PHARMACEUTICAL PREPARATIONS AND METHODS FOR ITS REGIONAL ADMINISTRATION
The present invention relates to pharmaceutical preparations, and in particular to pharmaceutical formulations that can be introduced, topically, locally, intrapelvic, intraperitoneally or directly into the reproductive organs of interest in effective amounts to treat various conditions, in particular local diseases of the female reproductive system , for example, pelvic, uterine, cervical and vaginal diseases that are present in this region of the body. BACKGROUND OF THE INVENTION It has long been known that the treatment of women's reproductive diseases with traditional methods of oral or systemic administration is related to problems of bioavailability of the drug and the concomitant complications of side effects due to unwanted absorption. of drugs in the systemic circulation. For example, the normal action of the digestive tract can decompose the orally administered active ingredients to decrease the efficacy of the drug delivery doses, or the pharmaceutical preparation can be modified by the passage through the liver or by the systemic circulation, or perhaps not achieve the appropriate levels in the area of interest. To counteract these undesirable actions, the dose of the active ingredient must be increased, which often leads to undesirable side effects. Danazol, an isoxazolo derivative of 17aeteniltestosterone (an androgenic hormone), is commonly administered to women for the treatment of endometriosis, at a dose of up to 800 mg daily. At high doses, adverse side effects are seen among which highlight weight gain, change of voice, appearance of facial and chest hair, loss of libido, acne and systems in the central nervous system ("CNS") , for example, depression, anxiety, fatigue, nausea, diarrhea, as well as the inhibition of pregnancy during treatment. Consult, for example, Spooner, Classification of Side Effects to Danazol Therapy, Winthrop Laboratories, Surrey, England. Therefore, it is highly desirable to provide new systems and methods for the administration of pharmaceutical products that would avoid such inconveniences. Mizutani, describes the administration of danazole vaginally with a suppository of 100 mg, and compared the results with oral administration with a dose of 400 mg. No effect on the hypothalamic-pituitary-ovarian axis was noted, although high concentrations were present in the ovary, uterus and serum, with negligible levels of serum, after vaginal administration. Mizutani, et al. , conducted their study according to a report by Igarishi, Asia-Oceania J. Obstet. Gynaecol 16 (1), 1-12 (1990), in the sense that the administration of danazole in a silicone vaginal canal reduced the endometrial tissue in the uterus and increased the incidence of pregnancy in treated women to a statistically significant degree. . The immediate disadvantage of both therapies, however, is that the formulation and delivery platform, for example, vaginal rings and other devices, are particularly unsatisfactory for women who already suffer the colic and pain related to endometriosis. The doses that were applied were also quite high and extremely variable and may have had a negative and cumulative deposit effect. The Igarashi implant and other proposed danazole formulations for the local release of danazol for the treatment of endometriosis, in which the effect is achieved by direct administration of the danazole to the tissue to be treated are described in the United States Patent. Number 4,997,653 granted to Igarashi and EPA 0 501 056 (col 2, lines 24-29 cf, the United States patent). Many other drug delivery systems are available, but they have not been invented for this purpose. Examples include U.S. Patent Number 3,921,636 issued to Zaffaroni, which describes a drug supply reservoir for the controlled and sustained release of water-soluble materials, as a function of the diffusion of water in the device and the dissolution of the device. drug to be released for the systemic or local effect (col 10, row 46). EPA 0 566 135 of Takeda Chemical Industries describes a preparation for the systemic delivery of proteins or peptides through the mucosal regions, for example, the mouth or the vagina, wherein delivery is enhanced by the inclusion of a derivative of a nucleotide of cytidine. WC 96 37232 of the University of Santiago de Compostela describes complexes of nanoparticles, emulsions or nanocapsules within a matrix formed by the formation of ionic complexes of a positively charged and water-soluble amino polysaccharide, and a negatively charged phospholipid, which They are useful for local or transmucosal administration of medications. WO 95 07071 of Edko Trading describes an ointment or cream for the intravaginal administration of antifungal drugs. U.S. Patent Number 5,510,116 issued to Nanosystems describes the preparation of a powder consisting exclusively of drug nanoparticles, for example, danazole, which is very soluble and, therefore, advantageous for systemic administration by injection. It is, therefore, an object of the present invention to provide formulations that are effective in treating conditions of the reproductive organs that are highly adapted to patients and are comfortable for them. It is a further object of the present invention to provide formulations and methods of administration which facilitate the extremely rapid absorption of the medicament in the affected region, with low systemic concentrations and few concomitant side effects. It is still another object of the present invention to provide a much greater bioavailability of medicament in formulations administered topically or locally, intrapelvic, intraperitoneal or directly in the reproductive organs of interest, in comparison with drugs administered in controlled release devices. COMPENDIUM OF THE INVENTION Formulations have been invented for the topical or local delivery of intrapelvic, intraperitoneal or directly into the organs of interest, to produce a regional effect, with lower levels of systemic medication than those obtained when an effective dose is administered systemically . In a preferred embodiment, the drug is administered to a region, for example, the female reproductive system, provides greater "comfort, greater bioavailability, fast and relatively high blood levels in the region to be treated, without causing systemic levels of the drug that could cause side effects The preferred formulations consist of micro or nanoparticles of drug, which can be formed with the drug alone or in combination with a carrier or polymer vehicle The excipient or polymer can be used to manipulate the release rates and to increase " the adhesion of the medicine to the affected region. The formulation of the medicament can be applied in the form of a dry powder, a liquid suspension or dispersion, a suspension or dispersion of hydrogel, sponges, or as an ointment, cream, lotion, foam or local suppository. Specific formulations of danazole are described. The studies in rats demonstrate the rapid absorption of danazole in affected tissues in endometriosis, with drug levels in serum that are almost undetectable. DETAILED DESCRIPTION OF THE INVENTION The compositions and methods for the administration thereof provide considerably lesser side effects with greater bioavailability and comfort, in comparison with conventional drug administration techniques, and avoid the need for oral and parenteral administration, the use of expensive biocompatible polymeric material, and the insertion into the body and the maintenance there of potentially infectious foreign objects, for example , intrauterine devices, vaginal rings and suppositories .. Formulations: The formulations are designed to facilitate maximum absorption in affected tissues with rapid spread throughout the region to be treated, with little or no increase in systemic blood levels of the drug. The formulations may consist only of the drug, the drug combined with excipient or polymeric material A. Medications The term "medication" may refer to any pharmaceutically active substance capable of being administered in a particulate formulation, which achieves the desired effect. medications can be natural synthetic or organic compounds, proteins or peptides, oligonucleotides, or polysaccharides or sugars. The medicaments may have any of several activities, which may be inhibitory or stimulatory, for example, antibiotic activity, antiviral activity, antifungal activity, steroid activity, cytotoxic or anti-proliferative activity, anti-inflammatory activity, analgesic or anesthetic activity, or may be useful as a contrast or other diagnostic agents. A description of the classes of drugs and species within each class can be found in Martindale, The Ext Pharmacopei, 31st edition, The Pharmaceutical Press, London (1996) and in Goodman and Gilman, The Pharmacological Basis of Therapeutics, (9th edition) , McGraw-Hill Publishing Company (1996)). Progestins, estrogens, antiestrogens and antiprogestins are examples of compounds with steroid activity. In a preferred embodiment, the drug is danazole or gestrinone in a micro or nanoparticle formulation. This can be achieved by spraying the medicament or by spraying the solution "of the medicament, for example, in a solvent extraction liquid, or other normal techniques." Danazole or gestrinone may be present as a complex with a cyclodextrin, for example, hydroxypropyl-β-cyclodextrin (HPB) In another preferred embodiment, the medicament is a polysaccharide, preferably a sulfated polysaccharide Examples of suitable sulfated polysaccharides are carageenan, dextran sulfate, heparin and fucoidin. B. Excipients and vehicles The drug substance may be "associated" in any physical form with a particulate material, for example, adsorbed or absorbed, adhered or dispersed or suspended in said matter, which may take the form of discrete particles or microparticles in any medicinal preparation, or be suspended or dissolved in a vehicle, for example, an ointment, gel, paste, lotion, sponge or dew. "" ~
Gelatin, "casein, lecithin, acacia gum, cholesterol," tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, and alcohol are among the normal excipients cestearyl, the cemacrogol emulsifying wax, the sorbitan esters, the polyoxyethylene alkyl ethers, the polyoxyethylene castor oil derivatives, the polyoxyethylene sorbitan grade acid esters, the polyethylene glycols, the polyoxyethylene stearates, the colloidol silicone dioxide, phosphates, sodium dodecylsulfate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, non-crystalline cellulose, aluminum magnesium silicate, tretanolamine, polyvinyl alcohol, polyvinylpyrrolidone, sugars and "starches" C. Polymeric materials. In a preferred embodiment, the medicament is present in or within micro or nanoparticles formed with a polymeric material. Additional materials may optionally be included in the particles, eg, diagnostic agents, including echogenic gases, radioactive materials (which may also be therapeutic by themselves) and magnetic materials for detection by MRI (Magnetic Resonance Imaging, by their acronyms in English) or PET (Positron Emission Tomography, for its acronym in English). Several polymers can be applied to increase adhesion to mucosal surfaces, to control the release as a function of the drug's diffusion speed outside the polymer matrix or the rate of degradation by hydrolysis or enzymatic degradation of the polymers or the alteration of the pH, and to increase the surface area of the drug in relation to the particle size. The polymers can be natural or synthetic, and can be biodegradable or non-biodegradable. Medicines with high molecular weight can be partially supplied by diffusion, but mainly by degradation of the polymer system. For this reason, biodegradable polymers, bioerodible hydrogels and protein delivery systems are particularly preferred when high molecular weight drugs are supplied. The polymers may be natural or synthetic polymers, although synthetic polymers are preferred given the better characterization of the degradation and release profiles. The polymer is selected based on the period during which release is desired, generally in the range of at least immediate release to release over a period of twelve months, although longer periods may be desirable. In some cases linear release can be very useful, although in others a pulse release or "volume release" can provide more effective results. The polymer can also be in the form of a hydrogel (typically absorbing up to 90% by weight of water) and, optionally, can be cross-linked with multivalent polymers or ions. Among the representative natural polymers are proteins such as zein, modified zein, casein, gelatin, gluten, serum albumin, and collagen, polysaccharides such as cellulose, dextrans and polyhyaluronic acid. Representative polymers include polyphosphazenes, polyvinyl alcohols, polyamides, polycarbonates, polyacrylates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, de-pslivinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes.
polyurethanes and their copolymers. Examples of suitable polyacrylates are polymethyl methacrylate, polyethylene methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, polyisodecyl methacrylate, polylauryl methacrylate, polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate, polyisobutyl acrylate and polyoctadecyl acrylate. Synthetically modified natural polymers include cellulose derivatives, for example, alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and nitrocelluloses. Examples of suitable cellulose derivatives are methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxybutylmethyl cellulose, cellulose acetate. , cellulose prspionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate and cellulose sulfate sodium salt. Each of the polymers described above can be obtained from commercial sources such as Sigma Chemical Co., of St. Louis Missouri, Polysciences, Warrenton, Pennsylvania, Aldrich Chemical Co. , Milwaukee, Wisconsin, Fluka, Ronkonkoma, New York and BioRoad, Richmond California, or can be synthesized from monomers obtained from these suppliers using normal techniques. The polymers described above can be characterized separately as biodegradable, non-biodegradable and bioadhesive polymers, as discussed in more detail below. 1. Biodegradable polymers Synthetic polymers include polyhydroxy acids, for example, polylactides, polyglycolides and copolymers thereof, polyethylene terephthalate, polybutyl acid, polyvaleric acid, polylactide-co-caprolactone, polyanhydrides. , the polyorthoesters and the mixtures and copolymers thereof. Among the natural biodegradable polymers are polysaccharides, for example, alginate, dextran, cellulose, collagen and their chemical derivatives (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations and other modifications made routinely by those skilled in the art), and proteins, for example, albumin, zein and copolymers and mixtures thereof, alone or in combination with synthetic polymers. In general, these materials are degraded either by enzymatic hydrolysis or by exposure to water in vivo, by surface or volume erosion. 2. Non-biodegradable polymers Examples of non-biodegradable polymers are ethylene vinyl acetate, polymethacrylic acid, polyamides, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinylphenol, and copolymers and mixtures of these. 3. Bioadhesive polymers Hydrophilic polymers and hydrogels tend to have bioadhesive properties. Hydrophilic polymers containing carboxylic groups (e.g., polyacrylic acid) tend to show the best bioadhesive properties. Polymers with the highest concentrations of carboxylic groups are preferred when soft tissue bioadhesivity is desired. Several cellulose derivatives, such as sodium alginate, carboxymethylcellulose, hydroxymethylcellulose and methylcellulose, also have bioadhesive properties. Some of these bioadhesive materials are soluble in water, while others are hydrogels. Quickly bioerodible polymers, for example, polylactide-co-glycolide, polyanhydrides and polyorthoes, whose carboxylic groups are exposed on the outer surface as their smooth surface is eroded, can also be used for bioadhesive drug delivery systems. In addition, polymers containing labile bonds, for example, polyanhydrides and polyesters, are famous for their hydrolytic reactivity. Their rates of hydrolytic degradation can usually be altered by simple changes in the polymer backbone. After degradation, these materials also expose the carboxyl groups of their outer surface and, consequently, these can also be used for bioadhesive drug delivery systems. D. Hydrogel matrices In another preferred embodiment, the medicament is present in the form of a micro or nanoparticle dispersion in a hydrogel matrix. The hydrogel matrix can be applied to cause the particles to remain in a particular location for a prolonged period of time, particularly when the hydrogel adheres to the surface of the tissue. The application of hydrogels to provide local drug delivery is described, for example, in U.S. Patent Number 5,410,016 issued to Hubbell et al. The particles to be incorporated in the hydrogel matrix can be formed solely with the medicament, or they can include the excipients or polymers described above. The drug can also be added to the matrix in the form of a dispersion or solution. The drug can be released from the particles through the dissolution of the particles, the hydrogel or both. Suitable hydrogels can be formed from synthetic polymers, for example, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylates, polyethylene terephthalate, polyvinyl acetate, and copolymers and mixtures of these, as well as natural polymers, for example, cellulose and it alginate, as described above. Among the exemplary materials, SEPTRAFIL ™ (sodium hyaluronate / modified carboxymethylcellulose, Genzyme)
Pharmaceuticals) and INTERCEED ™ (regenerated cellulose, Johnson &Johnson Medical, Inc.). II. Methods of administration The formulations are preferably administered locally within the region to be treated, for example, vaginally for the treatment of diseases of the ovaries and uterus. As used herein, "locally" may refer to topical application, generally on the surfaces of the mucosa or endometrium of the vagina or uterus, or to a particular portion of the vagina or uterus. As used herein, "regionally" refers to the reproductive organs and their surroundings, which include the uterus, the fallopian tube, the peritoneal space, the pelvic cavity, the ovaries, the perineum, the abdominal region, the rectovaginal region and the corresponding regions in males, and the urogenital tract, including the bladder, the urinary tract and the rectum. As used herein, "systemically" refers to the circulatory system and regions outside of the spaces described above. Pharmaceutical preparations administered vaginally, as described herein, are particularly effective in treating certain diseases of the female reproductive system, for example, the administration of danazol for the treatment of endometriosis, and in the treatment of other conditions. as urinary incontinence. It is desirable to administer the danazol formulations locally at doses that are lower than other delivery modalities, for example, oral delivery. In general, it has been found that transdermal doses are one quarter of the oral dose to obtain a similar efficacy. In this instance, it is possible to further decrease the dose (the ring supplied approximately 1 and 2 mg / day). Such dose administration "will ensure negligible or relatively low serum danazol levels to avoid undesirable side-effects related to oral" dosing, eg, hirsutism and other androgenic side effects. The following non-limiting examples more fully demonstrate the present invention. EXAMPLE 1: preparation of the gel products The drug substance, micronized danazol
(with Medication Master File Certification - DMF) was manufactured by Cipla Pharmaceuticals and was acquired from Byron Chemical Company. The drug substance was identified by UV absorption and was found to be identical to Danazol USP. It was noted that the individual impurities were not greater than 0.5%, and the total impurities gave "no more than 1.0% .The dry test was between 97% and 102% w / w of the dry base. particles were less than 5 microns in diameter and the remaining particles were between 5 and 15 microns in diameter.The micronised danazol was levigated in a commercial preparation of Jelly KY, which is composed of a hydroxyethyl cellulose polymer at 10 ml volume ( based on "weight, using a jelly density of 2.16 g / ml) to deliver a dose of 12 mg in 50 μl. The gels were smooth, uniformly white and fluid. Measurements of particle sizes were made with a Coulter particle size analyzer H4mD and s annotated as follows: Danazol powder:
Average of 6 measurements 3.2μg Individual measurement and variation 3.2μg ± 9μg 1 mg of gel: Average of 5 measurements 3. Oμg Individual measurement and variation 3.4μg + 1.5μg EXAMPLE 2: Administration to rats of microparticulate danazole formulation They were used for this experiment rats of the Sprague-Dawley strain. 1 mg of microparticulate danazol was supplied in a volume of 50 μl to the vaginal vault and the animals were sacrificed at the times indicated below: The uterus and the ovaries were separately homogenized and the blood was drawn. All weaves and biological samples were processed. The danazol was extracted and its assay was carried out using the HPLC methodology. Clinical trial of danazol: Danazol was extracted from serum and hexane / chloroform 80/20 tissue. For the tissues an aliquot of 1 ml was taken for each homogenized tissue. Danazol-extracted was reconstituted in a mobile phase of water / acetonitrile and a Beckman Ultrasphere of 5 microns, a 4.6 mm x 15 cm reversed phase column (C-18 RP) was used for all HPLC analyzes. A study of the recovery of danazol was carried out using the drug product of danazol. Recovery was determined by comparing the "extracted with the" non-extracted signal. A recovery of between 75 and 84% was obtained for "the extraction method." - Results of the study: Tissue and serum levels are summarized below in "Table 1: Table 1: Danazole levels in tissue and serum of rats SPEED AND UTERO- ng / g OVARIES ng / g SERUM ng / ml TIME
2 hours 0.43 0.33 0.21
4 hours 0.57 not detected not detected
6 hours 0.77 not detected not detected The results of this study show that the formulation used produced a preferential absorption of danazol in the uterus. In the above examples, concentrations of 1 mg per rat of 300 g of weight were administered. In the work of Mizutami, danazol concentrations of 100 mg per woman weighing 50 kg were administered. These concentrations are approximately equivalent. The data show that the suppository used by Mizutami caused uterine concentrations of danazol that were 105 times higher than the uterine concentrations of danazol provided by the microparticles of the previous examples. Such high local concentrations could result in considerable changes in the local supply of the "drug and the effects on the reproductive organs, for example, changes in the steroid sensitivity of the hormones and the effect of deposition." Igarashi administered a vaginal ring contained in silicone. This type of medication delivery device releases the medication on a constant basis, creating a continuous flow of medication and potentially a reservoir effect. Igarashi presents two examples in which danazol is administered through a vaginal ring. In both examples, the uterine concentration of danazol was 100 times higher than the uterine concentration of the previous examples. EXAMPLE 3: protocol for studies in primate models for endometriosis. The formulation of microparticles allows a considerable reduction of the dose delivered, greater bioavailability for the organs of interest with lower concentrations in tissues. Monkey protocol: The study with monkeys will demonstrate the efficacy of the microparticle formulation in an animal model of endometriosis, while also assessing the levels of "locally supplied danazol.The simian model for 'endometriosis will be applied to demonstrate the efficacy and safety The reason to use monkeys is to discover that certain monkeys will develop endometriosis naturally which is crucially similar to human disease, and monkeys are a good model to study the female reproductive system, both anatomically and physiologically, to test a vaginal product such as Danazol TVDT This study will help identify the dose required to treat human endometriosis and, in addition, to corroborate the preliminary evidence that danazol can be given vaginally for treatment of endometriosis with lower systemic levels. particles can be formulated in the presence of polyvinylpyrrolidone. I know "they will study three doses of Danazol TVDT in monkeys with endometriosis and they will be compared with orally administered danazol as described below." The study will be a nine-week, randomized, parallel study comparing the effects of oral danazol delivered in doses of 200 mg daily and three doses of Danazol TVDT: at 10 mg / day, - (one twentieth of the oral dose), 25 mg / day (one tenth of the oral dose) and 50 mg / day (one quarter of the oral dose) The results will demonstrate that the local supply of danazol in microparticles results in efficacy and low systemic levels.