MXPA01011480A - Pharmaceutical compositions comprising apocodeine and/or its derivatives. - Google Patents

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 APOCODE1NA AND / OR ITS DERIVATIVES DESCRIPTIVE MEMORY 5 The disorders associated with reduced sexual potency and a decrease in sexual desire are the most common problems for which adults resort to alternative medical practices instead of conventional medicine, a reason being that it is not possible to reach a 10 safe diagnosis with an adequate pharmacological medication. In addition to bringing together diverse activity, the drugs currently commercially available show the largest and most significant differences with respect to side effects, duration of action and ease of use. 15 These differences are the most important factors to consider when choosing a drug, because these determine both safety and compliance of the patient. In addition, safety of use and compliance make the most noticeable difference in drugs for which instructions are given that improve the quality of life and which are not "lifesaving" drugs. Important considerations regarding the choice of drug for the treatment of sexual impotence in men and for the stimulation of libido of men and women, involve the effects Secondary forced to be induced and security of use in a regime of self-administration. The current limitations in the treatment of impotence and in the stimulation of desire are due to the fact that there are effective drugs, 5 but they can only be used with extreme care considering the numerous and extremely serious side effects that can be induced, and there are also drugs effective which, although they do not present side effects, require highly sophisticated production technology, as a result of which, the product marketed is 10 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 different medicinal forms (patches, tablets, aerosols), overcomes the current limitations of the treatment in use to treat the pathologies in question, since, in the forms and doses 15 proposals, 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: 20 Pharmaceutical compositions (transdermal patches, chewable / sublingual tablets, including APC) and its derivatives, for the treatment of male impotence and for the stimulation of male and female libido.

(Pharmaceutical compositions (transdermal patches, tablets • ** a * ¿- ^ ~~ -. chewable / sublingual, aerosols) comprising apocodeine (APC) and / or its derivatives, for the treatment of impotence in men and for the stimulation of libido of men and women). The APC molecule and its derivatives are stable with respect to air and light. In the therapeutic indications mentioned above, APC is a potent drug that can be administered transdermally. The active principle (APC) is rapidly absorbed, quickly becomes effective (latency time 8 '- 18') and is also rapidly eliminated (half-life 30 '). Thus, in order to ensure that the patient has the required pharmacological coverage with effective, sufficient and constant levels in the blood, it will be necessary to have the individual take the drug in the physiological dose through the transdermal route for the time required to meet expectations. For transdermal administration, it will be sufficient to apply a slow release patch (TDDS = transdermal drug delivery system), referred to below as a TDDS patch, based on APC in order to provide coverage for approximately 8 hours. Three basic types of TDDS patch can be prepared, as schematically depicted in Figures 5, 5A and 5B.

Therefore, an objective of the present invention is a pharmaceutical composition comprising, in pharmaceutically acceptable and effective doses, APC or its derivatives. A further objective of the invention is a transdermal park comprising, as active principle, APC and / or its derivatives, this patch having a structure type I, type II or type III, and its shape and size being adequately dimensioned in relation to the application site and the desired dosage. A further objective of the invention is the use of APC and / or its derivatives, for the preparation of a transdermal patch for the treatment of impotence in men and for the stimulation of libido of men and women. You can prepare three basic types of transdermal patch (TDDS patch): Type It is a device comprising an impermeable supporting film in which is a matrix or tank in which an active substance is dissolved and / or dispersed. The matrix, on the side opposite the support, is coated with a membrane that is permeable to the active substance and regulates its cross-flow. An adhesive contact is formed in layers on the free side of the permeable membrane (adhesive layer), protected by a release band. The device is used as follows: the release band is detached and the device is placed on the desired part of the patient's body and applied with light pressure.

Type II: This device comprises an impermeable support film in which there is a matrix or tank in which an 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, like a kind of adhesive ring. The assembly is protected on the free side by a simple movable release band, as in type I. The device is used as follows: the release band is detached and the device is placed on the desired part of the patient's body and Apply 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 also acts as a reservoir matrix and is formed in layers on an impermeable support film. The deposit matrix is protected on one side by the support (reinforcement), and on the other side by the release band. He • ÉMütMi, **, "**" device is used as follows: the release band is detached and the device is placed on the desired part of the patient's body and applied with light pressure. The differences between the structures and shapes (rectangular or anatomical 5) of the three types of patch are specifically designed to compensate: • the interactions that may exist between the active principle, the adhesive (different types of adhesive can be used at the same time) ), support material and other materials, such as excipients, 10 stabilizers, etc. • improved stability at the preselected site of application • dosage (larger surface area = higher dose) In the present invention, in consideration of the physicochemical properties of APC and / or its derivatives, the preferred patch is the type 15 lll patch , and in particular the lll-type patch with acrylic adhesives, in rectangular form when it is desired to achieve constantly high doses for long periods, or in anatomical form when a rapid directed result is desired (for example, treatment of sexual impotence). The present invention will now be illustrated through its illustrative, non-limiting examples, in which reference will be made to the following figures, using analytical results obtained with a rectangular standard type lll of 40 cm 2. ^ & É mg ^ ¡u ^ j Figure 1 is a graph of the accumulation of APC over time. Figure 2 is a graph of the flow of APC over time. Figure 3 is the approximate curve representing the levels in human plasma at the indicated times, in relation to the active principles of APC. Figure 4 is a graph of the PE index on Logarithmic Doses (μg / kg). Figures 5, 5A and 5B are three basic types of TDDS patch represented schematically.

Method to manufacture the transdermal patch type III 1. The APC active ingredient or a derivative thereof is incorporated simultaneously with the other components (stabilizer, penetration activators, etc.) into the hot adhesive solution and is homogenized by stirring until the liquid adhesive matrix or deposit is formed; 2. the liquid adhesive matrix cools and acquires a "fibrous" consistency; 3. The process of lamination of the adhesive matrix in the support is carried out using a laminating machine continuously linked to a drying machine, according to the following phases: A. the blade of a blade is mounted across the full width of the conveyor belt of the laminating machine in which the release band is solidly placed; B. the "fibrous" adhesive matrix is poured in front of the blade which, as the conveyor belt advances, distributes a uniform layer (lamination) of adhesive matrix on the release band; C. the thickness of the layer is determined primarily by the distance between the edge of the blade and the release band passing under it; D. the release band, 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 FIG. scheme I later.

CUADR0 1 Drying phase Time (in minutes) T ° C Vent. (rpm) 1 15 40 700 700 20 20 1000 3 25 70 ° 1200 The described procedure allows the removal of the solvent, thus preventing its occlusion by the rapid formation of a surface crust. 4. Once the adhesive matrix has dried, the support film (reinforcement) is attached. This phase, known as "lamination" concludes the procedure. The procedure is described in the literature (9B, 10B, 11B) and produces a patch of TDDS in which the adhesive matrix is protected, on the one hand by the "reinforcement" and, on the other hand, by the movable release band. 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 TDDS patch type lll Adhesive matrix: formulation • active ingredient: APC or its derivatives; • antioxidant: sodium metadisulfite, disodium EDTA salt; • solubilization agent: a glycol; • Penetration activator: fatty acids; • acrylic resin to improve the cohesive strength: cationic copolymers based on dimethylaminoethyl methacrylate and methacrylic esters; • cellulose derivatives to improve the strength of ethylcellulose; - * - * - • surfactant: SDS (sodium dodecyl sulfate); • pressure contact adhesive: a mixture of two adhesives, A and B, in which A is an average-weight, non-self-adhering acrylic contact adhesive, with a high interlacing index, a skin irritation index of 0.20", classified as" minimally irritating "and containing 100% ethyl acetate as a solvent, and B is a high molecular weight acrylic adhesive, which self-monitors, with a moderate interlacing index, a skin irritation index of 0 , classified as "non-irritating" and containing a mixture of ethyl acetate, isopropanol, hexane and toluene as solvent.

Release band The release band is a polyester film laminated with silicone on one side (the side facing the adhesive matrix). The thickness is approximately 125 μm.

Reinforcement The reinforcement is a laminated polyester film, clear, occlusive, with a hot welding layer. The total thickness is approximately 51 μm.

Amount of active ingredient The amount of APC or its derivatives, referred to as APC, is 5% by weight of the adhesive matrix and corresponds to 5 mg / cm2 in the patch of TDDS. Most of the drug is dispersed in the matrix and acts as a reservoir, while the drug that is available for release and penetration is the dissolved drug.

Efficacy of application of the transdermal patch based on APC v / o its derivatives For this purpose, different batches of patches of different formulation containing APC and / or its derivatives were prepared. Using the technique of in vitro cellular penetration, recommended by the US FDA (1B, 2B, 3B), the following results were obtained, for example, with three different formulations given below, in which the pharmacologically active molecule was used as a starting point active of APC: Lot of APC / A, with the addition of penetration inductors: 1) APC 2.00% 2) Sodium metabisulfite 0.20% 3) Solubility 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% Lot of APC / B with the addition of penetration inductors, 4.5% of active principle dispersed in the matrix (deposit), 0.5% of active principle dissolved in the matrix. 1) APC / B 4.99% 2) Sodium metabisulphite 0.50% 3) EDTA 0.025% 4) Solubilization agent 9.96% 5) Fatty acid 1 7.96% 6) Fatty acid 2 3.97% 7) Acrylic resin 1.99% 8) Derivative of 0.25% cellulose 9) Surfactant 19.90% 10) Pressure sensitive adhesive 50.455% Lot of APC / C, with the addition of penetration inducers, 0.5% of active principle in the matrix (all the drug is dissolved): 1) APC / C 0.55% 2) Sodium metabisulfite 0.50% 3) EDTA 0.025% 4) Solubilization 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% Experimental results The in vitro penetration study with guinea pig skin, carried out in accordance with the aforementioned procedures, gave a penetration rate equal to the values reported in figure 1 (total amount) and figure 2 (flow) in the different times. The previously reported in vitro penetration data were analyzed by means of one of the most suitable pharmacokinetic models for the transdermal administration of drugs (10B, 11B), obtained with a patch of 40 cm2 (5 x 8 cm) and the following constants : Molecular weight 331.8 Water / alcohol distribution coefficient 0.05 Half-life 45 'Distribution volume 132 liters The approximate curve representing the levels in human plasma at the indicated times, in the case of application of a single patch of NPA / B, is illustrated in figure 3. It can be concluded that the skin permeability of APC is sufficient per se and can be increased or decreased by means of different penetration activators, such as fatty acids or alcohols. All the in vitro penetration studies were carried out in models using guinea pig skin, of which it is known to have permeability comparable to that of human skin and which gives more reproducible results than the latter. The chemical stability of APC in the patch formulation is achieved by adding an antioxidant (sodium metabisulfite) and is demonstrated by an accelerated stability test of 15 days at 40 ° C and 75% RH (relative humidity).

The surfactant (SDS) is added to dissolve most APC, since only dissolved APC is available for release and penetration. The patches also demonstrated good physicochemical properties, which those skilled in the art can optimize for the purposes of adhesion at the site of application and tolerance on the part of the individual undergoing treatment, without modifying the penetration rate of the active ingredient.

BIBLIOGRAPHY 1 B. Gummer LC, Chapter 9. The in vitro Evaluation of Transdermal Delivery. In Transdermal Drug Delivery Developmental Issues and Research Initiatives, edited by Hadgraft T 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 YW. 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. Rev. 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 electromechanical 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) 11 B Elias JJ, Chapter 1, The Microscope Structure of the Epidermis and its Derivatives. In Percutaneous Absorption, edited 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. 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 Compact 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, including apocopoine and / or its derivatives for the treatment of male impotence and for the stimulation of male and female libido. (Pharmaceutical compositions (transdermal patches, chewable / sublingual tablets, aerosols) comprising apocodein and / or its derivatives for the treatment of impotence in men and for the stimulation of libido of men and women). In the therapeutic indications mentioned above, APC is a potent drug that can be administered orally.

The active principle (APC) is rapidly absorbed, quickly becomes effective (latency time 8 '- 18') and is also rapidly eliminated (half-life 30 '). Thus, in order to ensure that the patient has the required pharmacological coverage with effective, sufficient and constant levels in the blood, it will be necessary to have the individual take the drug orally in the form of a chewable / sublingual tablet in a dosage of 150 mg /Tablet.

Product: APC 50 mg tablet Description: yellow tablets, 2-3 mm diameter esp Composition: active ingredient 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 machine for tablet formation. Main packaging: ampoules Experimental study in vivo: When APC is administered through the intragastric route in doses 100 times greater than those through the intraperitoneal route, there is an increase in P.E., without detecting any stereotypicity. Figure 4 shows: (B) the dose / effect relationship for induction of penile erection (PE) activity by oral apocodein (APC) in rats. The rats received apocodein solution or saline solution.

The animals were counted according to a double blind experimental plan. 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 f PE) induced by oral apocodein (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 dosage level in humans is 1/10 of the dose level for rats, the proposed dose will be: 20 (X 70) approximately 140 mg / dose = 150 mg / tablet 10 Aerosol In support of a request for patent titled: Pharmaceutical compositions (transdermal patches, chewable / sublingual tablets, sprays) comprising apocopoine and / or its derivatives for the treatment of male impotence and for the stimulation of male and female libido. (Pharmaceutical compositions (transdermal patches, chewable / sublingual tablets, aerosols) comprising apocodein and / or its derivatives for the treatment of impotence in men and for the stimulation of libido of men and women). In the therapeutic indications mentioned above, APC is a potent drug that can be administered orally in the form of an aerosol. The active principle (APC) is rapidly absorbed, quickly becomes effective (latency time 8 '- 18') and is also rapidly eliminated (half-life 30 '). Thus, in order to ensure that the patient has the required drug coverage with effective and sufficient levels in the blood, it will be necessary to have the individual take the drug orally in the form of an aerosol at a dosage level of 150 mg / dose. Description: Single dose bottle with dispensing cap (volume that can be supplied 1 ml).

Percentage of 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 aforementioned formulation is given by way of non-limiting illustration.

Manufacturing procedure: The suspension is prepared at the time of use and is distributed under aseptic conditions in the containers of the distribution machine, which automatically closes the bottles when holding the dosing cap to the neck of the container.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. Chewable / sublingual tablets, characterized in that they comprise 150 mg of apocodein per dosage unit.

2. The tablets according to claim 1, further characterized in that the apocodein is in the form of a pharmaceutically acceptable salt.

3. The tablets according to claim 2, further characterized in that said salt is its hydrochloride salt.

4. Use of apocodein or a pharmaceutically acceptable salt thereof for the preparation of a chewable / sublingual tablet for the treatment of impotence in men and for the stimulation of libido of men and women.

5. An aerosol characterized in that it comprises 150 mg / dose of apocodein as an active ingredient.

6. The aerosol according to claim 5, further characterized in that the apocodein is in the form of a pharmaceutically acceptable salt.

7. The aerosol according to claim 6, further characterized in that said salt is the hydrochloride salt.

8. - Use of apocodein or a pharmaceutically acceptable salt thereof for the preparation of an aerosol for the treatment of impotence in men and for the stimulation of libido of men and women.