IIIUS005708038A United States Patent 19 11 Patent Number: 5,708,038 Davis 45 Date of Patent: Jan. 13, 1998 54 METHOD OF USING ALOEVERA ASA Hart et al. (1988) J. of Ethnopharmacology 23:61-71. BOLOGICAL VEHICLE Malini and Vanithakumari (1992) J. Ethnopharmacology 75) Inventor: Robert H. Davis, King of Prussia, Pa. 36:51. 73) Assignee: Univera Pharmaceuticals, Inc., Malini and Vanithakumari (1990) J. Ethnopharmacology Broomfield, Colo. 28:221. 21 Appl. No.: 662,654 Primary Examiner-Carlos Azpuru 22 Filed: Jun. 13, 1996 Attorney, Agent, or Firm-Swanson & Bratschun L.L.C. (51 int. C. m. A61K 47/42 57 ABSTRACT 52 U.S. Cl. .................. 514/783 58) Field of Search .......................... 514/783; 424/195.1 The present invention provides a method for using Aloevera as a biological vehicle for the delivery of drugs. In one 56 References Cited embodiment Aloe vera is used as a biological vehicle to U.S. PATENT DOCUMENTS deliver the estrogen, B-estradiol and the androgen, testoster one propionate. The present invention also provides a 5,565,199 10/1996 Page et al. ........................... 424/195.1 method of treating symptoms and diseases mediated by OTHER PUBLICATIONS hormonal deficiencies or amenable to treatment by hor Davis et al. (1991) JAPMA 81:1. mones using Aloe vera as a biological vehicle. Elghamry and Shihata (1966) Plant Medica 14:352. Fjösne et al. (1990) The Prostate 17:1. 34 Claims, 3 Drawing Sheets 200 160 120 80 Control 40 HESSESE 0.005 0.01 0.1 Estradiol Benzoate (ug) U.S. Patent Jan. 13, 1998 Sheet 1 of 3 5,708,038 8 O 4 O 0.005 0.01 0.1 Estradiol Benzoate (ug) Fig. 1 U.S. Patent Jan. 13, 1998 Sheet 2 of 3 5,708,038 Saix Cxtax: stratic: Bexoatx (i.ii gag: :8:aisie:xxxixe .ii isg, six w x8 (38 kg Estradio: Bersaxate: {{..ii agri-kick Wera. 388 Big M s X U.S. Patent Jan. 13, 1998 Sheet 3 of 3 5,708,038 200 180 160 140 120 0.1 0.25 0.5 1.0 Testosterone Propionate (mg) Fig. 3 5,708,038 1. 2 METHOD OF USING ALOE WERA ASA pharmacologic agents. Ideally a vehicle should be nonirri BOLOGICAL WEHICLE tating and compatible with common medications. Criteria for vehicle selection include solubility of the active agent in FIELD OF INVENTION the vehicle and the ability of the vehicle to penetrate 5 physical barriers such as the stratum corneum and the lipid The present invention relates generally to a method of portion of the cell membrane. Consideration must also be using Aloe vera as a biological vehicle for the delivery of given to any interactions between the vehicle and the active drugs. Specifically, this invention describes a method of agent, the efficiency with which the vehicle releases the using Aloe vera as a biological vehicle to deliver the incorporated active ingredient, the molecular size and the estrogenic hormone, 3-estradiol, and the androgenic composition of the vehicle. Traditional vehicles for subcu hormone, testosterone. Further included in this invention is 10 taneous administration include oils which tend to be irritat a method for treating hormonal deficiencies and conditions ing. Aloe vera has been shown to be nonirritating and amenable to treatment with hormones using Aloe Vera as a nontoxic when injected subcutaneously in mice, even at biological vehicle for delivery of the hormone. massive doses. Occasionally, a vehicle will have a synergistic effect, such BACKGROUND OF THE INVENTION 15 that the final sum total of the activity in each system is Aloe is an intricate plant which contains many biologi greater than the sum of the components. As stated above, this cally active substances. (Cohen et al. in Wound Healing/ is highly desirable in that less of the pharmacologic agent Biochemical and Clinical Aspects, 1st ed. WB Saunders, can be used to achieve the same effect, thereby reducing or Philadelphia (1992)). Over 300 species of Aloe are known, eliminating any side effects associated with higher dosages. most of which are indigenous to Africa. Studies have shown The estrogens are a group of hormones which promote that the biologically active substances are located in three proliferation and growth of specific cells in the body and are separate sections of the aloe leaf-a clear gel fillet located responsible for the development and maintenance of sec in the center of the leaf, in the leaf rind or cortex of the leaf ondary female sex characteristics. The estrogens are mainly and in a yellow fluid contained in the pericyclic cells of the 25 responsible for cellular proliferation and growth of the vascular bundles, located between the leaf rind and the tissues of the sexual organs and of other tissues related to internal gel fillet, referred to as the latex. Historically, Aloe reproduction. Estrogens also participate in the menstrual products have been used in dermatological applications for cycle. Naturally occurring estrogens, such as B-estradiol, the treatment of burns, sores and other wounds. These uses estrone and estriol, are steroids produced primarily by the have stimulated a great deal of research in identifying 30 ovaries. B-Estradiol (referred to herein as estradiol) is compounds from Aloe plants that have clinical activity, involved in the maturation and cyclic function of accessory especially anti-inflammatory activity. (See, e.g., Grindlay sex organs and the development of the duct system in and Reynolds (1986).J. of Ethnopharmacology 16:117-151; mammary glands. Of the estrogen hormones, estradiol has Hart et al. (1988).J. of Ethnopharmacology 23:61-71). As a the greatest physiological activity. When administered to result of these studies there have been numerous reports of 35 ovariectomized mice, estrogens induce estrous and increase Aloe compounds having diverse biological activities, uterine weight. Studies have shown that microgram amounts including anti-tumor activity, anti-gastric ulcer, anti of estradiol can increase the weight of the immature rat diabetic, anti-tyrosinase activity, (See, e.g. Yagi et al. (1977) uterus in as few as six hours. (Astwood (1938) Anat. Rec. Z. Naturforsch 32c:731-734), and antioxidant activity 70:25). (International Application Serial No. PCT/US95/07404). In hypogonadal women and menopausal women the level Recent research has also shown that Aloe vera, a term of estrogens in the blood decreases, causing a number of used to describe the extract obtained from processing the symptoms, including nervousness, depression, irritability entire leaf, isolated from the Aloe vera species of Aloe can and insomnia. There is also evidence that diminished estro be used as a vehicle for delivering the corticosteroid, gen levels contributes to a number of diseases, such as hydrocortisone, administered both topically and 45 atherosclerosis and osteoporosis. Presently, estrogen subcutaneously, to the site of inflammation. (Davis et al. replacement therapy is the only effective treatment for relief (1991) JAPMA 81:1). Davis et al. studied the topical and of the symptoms associated with decreased estrogen levels. systemic anti-inflammatory activity of Aloe vera alone and Estrogens also have a protective effect against ischemic in combination with hydrocortisone acetate. This study heart disease, (Martin et al. (1993) PS.E.B.M. 202:288), revealed that Aloevera contributed in an additive way to the tend to decrease the risk of coronary artery disease and have activity of the steroid, suggesting that Aloe vera may be a favorable effect on plasma lipid and high density lipopro useful as a biological vehicle for hydrocortisone. The sig teins (antiatherogenic effect) in menopausal women. nificance of this finding is that if used in combination with Currently, estrogen hormones are therapeutically used to Aloe vera, the dosage of the steroid can be reduced, while treat any disorder attributable to estrogen deficiencies or any maintaining its biological activity, thereby reducing or 55 disorders amenable to estrogen therapy, such as various eliminating any toxic side effects associated with higher functional ovarian disorders, osteoporosis, certain coronary dosages. These studies also revealed that Aloe vera assists in disorders in women, problems and discomforts associated the penetration of hydrocortisone through the stratum cor with menopause, and certain types of cancer. Estrogens are neum. Since Aloe vera contains many hydrophilic also used in oral contraceptives. compounds, such as enzymes, amino acids and Estrogens can be administered orally, by intramuscular or carbohydrates, as well as, hydrophobic compounds, such as subcutaneous injection or by subcutaneous implantation. vitamins and sterols, Davis et al. postulate that pharmaco Astwood has established an estradiol response curve for logic agents of both solubilities can be placed in Aloe vera mice of between 0.002 ug to 0.1 g per day. The dose and carried through the epidermal barrier. (Davis et al. response curve for humans, as well as other animals, can be (1991) JAPMA 81:1). 65 extrapolated from these results by taking into account the A vehicle is a substance, usually without biological greater body weight of the person or animal under consid activity, which is used as a medium for the administration of eration. 5,708,038 3 4 Problems associated with estrogen therapy include; pre The present invention also includes an improved method menstrual tension, weight gain, fat deposition, fallopian tube for the prevention and treatment of symptoms and diseases blockage, increased risk of endometrial cancer and increased mediated by estrogen and androgen deficiencies or amenable risk of gall bladder disease. The risk of endometrial cancer to treatment with estrogen or androgen in patients suffering is dependant upon both the amount and duration of therefrom. This method comprises administration of athera treatment, thus estrogens are typically administered at the peutically effective amount of estrogen or androgen, lowest dose that will control symptoms. respectively, in combination with Aloe vera.