Hair loss prevention

Details Hair loss prevention Hair loss prevention

2002-01-11

2002-07-16

Criares, Theodore J. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S255050, C514S255060, C514S947000

Reexamination Certificate

active

06420352

ABSTRACT:

BACKGROUND
My invention relates to preparations useful for maintaining normal, healthy hair bulb function, for preventing hair loss, and for medically treating androgenic alopecia and like dermatological diseases. I will first review pertinent hair biology, then discuss prior art teachings in the field, and then describe my invention.
Hair Biology
Hair bulbs are responsible for normal, healthy hair growth and retention. Hair bulbs are located in the skin, about {fraction (3/16)} of an inch below the skin surface. They are located just above the fatty layer at the very lower most position of the skin.
The majority of facial and body hair growth is stimulated by androgens. However, the growth of scalp hair has been shown, in genetically programmed individuals, to be inhibited by 5&agr;-dihydrotestosterone (“DHT”) in individuals who exhibit a hereditary pre-disposition to baldness. Ebling,
Dermatol. Clin. S
. 467 (1987); Lucky, 4
Biochem. Soc. Transc
. 597 (1988); Brodland et al., 47
Cutis
173 (1991). DHT is produced by reducing testosterone with a 5&agr;-reductase enzyme. The phenotypic expression of baldness does not occur in the absence of testosterone. Androgenic alopecia or common baldness represents 99 percent of all cases of hair loss. Broadland, id.
The mechanism through which androgens regulate the biology of hair is by modulating the hair growth cycle. Ebling, 4
Biochem. Soc. Trans
. 597; Bergfield et al., 5
Dermatol. Clin
. 491. The effect of DHT on hair growth appears to be related to local rather than systemic levels of the hormone. This is because the capacity of scalp skin from balding individuals to convert testosterone (“T”) to DHT is greater than that observed in the scalp of non-balding individuals. Lucky, supra; Schweikert et al., 38
J. Clin. Endocrinol. Metab
. 811.
To prevent hair loss, maintain the health of hair bulbs, or to treat baldness, several compositions are known in the art. We discuss them now.
Hair Loss Prevention
Hair loss prevention preparations are known in the art. These include natural product preparations, biological products, vascular toners and testosterone blockers. Several prior art compositions are discussed in the accompanying Petition To Make Special and its accompanying references, the contents of which are incorporated herein by reference.
Natural Products. Several inventors disclose natural compositions. Casero, U.S. Pat. No. 5,340,579, discloses a composition comprising (a) mucopolysaccharides, (b) human umbilical cord extract, (c) tetrahydrofurfuryl nicotinate, and (d) pharmaceutically and cosmetically acceptable excipients. Buck, U.S. Pat. No. 5,512,275 and 5,609,858, discloses a formulation for the treatment of androgenic alopecia, comprising liquor carbonis detergens in combination with spirits of camphor, castor oil, isopropyl alcohol. Chizick et al., U.S. Pat. No. 5,972,345, discloses a combination of saw palmetto extract, African pygeum extract, and stinging nettle extract.
Biological Products. Hoke, U.S. Pat. No. 5,994,319, discloses using genetic material as a anti alopecia therapeutic. Hoke proposes using anti-sense oligonucleotides targeting 5-&agr; reductases in conjunction with other hair growth enhancers. Tien, U.S. Pat. No. 5,574,011, discloses the use of a class of LHRH analogs for treating male pattern baldness. Messenger, U.S. Pat. No. 6,020,327, discloses administering aromatase inhibitors to treat hair loss. Liao et al., U.S. Pat. Nos. 5,422,371 and 5,605,929, discloses a class of anti-androgenic compounds.
Vascular Toners. Several organic chemicals are known to affect the hair growth and hair retention cycle. These include minoxidil. I refer to minoxidil and similar kinds of compounds as “vascular toners,” because they are believed to be effective due to their impact on local blood circulation.
Minoxidil has been shown to stimulate hair growth or inhibit the loss of hair in a number of patients beginning to develop androgenic alopecia. Minoxidil is the generic name for 6-(1-piperidinyl)-2, 4-pyrimidinediamaine 3-oxide. Its preparation is disclosed in Anthony, W. C. et al., U.S. Pat. No. 3,382,247 (1968); McCall, J. M., et al., 40
J. Organic Chem
. 3304 (1975); Gorecki, D. K. J., 17
Analytical Profiles of Drug Substances
185 (Academic Press, New York 1988). It is more soluble (by weight minoxidil/volume of solvent) in non-polar solvents than polar ones (75 mg/ml in propylene glycol; 44 mg/ml in methanol; 6.5 in dimethyl sulfoxide; 2.2 mg/ml water).
Minoxidil is medically classified as an anti-hypertensive. It affects heart rate and rhythm. It has thus been used in an oral formulation as a cardiac drug. Andersson, O., 205
Acta Med. Scand
. 213 (1979); Moser, M., 26
Advan. Cardiol
. 38 (1979). over dosage may create cardiac arrhythmias or other adverse side effects. See e.g., Carlson, E. S., 39
Toxicol. Applied Pharmacol
. 1 (1977).
Minoxidil is also medically classified as an anti-alopecia agent. Its efficacy in treating early male pattern baldness has been described in numerous published articles. E.g., Olsen, E. A. et al., 13
J. Am. Acad. Dermatol
. 185 (1985); Novak, E., 24
Int. J. Dermatol
. 82 (1982). Its limited percutaneous absorption and secretion is described in Franz, J. T., 121
Arch. Dermatol
. 203 (1985).
The mechanism by which minoxidil alters the hair growth cycle is uncertain. It is thought to act by increasing vascular circulation to the hair follicle. It is known that minoxidil effectiveness is more pronounced in scalp areas which are more vascular.
Topical minoxidil is know to have certain shortcomings. It is effective in only about eight percent of adult male users. It produces “lanugo,” or baby-type, hair which is relatively thin. Further, and perhaps most significantly, after approximately 30 months of continuous use, minoxidil shows a sharp drop in effectiveness. After about thirty months of use, about half of the new hair growth falls out. Thus, while the user has somewhat more hair than originally, the user has less hair than originally seen.
Testosterone Inhibitors. Inhibitors of steroid metabolism, particularly those that inhibit the conversion of testosterone to dihydro testosterone, have shown effects on hair cycles, including inhibition of hair loss. One class of enzymes targeted by these inhibitors are the steroid 5-&agr; reductases.
Certain 5&agr;-reductase inhibitors have been shown to inhibit hair loss. For example, stump-tail macaque monkeys treated with the 5&agr;-reductase inhibitor 17b-N,N,- dimethylcarbamoyl- 4-methyl- 4-aza-5&agr;-androstan- 3-one undergo significantly less age related hair loss than untreated monkeys. Rittmaster et al., 65
J. Clin. Endocrinol. Metab
. 188 (1987). Similarly, finasteride, a 5&agr;-reductase inhibitor, miniaturizes scalp hair follicles, reversing the balding process. “Merck's Propecia Shows Promise In Hair Loss,”
Marketletter
(Mar. 31, 1997). These inhibitors are thought to work by inhibiting the reduction of testosterone to DHT, as DHT is considered to be the more active form. The use of a combination of finasteride and minoxidil demonstrated that, in combination, these two drugs increased the rate of hair growth when compared to either compound administered alone. Diani, 74
J. Clin. Endocrinol. Metabol
. 345.
Minoxidil used in conjunction with effectors of steroid metabolism, leads to enhanced hair growth and decreased rates of hair loss.
Testosterone blockers are known in the art (I use the term “testosterone blocker” to denote a competitive antiandrogen which inhibits the binding of testosterone or DHT onto its cell surface binding site, rather than a compound which is used to inhibit the reduction of testosterone into DHT.). Also known is their use systemically (orally or intravenously). As systemic therapeutics, they are known in the art as having a key shortfall: their long term efficacy is compromised by their blocking of the androgenic feedback inhibition of gonadotropin secretion. This interference results in elevated gonadotropin secretion, which in turn increases testicular secretion of testosterone. The

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