Patent Application
20160310505
The present invention is directed to the use of prostamides such as bimatoprost and its pro-drugs for the enhancement of leptin production and appetite suppression.
Leptin is major hormone produced in adipose tissue that has been shown to regulate appetite [Halaas J L, Gajiwala K S, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995; 269 (5223):543-546r] and alter the taste for sweetness of food [Kawai K, Sugimoto K, Nakashima K, Miura H, Ninomiya Y, Proc Natl Acad Sci USA. 2000 Sep. 26; 97 (20):11044-9]. Leptin is also a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss (Klok, “The Role of Leptin and Ghrelin in the Regulation of Food Intake and Body Weight in Humans: A Review.” Obes. Rev. 2007, January; 8 (1): 21-34).
Bimatoprost (AGN 192024) is a synthetic prostamide which has been used in intraocular pressure lowering therapeutics such as LUMIGAN® 0.03, LUMIGAN® 0.01 and GANFORT®. Bimatoprost has also been shown to induce eyelash and hair growth and is marketed for that purpose with the commercial product LATISSE®. Bimatoprost applied topically has also been shown to result in subcutaneous fat loss at sites distant from the application site (see
It is hereby proposed that in addition to other therapeutic uses, bimatoprost can mediate weight loss and gain through modulation of the appetite suppressing hormone leptin. An additional benefit may be maintaining weight control in non-obese individuals, that is in suppressing appetite in individuals with normal weight, use in conjunction with or without dieting, or as an adjunct to bariatric surgery, gastric banding (Lap-band) or other methods where weight control would be suitable (e.g., prolonged systemic steroid use, during smoking cessation programs to alleviate over-eating, or intake of foods high in sugar). Further, the use of bimatoprost as described in the present application can be applied to a wide range of disorders such as metabolic disease, type II diabetes, insulin resistance syndrome and non-alcoholic fatty liver. The delivery of bimatoprost may be topical, oral, systemic such as by skin patch, subcutaneous, sublingual and by suppository to obtain systemic exposure of the compound.
The term “prodrug” is used according to its plain ordinary meaning and is intended to mean compounds that require a chemical or enzymatic transformation in order to release the active parent drug in vivo prior to producing a pharmacological effect.
A “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
The terms “treat” “treating” or “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. For example, the certain methods presented herein successfully treat cancer by decreasing the incidence of cancer, in inhibiting its growth and or causing remission of cancer.
An “effective amount” of a compound is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease. Where recited in reference to a disease treatment, an “effective amount” may also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) a disease, disorder or condition, or reducing the likelihood of the onset (or reoccurrence) of a disease, disorder or condition or symptoms thereof. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations.
The term “topical” in the context of methods described herein relates in the customary sense to the administration of a compound or pharmaceutical composition which is incorporated into a suitable pharmaceutical carrier and administered at a topical treatment site of a subject. Accordingly, the term “topical pharmaceutical composition” includes those pharmaceutical forms in which the compound is administered externally by direct contact with a topical treatment site, e.g., the skin. The term “topical epidermal pharmaceutical composition” refers to a pharmaceutical composition suitable for administering directed to the epidermal layer of the skin, e.g., the palpebra, the supercilium, the scalp, or the body. The term “topical administering” refers to administering externally by direct contact with a topical treatment site. The term “topical epidermal administering” refers to administering externally by direct contact with the epidermis.
Some embodiments of the invention are included in the following paragraphs:
The present invention covers a novel use of bimatoprost including other known prostamides, and structural analogs of bimatoprost and its pro-drugs (non-limiting examples include acyl, acyl esters, amino acids and phosphates and prostamides as disclosed in U.S. Pat. No. 5,688,819 which is herein incorporated by reference). Bimatoprost was examined for the effect on hormones released from adipose tissue.
In
The compounds and pharmaceutical compositions disclosed herein can be prepared and administered in a variety of forms including a dermal or transdermal skin patch, a transdermal implant, cream, lotion, shampoo, solution, emulsion, gel, colloid, or foam. Accordingly, pharmaceutical compositions contemplated herein include a pharmaceutically acceptable carrier or excipient and one or more compounds described herein.
Pharmaceutical compositions contemplated herein may be prepared by combining a therapeutically effective amount of bimatoprost or another prostamide in combination with one or more pharmaceutically acceptable excipients. Pharmaceutical admixtures suitable for use in the present invention include those described in, for example, in P
The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.
Bimatoprost or another prostamide can be included in compositions of the embodiments disclosed herein in an amount of between 0.0001 and 15% (w/v), between 0.0001 and 10% (w/v), between 0.0001 and 5% (w/v), between 0.0005 and 3% (w/v), between 0.00075 and 2% (w/v), between 0.001 and 1.0% (w/v), between 0.001 and 0.1 (w/v), between 0.005 and 0.05% (w/v), or 0.01% (w/v) of the composition. In some embodiments, an amount of the active compound such as bimatoprost or another prostamide is 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 9% and 10% w/w.
In some embodiments, an effective amount, e.g., a therapeutically effective amount, of the active compound in a pharmaceutical composition is afforded at a concentration of about 1×10−7 to 50% (w/w), about 0.001 to 50% (w/w), about 0.01 to 50% (w/w), about 0.1 to 50% (w/w), or about 1 to 50% (w/w). In some embodiments, the therapeutically effective amount of the active compound such as bimatoprost or another prostamide in a pharmaceutical composition is 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% and 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 3.0%, 4.0% and 5.0% w/w.
A 51 year old Caucasian male who is morbidly obese applies a bimatoprost transdermal skin patch on his arm, which uniformly releases a 5% w/w bimatoprost formulation over a thirty day period. During the thirty-day period, the patient's leptin levels increase leading to suppressed appetite and weight loss. The patient loses 6 pounds more than he would have otherwise lost without using the bimatoprost transdermal skin patch.
A 43 year old Hispanic female applies a 3% w/w bimatoprost gel to her skin once a day. After several days, the 43 year old Hispanic female experiences elevated leptin levels which suppresses appetite. Over a sixty (60) day period, the patient maintains her weight through appetite suppression.
A 61 year old African-American male with elevated blood pressure has been determined by doctors to have prediabetes. In addition to being on a low fat, low sugar diet, the patient uses a transdermal bimatoprost patch which releases a 3% w/w bimatoprost formulation through the dermis and into the blood stream. The patient experiences an immediate increase in blood leptin levels and a reduction in appetite and experiences weight loss while using the bimatoprost patch.
A 70 year old Caucasian male is diagnosed with non-alcoholic fatty liver. The patient applies a transdermal bimatoprost patch which releases a 2% w/w bimatoprost formulation. The patient experiences a reduction in lipidosis in the liver that would have occurred had the patient not been administered bimatoprost.
A healthy 27 year old Caucasian female in an effort to lose weight is on a low fat diet. In order to suppress her appetite, the 27 year old Caucasian female applies a bimatoprost transdermal patch which continually releases 1% w/w bimatoprost for 30 days. As a result, her leptin levels rise and she experiences suppression of her appetite and greater weight loss in comparison to had she not applied the transdermal patch with bimatoprost.
This application is a continuation of U.S. patent application Ser. No. 14/209,099, filed on Mar. 13, 2014, which in turn claims the benefit of U.S. Provisional Patent Application Ser. No. 61/793,132, filed Mar. 15, 2013, the disclosures of which are incorporated herein by reference in their entireties.
| Number | Date | Country | |
|---|---|---|---|
| 61793132 | Mar 2013 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14209099 | Mar 2014 | US |
| Child | 14952208 | US |
