Treating radiation fibrosis

Details Treating radiation fibrosis Treating radiation fibrosis

2001-08-24

2003-03-25

Spivack, Phyllis G. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

Reexamination Certificate

active

06538030

ABSTRACT:

BACKGROUND
Phenylbutyrate, an aromatic fatty acid, can be purified from a biological sample (e.g., mammalian urine or plasma) or chemically synthesized. Sodium phenylbutyrate has been approved by the U.S. Food and Drug Administration as an orphan drug for treating hyperammonemia (Samid et al. (1992)
Cancer Res
. 52: 1988-1992). It has also been clinically used in patients with in-born genetic errors which lead to liver failure or urea cycle disorders.
Radiation fibrosis, a local defect, is a frequent sequela of therapeutic or accidental radiation overexposure of normal tissues. It results from a complex tissue repair response whose predominant characteristics are massive deposition of extracellular matrix and excessive fibroblast proliferation. An ulcer is also a local defect, i.e., excavation of the surface of an organ or tissue. There is a need for effective treatment of both disorders.
SUMMARY
The present invention is based on the unexpected discovery that certain aromatic fatty acids can be used to effectively treat an ulcer and radiation fibrosis.
Thus, this invention features a method for treating a subject having an ulcer or radiation fibrosis. The method includes topically administrating to the subject an effective amount of a compound and a pharmaceutically acceptable carrier. The compound, which can be synthesized by well-known methods or purchased from commercial suppliers, has the following formula:
R
1
and R
2
, independently, is H or C
1
~C
6
alkyl; R
3
is aryl or heteroaryl; and n is 0, 1, 2, 3, 4, 5, or 6. A subset of the compounds encompassed by the above formula are featured by that R
3
is phenyl, n is 0, 1, or 2, and each of R
1
and R
2
, independently, is H, methyl, or ethyl. Three exemplary compounds are 2-phenylbutyrate, 3-phenylbutyrate, and 4-phenylbutyrate.
Alkyl, aryl, and heteroaryl mentioned above include both substituted and unsubstituted moieties. The term “substituted” refers to one or more substituents (which may be the same or different), each in replace of a hydrogen atom. Examples of substituents include, but are not limited to, halogen, amino, hydroxyl, mercapto, cyano, C
1
~C
6
alkyl, C
1
~C
6
alkenyl, C
1
~C
6
alkoxy, aryl, heteroaryl, or heterocyclyl, wherein alkyl, alkenyl, alkoxy, aryl, heteroaryl, and heterocyclyl are optionally substituted with C
1
~C
6
alkyl, halogen, amino, hydroxyl, mercapto, cyano. The term “aryl” refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and pyrenyl. The term “heteroaryl” refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl moieties include, but are not limited to, pyridinyl, carbozolyl, and indolyl.
The term “aromatic fatty acids” used herein refers to all the compounds covered by the above formula, and includes the compounds themselves, as well as their salts and their prodrugs, if applicable. Such salts, for example, can be formed between a negatively charged substituent (e.g., carboxylate) on an aromatic fatty acid compound and a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing the aromatic fatty acids described above. As used herein, the term “treatment” refers to administration of a topical composition to a subject with the purpose to cure, heal, alleviate, relieve, remedy, ameliorate, improve or prevent an ulcer or radiation fibrosis, its symptoms or the predisposition toward it.
Also within the scope of this invention is the use of the above-described compounds for the manufacture of a medicament for the treatment of an ulcer or radiation fibrosis.
Other features or advantages of the present invention will be apparent from the following detailed description of several embodiments, and also from the appending claims.
DETAILED DESCRIPTION
One aspect of this invention is a method for treating a subject having an ulcer or radiation fibrosis by using a topical composition that contains an effective amount of one or more aromatic fatty acids described above and a pharmaceutically acceptable carrier.
An effective amount of an aromatic fatty acid is the amount of the compound which, upon administration to a subject in need of treatment or prophylaxis of an ulcer or radiation fibrosis, is required to confer therapeutic effect on the treated subject. It may range from 0.1% to 40% (e.g., 0.1% to 10%) by weight of a topical composition. As recognized by those skilled in the art, the effective doses vary depending on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments such as the use of other anti-ulcer or anti-radiation fibrosis agents. Effective amounts and treatment regimens for any particular subject (e.g., human, dog, or cat) will also depend upon a variety of other factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, the severity and course of the disease, and the patient's disposition to the disease.
A pharmaceutically acceptable carrier may include water, a solvent, an emollient, a surfactant, a preservative, or a combination thereof. Water, when present, can be in an amount of 5 to 95% by weight. Other than water, the biological acceptable carrier can also contain a relatively volatile solvent such as a monohydric C
1
-C
3
alkanol (e.g., methyl alcohol or ethyl alcohol) in an amount of 1 to 70% by weight, and an emollient such as those in the form of silicone oils and synthetic esters in an amount of 0.1 to 30% by weight. Anionic, nonionic, or cationic surfactants may also be included in the biological acceptable carrier. The concentration of total surfactants may be from 0.1 to 40% by weight. Examples of anionic surfactants include soap, alkyl ether sulfate and sulfonate, alkyl sulfate and sulfonate, alkylbenzene sulfonate, alkyl and dialkyl sulfosuccinate, C
1
-C
2
, acyl isethionate, acyl glutamate, C
8
-C
20
alkyl ether phosphate, and a combination thereof Examples of nonionic surfactants include C
10
-C
20
fatty alcohol or acid hydrophobe condensed with from 2 to 100 moles of ethylene oxide or propylene oxide per mole of hydrophobe; C
2
to C
10
alkyl phenol condensed with from 2 to 20 moles of alkylene oxide; mono and di- fatty acid ester of ethylene glycol; fatty acid monoglyceride; sobitan, mono- and di-C
8
to C
20
fatty acid; block co-polymer (ethylene oxide/propylene oxide); polyoxyethylene sorbitan, and a combination thereof. Preservatives may also be included in the biological acceptable carrier to prevent growth of potentially harmful microorganisms, and may be employed in an amount of 0.01 to 2% by weight. Examples of preservatives include alkyl ester of para-hydroxybenzoic acid, hydantoin derivative, propionate salt, and a variety of quaternary ammonium compounds. Each preservative should be selected based on its compatibility with other ingredients in the topical composition.
A topical composition for practicing this invention may be provided as an aqueous, anhydrous or emulsion-like formulation, such as oil, cream, spray (aerosol or non-aerosol), gel (oral or non-oral), or ointment. When an anhydrous formulation is desired, various forms may be adopted, e.g., sticks, roll-ons, adhesive patches, or overnight masks. Peelable masks can be formulated by placing the composition as a gel or paste on a protective layer made of a film-forming polymer (e.g., polyvinyl alcohol) and an adhesive promoting polymer (e.g., hydrophobic acrylate or methacrylate polymer, such as Pemulen TR2.RTM. from the B. F. Goodrich Company).
An example of such a topical composition used for treating an ulcer or radiation fibrosis is an ointment. An ointment composi

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