COMPOSITION FOR SUPPLEMENTAL TREATMENT OF MALE CLIMACTERIC

Abstract: A unique composition for treatment of the psychologic, somatic and endrocrinologic clinical entities of male climacteric comprising pituitary and hypothalmic glandular concentrates and orchic concentrates as sources of hormonal precursors, selected vitamin supplement and an essential mineral supplement and substantially equivalent amounts of thiamine hydrochloride and L-glutamic acid.

Description: COMPOSITION FOR SUPPLEMENTAL TREATMENT OP MALE CLIMACTERIC Technical Field The present invention generally relates to pharmaceutical compositions for the treatment o ' male climacteric or impotence, and, in particular, to a therapeutic composition as an adjunct to traditional climacteric therapy. Background of the Invention It is now understood that male climacteric, i.e. the decrease in sexual function occuring in human males during the late fourth decade and throughout the fifth decade of life, is a composite of psychologic, somatic and endocrinologiσ clinical entities. From the standpoint of endocrinology, male climacteric occurs through the decrease in secretion of testosterone, though not as rapid a decrease in sexual hormonal secretion as that associated with female menopause. The decreased presence of testosterone adversely affects spermatogenesis which occurs within the seminiferous tubule cells of the testes. Spermatogensis is assisted by the presence of testosterone secreted by interstitial cells of Leydig proximally associated with the seminiferous tubules. Because of the depressed levels of testosterone and consequent decrease in spermatogenesis, the seminiferous tubules undergo degeneration and aplasia. Spermatogenesis is the result of complex hormonal pathways. Specifically, the hypothalmus secretes a release hormone or factor which acts upon the anterior pituitary to secrete two types of gonadotropic hormones, namely follicle-stimulating hormone (FSH) and luteinizing hormone (LH) . Though LH ' is often associated with ovulation in the female, it also stimulates the production of testosterone by the interstitial Leydig cells of the testes. Likewise, secretion of FSH by the anterior pituitary gland directs spermatogensis by the seminiferous tubules. The levels of LH and FSH are controlled through negative feedback regulation by the qualtity of hormone produced by the target or end- organ. For LH regulation, the increased presence of testosterone has an inhibitory affect on the further production and secretion of LH by the anterior pituitary as well as on the production and secretion of LH/FSH - release hormone by the hypothalmus. In regulation of the level of FSH, spermatogenesis itself, in some unexplained way, inhibits the further secretion of FSH by the anterior pituitary and release hormone by the hypothalmus. The additional testicular hormone, (not testosterone) responsible for the inhibitory feedback of FSH has been called inhibin. As a result of the above-described regulatory mechanisms levels of both LH and FSH in male climacteric are increased because of the absence of inhibitory feedback by testosterone or inhibin, respectively. In the literature of the prior art, the above-described hormonal imbalances associated with male climacteric were treated by replacement therapy, i.e. direct injection of testosterone or one of its derivatives, such as testosterone propionate, cyclopentylpropionate, enanthate or methyltestosterone. In addition to replacement therapy, gonadal stimulation therapy also has been conducted through use of human chorionic gonadotropin. Etter, Hypogonadal Impotence In Middle-Aged Men, 17 Arizona Medicine, No. 4 pp. 217- 220 (Apr. 1, 1960). Notwithstanding the endocrinologic aspects of male climacteric, there is also associated certain psychological symptoms. The male climacteric is psychologically profiled as having excessive fatigue, loss of business and social interest, loss of libido, irritability, insominia, and anorexia. The composition of choice in the treatment of the psychological symptoms of male climacteric has been human chorionic gonadotropin fortified with thiamine hydrocloride and L(+) glutamic acid. This fortified composition had been recognized as being therapeutically more affective as it addressed both the endocrinologic and psychologic aspects of climacteric. See, 17 Arizona Medicine, pp. 217-220 referred to above. Of course, thiamine hydrocloride, commonly Vitamin B^, is a recognized antineuritic whereas the L- stereoisomer of glutamic acid acts as a stimulant of the central nervous systems. However, no known therapeutic composition exists which, when administered by itself or, as a supplement to replacement therapy or gonadal stimulation therapy, contains components for treatment of the psychologic, somatic and endocrinologic clinical entities associated with male climacteric. Given the complexities presented by these clinical entities, it was often difficult for the physician to specifically diagnose the precise origin of climacteric. Hence, a need existed for a composition which treats male climacteric on an etiological holistic basis. Further, the composition should also provide nutritive support for cellular and subcellular structures upon re-initiation of testosterone secretion and spermatogenesis. summ ry of the Invention According to the present invention, a composition has been developed which includes vitamin supplments, a specific dietary mineral supplement and various glandular and organ concentrates which in the presence of thiamine hydrocloride and L-glutamic acid, known in the art for effective treatement of psychological symptoms, achieves a holistic treatment of male climacteric. The present invention may be used in initial treatment of climacteric before resort to traditional testosterone replacement therapy or gonadal stimulation therapy or as an adjunct to these methods of treatment. Preliminary testing indicates that unexpected and beneficial therapeutic results are achieved by the synergisti interaction between the components of the present invention. Generally, the present composition comprises substantially equivalent amounts of thiamine hydrocloride and L-glutamic acid, major equivalent amounts of ascorbic acid and orchic (i.e. testicular) concentrate combined with minor, equivalent amounts of pituitary and hypothalmic glandular concentrates and therapeutic amounts of Vitamin A, Vitamin E and zinc as a mineral supplement. Orchic concentrate serves as a source of hormonal precursors for testosterone. Likewise, pituitary glandular concentrate serves as a source of hormonal precursors for FSH and LH while hypothalmic glandular concentrate serves as a source of hormonal precursors for LH/FSH release hormone. In another formulation of the present invention, human chorionic gonadotropin may be substituted for orchic concentrate. Being active hormone, human chorionic gonadotropin has a more direct and stronger stimulatory effect on the testes than the hormonal precursors found in orchic concentrate which require subsequent biosynthesis. Other and more detailed aspects of the present invention will be apparent from the following detailed description of the present composition as well as by the claims. Detailed Description of the Present Invention As previously discussed, an object of the present invention is to provide for the holistic treatment of the psychologic, somatic and ' ϋ ^- ** endocrinologic clinical aspects of male climacteric. While providing thiamin hydrochloride and glutamic acid for treatment of psychologic symptoms, the present invention further provides essential nutritive support for testicular cell development as well as hormonal precursors from which the various active hormones can be biosynthesized. As described hereinafter, the relative quantities of the active ingredients contained in the preferred formulation of the present invention will be described in terms of a percentage of the total weight of the preferred unit dosage form, i.e. tablets. For present purposes, a tablet weight of about 700 mg is selected for the preferred formulation of the present invention. Of course, it is understood that since the amounts of inactive ingredients, •e.g. lubricants, binders and fillers, may vary, the weight of each active ingredient as a percentage of the preferred unit dosage form will likewise vary. In the preferred formulation of the present invention, testosterone precursors obtained from orchic concentrate are provided for biosynthesis of active testosterone by the Leydig cells thereby to increase depressed levels of testosterone associated with male climacteric. Orchic concentrate may constitute about 30% of the weight of the tablet with a preferred amount 200 mg per unit dosage form accounting for about 28.5%. Likewise, FSH and LH precursors obtained from pituitary glandular concentrate permits biosynthesis of FSH and LH. Such pituitary hormones will be required to return the system to negative feedback control upon increased secretion OMPI of testosterone and re-initiation of spermatogenesis. Further, LH/FSH - release hormone precursors obtained from hypothala ic glandular concentrate will also permit biosynthesis of release-hormone when male sexual function returns and the regulatory feedback system returns to equilibrum. Both pituitary and hypothalmic glandular concentrates are present in the preferred formulation in generally equivalent amounts though are essentially unmeasurable as a percentage of total weight of the preferred unit dosage form. Preferably, each glandular concentrate is provided at a level of about 30 eg each. Given that these concentrates provide amino acid precursors of active hormones, quantities exceeding 30 meg are within the scope of the present invention. In using- glandular and orchic concentrates in preparing the present invention, it is preferred that the residues of such concentrates be used because of the greater quantities of precursors contained therein. In addition to the above mentioned hormonal precursors, the present invention also includes Vitamin A in a preferred amount of about 2500 Iϋ/tablet or about 4.5% by weight. The Palmitate form of Vitamin A is preferred due to its increased stability to oxidation. Because of the lower biopotency of palmitate form (1.817x10*- Iϋ/g) , relative to acetate form, greater levels of Vitamin A beyond the preferred 2500 Iϋ are within the range of operability of the present invention. Vitamin A is included in the present invention as part of the holistic treatment of male climacteric as Vitamin A deficiency has been associated with the disruption of spermatogenesis. de Kretser, Endocrinology of Male Infertility, 35 British Medical Bulletin, pp. 187-192 (1979). All formulations of the present invention, including the preferred formulation, include Vitamin E, preferably in the powder form of d-alpha-tocopheryl succinate having a biopotency of 1.21 10 » 1 mg (1 Iϋ Vitamin E = 1 mg dl-alpha tocopheryl acetate) . In the art. Vitamin E is disclosed as being a first line defense against peroxidative damage to cellular and subcellular elements thereby permitting cell structures to cope with disease, physical and chemical insults and other stresses. The preferred amount of d-alpha- tocopheryl succinate is about 30 IU/tablet and about 3.5% to about 5% by weight. Given the unexplained efficaciousness of Vitamin E in human reproduction, and the fact that megadoses of Vitamin E have no known adverse clinical effects, the operative amount of Vitamin E can exceed the preferred amount up to 1000 IU. The present composition also includes ascorbic acid which is believed to serve as an anti- agglutinogenic agent for semen or spermatozoa. The preferred amount of ascorbic acid is about 200 mg/tablet and is present in a generally equivalent level as the orchic concentrate, i.e. about 20-30% by weight. Also included in the present invention as an essential mineral supplement is zinc which is found in high levels in the prostate glands and spermatozoa. It has been established in the medical literature that a deficiency of zinc is characterized, among other things, by hypogonadism. Any pharmaceutically acceptable salt of zinc, such as zinc gluconate, may be used in the present composition. The preferred therapeutic amount of zinc in the present invention is about 20 mg/tablet or 2.8% by weight. Finally, in all formulations of the present invention including the preferred formulation, both thiamin hydrochloride and L- glutamic acid are included in generally equivalent amounts. Thiamin hydrochloride is a known anti- neuritic while L-glutamic acid is a proven analeptic of the central nervous system. The preferable amount of thiamin hydrochloride found to be therapeutic is about 50 mg or 7% to about 10% by weight. The preferable amount of L-glutamic acid found to be therapeutic is about 50-53 mg and also about 7-10% by weicfht of a tablet. The above-described preferred formulation includes precursors for each hormone implicated in climacteric as well as a selected amino acid, various vitamin supplements and an essential mineral supplement to provide either an alternative to traditional methods of treatment or as a supplement to these treatment modes. However, when gonadal stimulation therapy is chosen, an alternative formulation of the present invention can be used in which the above described active ingredients, with the exception of orchic concentrate, are present in the same preferred amounts. In this formulation, orchic concentrate is substituted for the active hormone human chorionic gonadotropin (hCG), a glycoprotein obtained from human pregnacy urine. hCG has been demonstrated in the literature as stimulating ' 10 testosterone production and secretion by the Leydig cells. Further, the effectiveness of hCG in treating climacteric is enhanced by both thiamin HCI and glutamic acid. In this alternative formulation, unit dosage forms, i.e. tablets preferably of about 450 mg are used. hCG, in dry powder form, is included in an amount equivalent to about 200 Iϋ/tablet (1 Iϋ = 0.1 mg) or about 4-5% by weight of the preferred unit dosage form. As an active hormone, hCG is consequently more biologically effective and can be included in smaller amounts in this embodiment than orchic concentrate which contains only hormonal precursors. As a result of the substitution of hCG for orchic concentrate, ascorbic acid assumes by weight between 40%-50% of the preferred unit dosage form. As previously mentioned, informal evaluations of the present invention have indicated that it is unexpectedly more efficacious as a sole therapeutic composition and as an adjunct to prior art methods and compositions for treatment of male climacteric. Formal clinical testing is being conducted at University of Alabama School of Medicine at Mobile, Alabama in order to develop more definitive results supporting the efficacy of the present composition in the treatment of male climacteric. In using the compositions of the present invention, one or more unit dosage forms would be orally taken by a male subject experiencing climacteric. The number of unit dosage forms taken will depend on the particular quantities of glandular or organ concentrate, vitamin supplement or in the case of an alternative embodiment of the present invention, on the presence of hCG contained in the dosage form. In the preferred unit dosage form of about 700 mg where Vitamin C and orchic concentrates are present in substantially equivalent amounts and both pituitary glandular concentrate and hypothalmic glandular concentrates are present in minor equivalent amounts of 30 micrograms each, two unit dosage forms (e.g. tablets) taken about ever 6-8 hours will be required to obtain the desired therapeutic effect. Either formulation of the present invention is preferably prepared through dry granulation and direct compression. These procedures are described in detail in Remington's Pharmaceutical Sciences, A. Ossol ed.. Mack Pub., Boston, Mass. (16th ed. 1980) pp. 1563-1565, the disclosure of which is incorporated herein by reference. Essentially the steps of the preferred method of manufacturing the present composition includes weighing amounts of respective active and inactive ingredients, screening all ingredients to a micro-fine granulate pressing out tablets in a standard tablet press. All vitamins, minerals and amino acids must first be passed through a screen of proper mesh to obtain an appropriate size of granules suitable for tabletting. Additional milling in a Stokes tornado mill or Fitzpatrick comminuting mill may be necessary in order to obtain a micro granulate to increase bioavailability and therefore absorption of the composition. Next, the glandular and organ concentrates as well as any hormone must also be "ξjREA. OMPI screened. During mixing and screening all glandular and organ concentrates and hormone must be maintained under low temperature and humidity (less than 30%) conditions as well as reduced illumination since glandular and organ concentrates and hormones are both thermally labile, hygroscopic as well as being photosensitive. However, it is preferable that each of the concentrates and any hormone be screened separately to avoid clumping and adhesion prior to mixing. All ingredients, except for the glanular and organ concentrates and any hormone, are placed in a ribbon mixer and blended under low temperature and humidity and reduced illumination conditions until a uniformly blended first granulation is obtained. After preparation of the first granulation, the glandular and organ concentrates as well as any hormone are blended into the first granulation for about two hours under the same environmental conditions to obtain a second granulation. Next, a pharmaceutically acceptable powdered lubricant such as hydrogenated vegetable oil or hydrogenated castor oil, carriers such as microcrystalline cellulose (Avicel, FMC Corp.) or dicalcium phosphate dihydrate (Di-Cal, Stauffer) together with other excipients and a selected F.D. & C. tablet dye, are blended into the second granulation to obtain a third granulation. After preparation of a third granulation, the die cavity of a tablet press such as Stokes BB- 2 press, is filled with an appropriate amount of the third granulation and compressed into a tablet using a 5/8 inch punch. Compaction pressure must OMPI 13 be monitored since compaction must take place only under a pressures ranging from 4.0 kg to no more than 4.5 kg. Lesser pressures will result in insufficient tablet compaction while greater pressures may have a deleterious effect on the glandular and organ concentrates and on the vitamins. Further, greater compaction pressures may hamper enteral dissolution of the tablet and prolong disintegration within the patient. Finally, a light to medium thickness of edible enteral coating and sealent is applied to the tablets and buffed to a gloss if desired. Any edible coating and sealent known in the art, such as Zein, will suffice as a coating and sealent. A discussion of enteric coating methods useful in preparation of the present invention can be found in Remington's Pharmaceutical Sciences, pp. 1590- 1591, the disclosure of which is incorporated by reference herein. The following examples are given to further illustrate the present invention. It is to be understood, however, that the invention is not necessary limited to the concentrations or quantities of ingredients disclosed. EXAMPLE 1 Formula using Orchic Concentrate using the procedure disclosed above, a tablet was prepared having the following composition: Ingredients mg/Tablet % Weight Part A 1.. Thiamine hydrochloride 50.000 7.143 2. L-glutamic acid 53.000 7.571 3. Ascorbic acid 200.000 28..571 4. Vitamin A (Palmitate) 4.543 .0649 (2500 Iϋ) 5. Pituitary glandular cone. .030 «-_._—• (American Labs, Omaha, Neb.) 6. Hypothalmic glandular cone. .030 (American Labs, Omaha, Neb.) 7. Zinc (Zn+2) 20.000 2.857 8. Vitamin E 24.793 (d-alpha-tocopheryl (30 IU) 3.541 succinate) 9. Orchic concentrate 200.000 28.571 552.396 78.391 Part B Lubricant (hydrogenated) vegetable oil powder) ) 2. Binders and Fillers )147.604 21.681 (bile salts and ) dicalcium phosphate) ) 3. Starch (Potato) ) 700.000 100.000 Λ ι - . EXAMPLE 2 Formula Substituting hCG For Orchic Concentrate Using the procedure disclosed above, a tablet was prepared having the following composition: Ingredients mg/tablet % Weight Part A 1. Thiamine hydrochloride 50.000 11.111 2. L-glutamic acid 53.000 11.777 3. Ascorbic acid 200.000 44.444 4. Vitamin A (Palmitate) 4.543 1.009 (2500 IU) 5. Pituitary glandular cone. .030 (American Labs, Omaha, Neb.) 6. Hypothalmic glandular cone. .030 (American Labs, Omaha, Neb.) 7. Zinc (Zn +2 ) 20.000 4.444 8. Vitamin E 24.793 (d-alpha-tocopheryl 5.509 succinate) Human chorionic gonadotropin (dry 20.000 powder) (200 Iϋ) 4.444 372.396 82.738 Part B 1. Lubricant (hydrogenated vegetable oil powder) 2. Binders and Fillers 77.604 17.262 (bile salt and dicalcium phosphate) 3. Starch (Potato) 450.0 100.000 While the invention has been described - with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope therof. Therefore, it is intended that the invention not be limited to a particular embodiment disclosed as the best mode contemplated for carrying out the invention, but that the invention will include all embodiments falling within the scope of the appended claims. OMPI

Claims: CLAIMS 1. A pharmaceutical composition for oral administration in a selected unit dosage form for treatment of male climacteric comprising: substantially equivalent amounts of thiamine hydrocholoride and biologically active glutamic acid; equivalent major amounts of ascorbic acid and orchic concentrate, the orchic concentrate being a source of amino acid precursors for testosterone; equivalent minor amounts of pituitary glandular concentrate and hypothalmic glandular concentrate, the pituitary glandular concentrate being a source of amino acid precursors for gonadotropic hormones such as FSH and LH, the hypothalmic glandular concentrate being a source of amino acid precursors for LH/FSH-release hormone; and selected therapeutic amounts of Vitamin A, Vitamin E and zinc; in admixture with pharmaceutically acceptable carriers, lubricants, fillers and other excipients. 2. The pharmaceutical composition of Claim 1 wherein said biologically active glutamic acid comprises L-glutamic acid. 3. The pharmaceutical composition of Claim 1 wherein said Vitamin A component includes Vitamin A palmitate. 4. The pharmaceutical composition of Claim 1 wherein said Vitamin E component includes d- alpha-tocopheryl succinate. 5. The pharmaceutical composition of - Claim 1 wherein said pituitary and hypothalmic glandular concentrates are present in amounts of about 30 meg per tablet. 6. The pharmaceutical composition of Claim 1 wherein ascorbic acid and orchic concentrates are present by weight between 25%-30% of a selected unit dosage form. 7. The pharmaceutical composition of Claim 1 wherein thiamine hydrochloride and glutamic acid are present by weight between 5%-10% of the selected unit dosage form. 8. In a pharmaceutical composition for the treatment of male climacteric having a therapeutic amount of human chorionic gonadotropin and substantially equivalent amounts of thiamine hydrocholoride ' and L-glutamic acid, the improvement fortifying said composition by comprising: a major amount of ascorbic acid; substantially equivalent minor amounts of pituitary glandular concentrate and hypothalmic glandular concentrate, the pituitary glandular concentrate being a source of amino acid precursors of gonadotropic hormones such as FSH and LH, the hypothalmic glandular concentrate being a source of amino acid precursors for LH/FSH - release hormone; and selected therapeutic amounts of Vitamin A, Vitamin E, and an amount of zinc equivalent to the therapeutic amount of chorionic gonadotropin; in admixture with pharmaceutically acceptable carries, lubricants, fillers and other excipients. 9. A process for the dry preparation of a composition for supplementary treatment of male climacteric including glandular and organ concentrates, vitamin supplements and essential amino acid and mineral components comprising the steps of: (a) screening selected active ingredients comprising at least Vitamin A, Vitamin E, zinc, ascorbic acid, substantially equivalent amounts of thiamin HC1 and L-glutamic acid; (b) independently screening other selected active ingredients comprising at least pituitary glandular concentrate, hypothalmus glandular concentrate and testieular concentrate in a n amount equivalent to the amount of ascorbic acid; (c) blending the vitamins, mineral and amino acid to obtain a first granulation; (d) admixing the pituitary, hypothalmus and testieular concentrates into the first granulation to obtain a second granulation; (e) admixing pharmaceutically acceptable binders, lubricants and other excipients to the second granulation to obtain a third granulation; and (f) compressing said third granulation under a selected compaction pressure to form a tablet. - REAT O PI Λ . wo 10. The process of Claim 1 wherein said compaction pressure ranges from 4.0 kg to 4.5 kg.

Inventors: BILTON GERALD L, BILTON, GERALD, L.
Applicants: BILTON GERALD L, BILTON, GERALD, L.
Application year: 1983
Main classification: A61K35
IPC codes: A61K35