, for the preparation of a transdermal patch for the treatment of male impotence and for the stimulation of male and female libido. Three basic types of transdermal patch (TDDS patch) can be prepared: TYPE I: is a device comprising an impermeable support film on which is a matrix or reservoir in which the active substance is dissolved and/or dispersed. The matrix, on the side opposite the support, is coated with a membrane which is permeable to the active substance and regulates its cross-flow. A contact adhesive is layered on the free side of the permeable membrane (adhesive layer) , protected by a release strip. The device is used as follows: the release strip is pulled off and the device is positioned over the desired part of the patient's body and applied with light pressure. TYPE II: This device comprises an impermeable support film on which is a matrix or reservoir in which the active substance is dissolved or dispersed. It lacks the membrane which is permeable to the active substance, which modulates the cross-flow, as a result of which the matrix is free on one side and comes into direct contact with the epidermis. The adhesive is located around the edge of the device, as a kind of adhesive ring. The assembly is protected on the free side by a single removable release strip, as in type I. The device is used as follows: the release strip is pulled off and the device is positioned over the desired part of the patient's body and applied with light pressure. TYPE III: This is also known as a "drug in an adhesive matrix" assembly. In this device, the pharmacological dose is housed directly, in dissolved or dispersed form, in the adhesive, which thus also acts as a reservoir matrix and is layered on an impermeable support film. The adhesive matrix is protected on one side by the support (backing) , and on the other side by the release strip. The device is used as follows: the release strip is pulled off and the device is positioned over the desired part of the patient's body and applied with light pressure. The differences between the structures and shape (rectangular or anatomical) of the three types of patch are specifically designed to compensate for: • the interactions which may exist between the active principle, the adhesive (different types of adhesive can be used at the same time) , the support material and other materials, such as excipients, stabilizers, etc . • the improved stability on the preselected site of application the dosage (greater surface area = greater dosage) In the present invention, in consideration of the physicochemical properties of APC and/or its derivatives, the preferred patch is the type III patch, and more preferably the type III patch with acrylic adhesives, in rectangular shape when it is desired to achieve constantly high doses for long periods, or in anatomical shape when a targeted rapid result is desired (e.g. treatment of sexual impotency) . The present invention will now be illustrated by means of its illustrative, non-limiting examples, in which reference will be made to the following figures, using analytical results obtained with a 40 cm 2 standard rectangular type III patch. Fig. 1 is a graph of the accumulation of APC over time. Fig. 2 is a graph of the flow of APC over time; Fig. 3 is the approximate curve representing the levels in human plasma at the times indicated, relative to the APC active principles. - 10 - Method for manufacturing the type III transdermal patch 1. The active principle APC or a derivative thereof is incorporated simultaneously with the other components (stabilizer, permeation activators, etc.) into the hot adhesive solution and is homogenized by stirring until the liquid adhesive matrix or reservoir is formed; 2. the liquid adhesive matrix is cooled and acquires a "thready" consistency, 3. the process of lamination of the adhesive matrix on the support is carried out using a laminating machine linked continuously to a drying machine, according to the following phases: A. the blade of a knife is mounted across the entire width of the conveyor belt of the laminating machine on which the release strip is solidly positioned; B. the "thready" adhesive matrix is poured in front of the blade which, as the conveyor belt advances, distributes a uniform layer (lamination) of adhesive matrix over the release strip; C. the thickness of the layer is determined mainly by the distance between the edge of the knife blade and the release strip passing underneath it; D. the release strip, loaded with the adhesive matrix, rotates inside the drying machine, in which the adhesive matrix is solidified by evaporation of the solvent, obtained by gradually increasing the "ventilation" temperature as reported in scheme I below. Scheme I Drying phase Time (in minutes) T°C Vent, (rpm) 1 15 40° 700 2 20 55° 1000 3 25 70° 1200 The process described allows the removal of the solvent, thus avoiding its occlusion by the rapid formation of a surface crust. 4. Once the adhesive matrix has dried, the support film (backing) is affixed. This phase, known as "lamination" concludes the process. The process is described in the literature (9B,10B,11B) and produces a TDDS patch in which the adhesive matrix is protected, on the one hand, by the "backing" and, on the other hand, by the removable release strip. It is very important to use an adhesive which is inert and permeable with respect to APC and its derivatives, whose adhesive properties (cohesion, adhesion and interlacing) are not adversely affected by this active principle and/or by excipients, or by any other material added. Composition of the type III TDDS patch Adhesive matrix: formulation • active principle: APC or its derivatives ,- • antioxidant: sodium metadisulphite, EDTA disodium salt; • solubilizing agent: a glycol; • permeation activator: fatty acids; • acrylic resin to improve the cohesive force: cationic copolymers based on dimethylaminoethyl methacrylate and methacrylic esters • cellulose derivatives to improve the ethylcellulose force; • surfactant: SDS (sodium dodecyl sulphate); • pressure-contact adhesive: mixture of two adhesives, A and B, in which A is an acrylic contact adhesive of average molecular weight which is not self-bonding, with a high interlacing index, a dermal irritation index of 0.20, classified as "minimally irritant" and containing 100% ethyl acetate as solvent; and B is an acrylic adhesive of high molecular weight, which is self-bonding, with a moderate interlacing index, a dermal irritation index of 0, classified as "non- irritant" and containing a mixture of ethyl acetate, isopropanol, hexane and toluene as solvent. Release strip The release strip is a polyester film laminated with silicone on one side (the side facing the adhesive matrix) . The thickness is approximately 125 μm. Backing The backing is a laminated, clear, occlusive polyester film with a heat-welding layer. The total thickness is approximately 51 um. Amount of active principle The amount of APC or its derivatives, referred to as APC, is 5% by weight of the adhesive matrix and corresponds to 5 mg/cm 2 in the TDDS patch. Most of the drug is dispersed in the matrix and acts as a reservoir, while the drug which is available for release and permeation is the dissolved drug. Application efficacy of the transdermal patch based on APC and/or its derivatives Various batches of patches of different formulation containing APC and/or its derivatives were prepared for this purpose. Using the technique of in-vitro cell permeation, recommended by the US FDA (IB, 2B,3B), the following results were obtained, for example, with three different formulations given below, in which the pharmacologically active molecule was used as APC active principle: APC/A batch, with addition of permeation inducers : 1 ) APC 2 . 00% 2) Sodium metabisulphite 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% APC/B batch with addition of permeation inducers, 4.5% active principle dispersed in the matrix (reservoir) , 0.5% active principle dissolved in the matrix. 1) APC/B 4.99% 2) Sodium metabisulphite 0.50% 3) EDTA 0.025% 4) Solubilizing agent 9.96% 5) Fatty acid 1 7.96% 6) Fatty acid 2 3.97% 7) Acrylic resin 1.99% 8) Cellulose derivative 0.25% 9) Surfactant 19.90% 10) Pressure-sensitive adhesive 50.455% APC/C batch, with addition of permeation inducers, 0.5% active principle in the matrix (all of the drug is dissolved) : 1 ) APC/C 0 . 50% 2) Sodium metabisulphite 0.50% 3) EDTA 0.025% 4) Solubilizing agent 9.96% 5) Fatty acid 1 7.96% 6) Fatty acid 2 3.97% 7) Acrylic resin 1.99% 8) Cellulose derivative 0.25% 9) Surfactant 19.90% 10) Pressure-sensitive adhesive 50.945% Experimental results The study of in-vitro permeation with guinea- pig skin, carried out in accordance with the procedures mentioned, gave a permeation rate equal to the values reported in Fig. 1 (total amount) and in Fig. 2 (flow) at the various times . The in-vitro permeation data reported above were analysed by means of one of the most adequate pharmacokinetic models for the transdermal administration of drugs (10B,11B), obtained with a 40 cm 2 (5x8 cm) patch and the following constants: molecular weight -331.8 water/alcohol coefficient of distribution: 0.05 half-life 45' distribution volume 132 litres The approximate curve representing the levels in human plasma at the times indicated, in the case of application of a single NPA/B batch patch, is illustrated in Fig. 3. time h It may be concluded that the skin permeability of APC is sufficient per se and can be increased or decreased by means of various permeation activators such as fatty acids or alcohols. All of the in-vitro permeation studies were carried out on models using guinea-pig skin, which we know has comparable permeability to that of human skin and which gives more reproducible results than the latter. The chemical stability of APC in the formulation of the patch is achieved by adding an antioxidant (sodium metabisulphite) and is demonstrated by means of a 15-day accelerated stability test at 40°C and 75% RH (relative humidity) . The surfactant (SDS) is added to dissolve most of the APC, since only the dissolved APC is available for release and permeation. The patches also demonstrated good physico- chemical properties, which can be optimized by those skilled in the art for the purposes of adhesion at the site of application and tolerability by the individual undergoing the treatment, without modifying the rate of permeation of the active principle. BIBLIOGRAPHY IB. Gummer LC, Chapter 9. The in vitro Evaluation of Transdermal Delivery. In Transdermal Drug Delivery Developmental Issues and Research Initiatives, edited by Hadgraft J and 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, edited by Chien Y . Marcel Dekker, Inc. New York (1987) 3B. Priborski J and Muhylbachova E, Evaluation on 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 T. 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. Pharmacol. 7:245-252 (1993) 8B. E. Sam 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 Converting Technology and Equipment. Donatas Satas eds. New York, Van Nostrand Reinhold 60-80 (1984) 11B Elias JJ, Chapter 1, The Microscopic Structure of the Epidermis and its Derivatives . In Percutaneous Absorption, edited by Bronaugh RL and Maibach HI. 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. Ne meyer et al . Apopines . 48. Emantioselectivity of (R)-(-) and (S)-(+)-N-n- Propylnorapomorphine on Dopamine Receptors. J. Med. Chem. 1983,26,516-521. 14B. Richard F. Cox et al . Effects of N-n- Propylnorapomorphine Enantiomers on single Unit activity of Substantia Nigra Pars Compacta and Ventral Tegmental Area Dopamine Neurons . The Journal of Pharmacology and Experimental Therapeutics; 1988, 7, pages 355-362. Chewable/sublingual tablets Description in support of a patent application entitled: Pharmaceutical compositions (transdermal patches, chewable/sublingual tablets, sprays) comprising apocodeine and/or its derivatives for the treatment of male impotence and for the stimulation of male and female libido. In the abovementioned therapeutic indications, APC is a powerful drug which can be administered orally. The active principle (APC) is rapidly absorbed, becomes effective rapidly (latency time 8'-18') and is equally rapidly eliminated (half-life 30'). Thus, in order to ensure that the patient has the required pharmacological cover with effective, sufficient levels in the blood, it will be necessary to make the individual take the drug orally in the form of a chewable/sublingual tablet at a dosage of 150 mg/tablet. Product: 150 mg APC tablet Description: yellow tablets, 2-3 mm thick and 8 mm in diameter Composition: active principle APC 150 mg Excipients: corn starch 8 mg tribasic citrate 43 mg magnesium stearate 2 mg total 200 mg Manufacturing process: dry mixing, precompression and compression with a rotating tabletting machine Primary packaging: blisters in vivo experimental study: When APC is administered via the intragastric route at doses 100 times greater than those via the i.p. route, there is an increase in P.E., without any stereotypicity being detected. Graph (B) the dose/effect ratio for induction of the penile erection (PE) activity by means of oral apocodeine (APC) in rats. The rats received apocodeine solution or saline solution. The animals were counted in accordance with a double-blind experimental plan. The penile erections were recorded continuously. The penile erection index (PEI) was obtained by multiplying the percentage of rats affected by the average number of penile erections per rat . Table 2. penile erection (PE) induced by oral apocodeine (APC) in rats The number of animals is given in parentheses The effective dose is between 10 and 40 mg/kg, the optimum being 20 mg/kg. Assuming that the theoretical human dosage level is 1/10 of the dosage level for rats, the dosage we are proposing will be: 20 ( x 70) about 140 mg/ dose = 150 mg/tablet 10 SPRAY In support of a patent application entitled: Pharmaceutical compositions (transdermal patches, chewable/sublingual tablets, sprays) comprising apocodeine and/or its derivatives for the treatment of male impotence and for the stimulation of male and female libido. In the abovementioned therapeutic indications , APC is a powerful drug which can be administered orally in the form of a spray. The active principle (APC) is rapidly absorbed, becomes effective rapidly (latency time 8 '-18') and is equally rapidly eliminated (half-life 30'). Thus, in order to ensure that the patient has the required pharmacological cover with effective, sufficient levels in the blood, it will be necessary to make the individual take the drug orally in the form of a spray at a dosage level of 150 mg/dose. Product: APC single-dose spray Description: single-dose bottle with distribution cap (deliverable volume 1 ml) . % composition A. P.: APC and/or its derivatives 15% Menthol 0.84% Thymol 0.40% Tannic acid 1.68% Alcohol 45.00% Purified water 37.08% total 100 The abovementioned formulation is given by way of non-limiting illustration. Manufacturing process : The suspension is prepared at the time of use and is distributed under aseptic conditions into the containers of the distributing machine which automatically closes the bottles by clamping the metering tap onto the neck of the container.

Claims: Claims 1. Pharmaceutical composition comprising APC and/or its derivatives in pharmaceutically acceptable and effective doses. 2. Pharmaceutical composition according to Claim 1, in which the said APC derivatives are organic derivatives or salts. 3. Pharmaceutical composition according to Claim 1, in which the said salt is its hydrochloride salt. 4. Transdermal patch comprising APC and/or its derivatives as active principle. 5. Transdermal patch according to Claim 4 , in which the APC derivatives are organic derivatives or salts . 6. Transdermal patch according to Claim 5, in which the said salt is its hydrochloride salt. 7. Use of APC and/or its derivatives for the preparation of a transdermal patch for the treatment of male impotence and for the stimulation of male and female libido. 8. Chewable/sublingual tablets comprising APC and/or its derivatives as active principle. 9. Chewable/sublingual tablets according to Claim 8, in which the APC derivatives are organic derivatives or salts. 10. Chewable tablets according to Claim 9, in which the said salt is its hydrochloride salt. 11. Use of APC and/or its derivatives for the preparation of a tablet for the treatment of male impotence and for the stimulation of male and female libido. 12. Spray comprising APC and/or its derivatives as active principle. 13. Spray according to Claim 12 , in which the APC derivatives are organic derivatives or salts. 14. Spray according to Claim 13, in which the said salt is its hydrochloride. 15. Use of APC and/or its derivatives for the preparation of a spray for the treatment of male impotence and for the stimulation of male and female libido.

Inventors: BARALDI MARIO, BARALDI, MARIO
Applicants: BARALDI MARIO, UNIHART CORP, BARALDI, MARIO, UNIHART CORPORATION
Application year: 2000
Main classification: A61K9
IPC codes: A61K9, A61K31, A61P15, C07D221