KR20010043014A - Methods for treating hot flashes and gynaecomastia - Google Patents

Abstract

The present invention relates to a method for inhibiting a transient hot sensation or female ' s disease of a subject. The method of the present invention is characterized by administering an LHRH antagonist to a subject in need of treatment to suppress the transient hot sensation or female < RTI ID = 0.0 > gynecomastia < / RTI > of the subject. In a particular preferred embodiment, the present invention provides a method of inhibiting menopausal-related transient hot sensation wherein an LHRH antagonist is administered to inhibit a transient hot sensation of a subject in need of a postmenopausal-related, transient hot sensation treatment.

Description

[0001] METHODS FOR TREATING HOT FLASHES AND GYNAECOMASTIA [0002]

Women in menopause often experience many symptoms of estrogen deprivation caused by ovarian failure. The most common symptom in women up to 85% of menopausal women is a "hot flash" paroxysmal disorder, which causes sudden heat and sweating. The transient hyperthermia of vasomotor activity is also the most frequent side effect associated with tamoxifen, an anti-estrogen drug used in the treatment of breast cancer. It is not uncommon but not uncommon to be associated with hormones as the cause of transient hot sensations. One example is the lack or lack of alcohol dehydrogenase. People with this enzyme deficiency tend to redden their faces especially when consuming alcohol. Other common causes of transient hot sensation are carcinoid syndrome or chromaffin cell tumor.

The most common treatment for transient hyperthermia is oral or intradermal administration or transplantation of estrogen, but some women do not receive estrogen treatment. It is also undesirable to use estrogen therapy for patients with hormone-sensitive cancers (eg, breast cancer). Although other therapeutic methods have been different, transient hottherapeutic treatments such as steroids, alpha-adrenergic agonists and beta-blockers have been studied. Progestins such as acetic acid mestrol and medroxy progesterone have been shown to restore 25 to 85% and 75 to 100%, respectively, of a transient hot sensation, but no studies have been done on whether it will last for a long time. Such treatments may be avoided due to side effects such as thromboembolism, edema, weight gain, lipid changes, and death from cardiovascular disease.

Neither the central activity nor the adrenergic activity appears to be involved in the generation of transient hot sensation. Thus, epinephrine release inhibitors have not been used for transient hot sensation relief. CLONIDINE ^TM for transdermal administration is to reduce the frequency and severity of hot flashes caused by tamoxifen, but is different from the results for the oral administration of clonidine for. Side effects associated with clonidine treatment include drowsiness, constipation, orthostatic hypotension, dry mouth, headache, nausea, fatigue and loss of libido. Methyldopa was found to reduce the transient hot sensation by 30%, but there were side effects such as fatigue, weakness, dizziness and nausea. There is also a report on the use of naproxen beta-blockers, VERALIPRIDE ( ^TM) and NAXOLONE ( ^TM ).

Female gonorrhea is the overgrowth of male breast tissue, which can be pathological causes such as physiological causes such as puberty, aging, drugs, cancer, liver failure, kidney failure, and hormone imbalance. In the pathogenesis, the most common cause of female gynecomastia is increased estrogen: testosterone ratio. Surgical treatment (mastectomy) is somewhat expensive, but it is a common treatment. Recently, lipectomy is also used as a treatment method. Tamoxifen and DANAZOL ^TM have been shown to mitigate about 70% of women with masturbation in middle-aged men (Parker LN et al., Metabolism, 1986, 35: 705-8, Ann Roy Coll Surg, 1990, 72: 286-8 Reference). CLOMIPHENE ^TM is unavailable and found to have adverse effects (Ploudre PV et al., Am. J. Dis. Child., 1983, 137: 1080-2). Thus, there is a need for development of a method for treating transient hot flushes or female puffy patients, which is effective without adverse effects.

SUMMARY OF THE INVENTION

The present invention relates to an effective method of inhibiting a subject suffering from a transient hot sensation or female < RTI ID = 0.0 > In general, the therapeutic method of the present invention is to suppress transient hot sensation or female < RTI ID = 0.0 > embryonic < / RTI > symptoms to a subject by administering an LHRH antagonist to a subject suffering from or at risk of having a transient hot sensation or female '

Accordingly, one aspect of the present invention relates to a method for suppressing transient hot sensation by administering an LHRH antagonist to a subject to suppress a transient hot sensation to the subject. In another embodiment, the present invention provides a method for treating transient hot sensation, comprising first selecting a subject requiring treatment for transient hot sensation, and then administering the LHRH antagonist to treat the transient hot sensation of the subject. Subjects requiring treatment for transient hyperthermia are those who are currently suffering from transient hyperthermia or who are at risk due to this transient hyperthermia. In a particularly preferred embodiment, the present invention provides a method of treating a transient hot sensation patient associated with menopause. In this method, a subject in need of a postmenopausal-related transient hot sensation treatment is selected and an LHRH antagonist is administered to treat the postmenopausal-related transient hot sensation of the subject. Patients in need of postmenopausal-related transient hyperthermia treatment are currently suffering from or suffering from menopausal-related transient hyperthermia. In addition to postmenopausal-related transient hot sensation therapies, the methods of the present invention may also be used to treat transient hypertension resulting from other diseases or treatments, such as prostate cancer treatment, tamoxifen acetic acid treatment, alcohol dehydrogenase deficiency or transient hyperthermia due to carcinoid syndrome / Can be used for hot sensation treatment.

Another aspect of the present invention encompasses a method of inhibiting a female ' s disease of a subject by administering an LHRH antagonist to a subject to inhibit female ' s disease. In another embodiment, the present invention provides a method of treating a female schizophrenic patient, comprising first selecting a subject in need of treatment for female gorup, and then administering the LHRH antagonist to the subject. Patients needing treatment for women with gynecomastia refer to those patients who are currently suffering from or at risk of female gynecomastia. In a preferred embodiment, the female ' s disease of the patient is caused by a hormone imbalance.

Any LHRH antagonist that efficiently inhibits LHRH-R receptor activity can be used in the methods of the invention. However, especially preferred LHRH antagonist has the following ^{structure: Ac-D-Nal 1,} 4-Cl-D-Phe 2, D-Pal 3, N-Me-Tyr 5, D-Asn 6, Lys (iPr) ⁸ , D-Ala ¹⁰ -LHRH (hereinafter referred to as PPI-149).

In a preferred embodiment of the present invention, the subject is a mammal, most preferably a human.

In another preferred embodiment, the LHRH antagonist is administered to the patient via a parenteral route, and is preferably administered via injection, most preferably intramuscularly or subcutaneously / intradermally.

In another preferred embodiment, the LHRH antagonist is to administer the pharmaceutical acceptable form of the agent to the subject. The pharmaceutically acceptable formulation would be a dispersion system. For example, the dosage form is a lipid system (e.g., a liposomal formulation) or a polymeric system (e.g., a polymeric microparticle). In a particularly preferred embodiment, the dosage form comprises an LHRH antagonist and an anionic carrier macromolecule (e.g., carboxymethylcellulose) in an insoluble complex.

In a preferred embodiment, the LHRH antagonist is administered at a dose of, for example, about 15-300 ug / kg / day, 15-200 ug / kg / day, or 15-100 ug / kg / day. The LHRH antagonist is administered sequentially using a sustained-release formulation such as a formulation in which the LHRH antagonist can be slowly released into the tissue of the subject or a formulation in an osmotic pump. For continuous treatment of the subject, an LHRH antagonist will be administered to the subject for at least one month, preferably three months or more, more preferably six months or more. In order to obtain a sustained therapeutic effect for longer periods, the slow release formulation should be re-administered. For example, a sustained therapeutic effect over a period of months (eg, 6 months) can be re-administered monthly using a sustained-release formulation that delivers the LHRH antagonist for one month. Likewise, to achieve sustained therapeutic efficacy over several weeks using a sustained-release formulation that delivers LHRH antagonist for a week, it may be re-administered weekly. The sustained-release formulation provided herein (see, e.g., Example 3) delivers LHRH antagonist for at least about one month, so it may be re-administered monthly to achieve a long-term therapeutic effect.

The LHRH antagonist may be administered to the subject alone or in combination with at least one other therapeutic agent. Examples of other therapeutic agents include LHRH agonists, anti-androgens, anti-estrogens and sex-steroid biosynthesis inhibitors, which are administered in conjunction with LHRH antagonists.

In another embodiment, the LHRH antagonist is administered with a sex hormone such as estrogen or testosterone. For example, estrogen replacement therapy is often used during (and after) menopause to alleviate certain symptoms associated with menopause, so that estrogen (and / or other related female hormones such as progesterone) and LHRH The subject is treated with both antagonists. The use of LHRH antagonists in combination with estrogen (and / or related female hormones) may use less hormones than when using hormones alone. A similar co-treatment can also be used for the administration of testosterone (and / or a related male hormone).

Further features and advantages of the present invention will appear more clearly in the following description and claims.

The present invention provides a method for suppressing transient hot sensation or female pneumonia in a subject. The method of the present invention is generally characterized by administering an LHRH antagonist to a subject to inhibit a transient hot sensation or female < RTI ID = 0.0 > In certain embodiments, the methods of the invention include administering LHRH to treat transient hot flushes or female < RTI ID = 0.0 > mammoge < / RTI > The transient hottherapeutic method of the present invention can be used, for example, in the treatment of menstrual pain, tamoxifen acetic acid treatment, prostate cancer treatment, alcohol dehydrogenase deficiency or transient hot sensation caused by carcinoid syndrome / chromaffin cell tumor. The method of the present invention for treating female mammogia can be used for the treatment of female mammogia due to hormone imbalance and the like. The pathophysiology of transient hot sensation is not known precisely, but it is likely to be related to the setpoint change of the body temperature control center located in the hypothalamus. For blood samples taken from women with transient hyperthermia, we recorded the onset of transient hyperthermia as a function of gonadotropin releasing hormone (GnRH) release and consequent luteinizing hormone (LH) uptake in the hypothalamus. This increase in LH is believed to lead to a set point reduction in the body temperature control center. A transient hot sensation occurs to achieve equilibrium. Without wishing to be bound by such a mechanism, the ability of the LHRH antagonist of the present invention to inhibit transient warmth is due, at least in part, to inhibition of the LH Mac that reduces the set point of the body temperature control center.

The term " LHRH antagonist " as used herein refers to a compound that inhibits the luteinizing hormone free hormone receptor to inhibit luteinizing hormone release. The term " LHRH antagonist " is interchangeable with the term " LHRH-R antagonist ", which refers to a compound that inhibits LHRH-R to inhibit the release of LH. LHRH antagonists are described, for example, in the following references: U.S. Patent 5,470,947 (Folkers et al.); U.S. Patent 5,843,901 (Roeske et al.); U.S. Patent 5,413,990 (Haviv); U.S. Patent 5,300,492 (Haviv); U.S. Patent 5,371,070 (Koerber et al.); U.S. Patent 5,296,468 (Hoeger et al.); U.S. Patent 5,171,835 (Janaky et al.); U.S. Patent 5,003,011 (Coy et al.); U.S. Patent 4,431,635 (Coy); U.S. Patent 4,992,421 (De et al.); U.S. Patent 4,851,385 (Roeske); U.S. Patent 4,801,577 (Nestor. Jr. et al.); And U.S. Patent 4,689,396 (Roeske et al.).

For example, preferred LHRH-R antagonists that can be used in the methods of the invention include peptides having the following structure or pharmaceutically acceptable salts thereof:

A-B-C-D-E-F-G-H-I-J

From here

A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar or Ac-D-Pal;

B is His or 4-Cl-D-Phe;

C is Trp, D-Pal, D-Nal, L-Nal-D-Pal (N-O) or D-Trp;

D is Ser;

E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys (iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile;

F is

G is Leu or Trp;

H is Lys (iPr), Gln, Met or Arg;

I is Pro;

J is Gly-NH ₂ or D-Ala-NH _2.

In a preferred embodiment, Y is selected from an ylide, a tertiary amine oxide, a nitrile oxide, a pyridine-N-oxide, and a pyridinium amphoteric ion. In a particularly preferred embodiment, Y is an ylide, a pyridine-N-oxide or a pyridinium amphoteric ion. In a preferred embodiment, the peptide has the structure:

Ac-D-Nal-4- Cl-Phe-D-Pal-Ser-Tyr-D-Pal (NO) -Leu-Lys (iPr) -Pro-D-Ala-NH 2.

In another preferred embodiment, the peptide comprises the following structure or a pharmaceutically acceptable salt thereof:

Ac-D-Nal-4- Cl-D-Phe-D-Pal-Ser-Tyr-D-Pal (CH 2 COO -) -Leu-Lys (iPr) -Pro-Ala-NH 2.

In another aspect, the LHRH-R antagonist used in the method of the present invention comprises a peptide having the following structure or a pharmaceutically acceptable salt thereof;

A-B-C-D-E-F-G-H-I-J

Here, assuming that at least one of F and H is Q,

A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar or Ac-D-Pal;

B is His or 4-Cl-D-Phe;

C is Trp, D-Pal, D-Nal, L-Nal-D-Pal (N-O) or D-Trp;

D is Ser;

E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys (iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile;

F is D-Arg, D-Lys (iPr), D-Pal (iPr), D-Cit or Q;

G is Leu or Trp;

H is Lys (iPr), Gln, Met, Arg or Q;

I is Pro;

J is Gly-NH ₂ or D-Ala-NH _2.

In a preferred embodiment, F is Q and Z is a cationic pyridinium moiety. In a preferred embodiment, Z is an N-benzylpyridinium moiety. In another preferred embodiment, F is Q and Z is a sulfonium moiety. In another preferred embodiment, H is Q and Z is a sulfonium moiety. In a particularly preferred embodiment, the peptide comprises a peptide having the following structure or a pharmaceutically acceptable salt thereof:

Ac-Sar-4-Cl- D-Phe-D-Nal-Ser-Tyr-D-Pal (Bzl) -Leu-Lys (iPr) -Pro-Ala-NH 2.

In another particularly preferred embodiment, the peptide comprises the following structure or a pharmaceutically acceptable salt thereof:

Ac-D-Nal-4- Cl-D-Phe-D-Trp-Ser-Tyr-D-Met (S + Me) -Leu-Arg-Pro-Ala-NH 2.

In a particularly preferred embodiment, the peptide comprises the following structure or a pharmaceutically acceptable salt thereof:

Ac-D-Nal-4- Cl-D-Phe-D-Pal-Ser-Tyr-D-Arg-Leu-Met (S + Me) -Pro-Ala-NH 2.

In another aspect, the LHRH-R antagonist used in the method of the invention comprises a peptide having the following structure or a pharmaceutically acceptable salt thereof:

A-B-C-D-E-F-G-H-I-J

From here,

A is p-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar or Ac-D-Pal;

B is His or 4-Cl-D-Phe;

C is Trp, D-Pal, D-Nal, L-Nal-D-Pal (N-O) or D-Trp;

D is Ser;

E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys (iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile;

F is

G is Leu or Trp;

H is Lys (iPr), Gln, Met or Arg;

I is Pro;

J is Gly-NH ₂ or D-Ala-NH _2.

In a preferred embodiment, T is selected from an ylide, a sulfonium moiety, an a-halocarbonyl, a sulfate, a sulfonate, an alkyl halide, and a benzyl halide. In a particularly preferred embodiment T is? -Halocarbonyl.

In another embodiment, the LHRH-R antagonist used in the method of the present invention comprises a peptide having the following structure or a pharmaceutically acceptable salt thereof:

A-B-C-D-E-F-G-H-I-J

From here

A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar or Ac-D-Pal;

B is His or 4-Cl-D-Phe;

C is Trp, D-Pal, D-Nal, L-Nal-D-Pal (N-O) or D-Trp;

D is Ser;

E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys (iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile;

F is

G is Leu or Trp;

H is Lys (iPr), Gln, Met or Arg;

I is Pro;

J is Gly-NH ₂ or D-Ala-NH _2.

In another aspect, the LHRH-R antagonist used in the method of the present invention comprises a peptide having the following structure or a pharmaceutically acceptable salt thereof:

A-B-C-D-E-F-G-H-I-J

From here

A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar or Ac-D-Pal;

B is His or 4-Cl-D-Phe;

C is Trp, D-Pal, D-Nal, L-Nal-D-Pal (N-O) or D-Trp;

D is Ser;

E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys (iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile;

F is

G is Leu or Trp;

H is Lys (iPr), Gln, Met or Arg;

I is Pro;

J is Gly-NH ₂ or D-Ala-NH _2.

In a preferred embodiment, L is selected from D-Cit, D-Asn, D-Gln and D-Thr.

Preferred LHRH antagonists have excellent LHRH antagonistic activity and low histamine-releasing activity (e. G., A histamine release ED ₅₀ of an in vitro histamine release assay standard of at least 3 μg / ml, preferably at least 5 μg / At least 10 [mu] g / ml) and exhibit water solubility. The effects of LHRH candidate antagonists that inhibit LH release are described, for example, by Corbin and Beattie, Endocrine Res. Commun. 2: 1 (1975). In this assay, the LHRH antagonistic activity of the candidate compound is analyzed by measuring the anti-ovulatory activity (AOA) of the compound in the rat. Preferably, the histamine-releasing activity is assayed by the method described in U.S. Patent No. 4,851,385 (Roeske). Preferred LHRH antagonists having low histamine-releasing activity and being water soluble include the compounds described in PCT Publication No. WO 96/40757, the entirety of which is incorporated herein by reference. Particularly preferred LHRH antagonists have the following structure:

By ^{Ac-D-Nal 1, 4} -Cl-D-Phe 2, D-Pal 3, N-Me-Tyr 5, D-Asn 6, Lys (iPr) 8, D-Ala 10 -LHRH (PPI-149 And is described in U.S. Patent No. 5,843,901).

Alternatively, the methods of the present invention can use any compound known to have LHRH antagonistic activity. These LHRH antagonists are suited generally not as, Nal-Glu (structure: Ac-D-Nal (2 ) 1, 4-Cl-D-Phe 2, D-Pal 3, Arg 5, D-Glu 6 (AA) , D-Ala ¹⁰ -LHRH) and SB-75 (also known as CETRORELIX ^TM , structures: Ac-D-Nal ¹ , 4-Cl-D-Phe ² , D-Pal ³ , D-Cit ⁶ , ^10- LHRH). ≪ / RTI > Another example of an LHRH antagonist that can be used in the method of the present invention have the following ^{structure: Ac-D-Nal 1,} 4-Cl-D-Phe 2, D-Pal 3, N-Me-Tyr 5, D -Lys (N-epsilon-nicotinoyl) ⁶ , Lys (iPr) ⁸ , D-Ala ¹⁰ -LHRH (European Patent No. 400 065 B).

As used herein, the term " inhibiting " (used to " inhibit a transient hot sensation " or " inhibit female genitourism ") refers to alleviating or ameliorating transient hot flashes or female complications. The term " inhibiting " includes both partial inhibition and total inhibition.

As used herein, the term " treating " means performing a specific therapeutic regimen for a patient for the purpose of alleviating symptoms or preventing a particular disease.

The term " subject " as used herein includes animals, preferably mammals, most preferably human, that are sensitive to transient hot sensation and / or female ' s disease. In a preferred embodiment, the subject is a primate. In a more preferred embodiment, the primate is human. Other examples of subjects include dogs, cats, goats, and cows.

The term " transient hot sensation " is a term that leads to a paroxysmal disorder of body temperature characterized by sudden body temperature elevation and concomitant sweating.

The term " anti-estrogen " as used herein refers to a compound that antagonizes the release or action of estrogen. Anti-estrogens are known in the art as derivatives of tamoxifen and trioxifen, toremifene, droloxifene, and are commonly available (for example, tamoxifen is a product of ICI Pharmaceuticals, Inc. under the trade name NOLVADEX ^TM ) .

The term " anti-androgen " as used herein refers to a compound that antagonizes the release or action of androgens. Anti-androgens are known in the art, such as, for example, in U.S. Pat. No. 4,386,080, and are commonly available, such as ANDORCUR ^™ , a product of the Schering Aktiengesellschaft. It also includes steroidal anti-androgens and non-steroidal anti-androgens. Specific examples of nonsteroidal androgens include, but are not limited to, flutamide (4'-nitro-3'-trifluoromethylisobutyranilide; available as EULEXIN ^™ from Schering-Plow), bicalutamide and nilutamide .

As used herein, the term " LHRH agonist " refers to a compound that stimulates luteinizing hormone free hormone receptors (e. G., Compounds having LHRH activity) such that the luteinizing hormone is released. LHRH agonists have LH-free activity superior to native LHRH (termed the " second agonist "). A number of LHRH agonists and second agonists are known in the art. Commonly available LHRH agonists are: leuprolide (LUPRON ^TM from Abert / Tiapi), goserelin (ZOLADEX ^TM from Zeneca), boserelin from Zest), tryptorelin D-Trp-6-LHRH and DEBIOPHARM ^™ ), naparerine (SYNAREL ^™ from Syntex), rutrorelin (from Stent), cystorelin (from Sturst), Gonadorerin And hysterelin (manufactured by Ortho).

The term "sexual-steroid biosynthesis inhibitor" includes an adrenal-steroid biosynthesis inhibitor (eg, aminoglutethimide) and a testosterone-steroid biosynthesis inhibitor (eg, ketoconazole) or combinations thereof.

Pharmaceutically acceptable formulation

In the method of the present invention, the LHRH antagonist is generally administered in a pharmaceutical acceptable formulation. The pharmaceutical formulations of the present invention that are pharmaceutically acceptable include those generally comprising a LHRH antagonist and a pharmaceutically acceptable carrier and may be in the form of pharmaceutical compositions comprising macromolecular complexes, nanocapsules, synthetic polymers in the form of microspheres or beads, And oil-in-water emulsions.

In a particularly preferred embodiment, the pharmaceutical formulation is a water-insoluble composite body LHRH antagonist ^{(preferably, Ac-D-Nal 1,} 4-Cl-D-Phe 2, D-Pal 3, N-Me-Tyr 5, Dy-Asn ⁶ , Lys (iPr) ⁸ , D-Ala ¹⁰ -LHRH structures) and carrier macromolecules, preferably those described in U.S. Serial No. 08 / 762,747 and copending application PCT Application No. PCT / US97 / 22881, both of which are incorporated herein by reference in their entirety. In summary, a complex of an LHRH antagonist and a carrier macromolecule can be combined with an LHRH antagonist and a carrier macromolecule under conditions where a substantially insoluble complex is formed (e.g., mixing the LHRH antagonist with the carrier macromolecule aqueous solution until the complex precipitates) Carrier macromolecules. The complex may be in solid form (e. G., Granules, powders or lyophilizates), and the powder form of the complex is finely divided to a sufficient degree to achieve a stable suspension or semi-solid dispersion. The complex may be sterilized, for example, by gamma irradiation or electron beam irradiation prior to administration in vivo. Preferred carrier macromolecules for use in the complex are anionic polymers such as anionic polyalcohol derivatives or fragments thereof and salts thereof (e.g., sodium salts). The anionic moiety capable of deriving the polyalcohol includes, for example, a carboxylic acid group, a phosphoric acid group or a sulfuric acid group. Particularly preferred anionic polymers are anionic polysaccharide derivatives or fragments thereof and salts thereof (e.g., sodium salt). The carrier macromolecules include a single molecular species (e.g., one type of polymer) or two or more different molecular species (e.g., two types of polymer blends). Examples of specific anionic polymers include, but are not limited to, carboxymethylcellulose, alginates, alginates, anionic acetic acid polymers, anionic acrylic polymers, xanthan gum, sodium starch glycolate and fragments, derivatives and pharmaceutically acceptable salts thereof, Anionic carrageenan derivatives, anionic polygalacturonic acid derivatives, and sulfated polystyrene derivatives and sulfonated polystyrene derivatives. A preferred anionic polymer is carboxymethylcellulose sodium salt. In a particular embodiment, the macromolecule sodium carboxymethylcellulose and PPI-149, an LHRH antagonist, are mixed at a ratio of 0.2: 1 (carrier macromolecule: peptide compound). In other embodiments, the ratio of the carrier macromolecule to the peptide compound is, for example, 0.5: 1, 0.4: 1, 0.3: 1, 0.25: 1, 0.15: 1 or 0.1: 1. In a preferred embodiment, the peptide content of the solid ionic complex of the LHRH antagonist and the carrier macromolecule is 57%, 60%, 65%, 70%, 75%, 79% or more by weight. Such a dosage form containing an LHRH antagonist and a carrier macromolecule has the additional advantage of continuously delivering the LHRH antagonist into the subject's tissue at the time of administration.

In another embodiment, the pharmaceutical acceptable dosage form comprises a polymeric substrate. The term " polymer " or " polymeric " is known in the art and has a structural external structure made up of repeating monomeric units. The term also includes natural or naturally occurring copolymers and homopolymers. Straight polymers, prickly polymers and cross-linking polymers are also included herein. For example, polymeric materials suitable for preparing the pharmaceutically acceptable dosage forms employed in the present invention include naturally derived polymers such as albumin, alginate, cellulose derivatives, collagen, fibrin, gelatin, polysaccharides, And synthetic polymers such as polyester (PLA, PLGA), polyethylene glycol, poloxamer, polyanhydrides, pluronics. These polymers are biocompatible and have the ability to degrade free biodegradation without the production of toxic byproducts upon degradation, as well as altering the free mode and duration of the LHRH antagonist by manipulating the kinetic properties of the polymer. As used herein, the term " biodegradable " means that the polymer degrades outside of the time determined by enzymatic or hydrolytic action and / or similar mechanisms within the body of the subject. The term " biocompatibility " as used herein means that the polymer is not toxic or harmful and does not cause an immune rejection reaction, thereby being suitable for living tissues or organisms.

Polymers can be prepared using methods known in the art (Sandler, SR; Karo, W. Polymer Syntheses: Harcourt Brace: Boston, 1994; Shalaby, W .; Ikada, Y .; Langer, The polymer is designed to be flexible, the distance between the living side chains and the linker length between the polymer backbone and the polymer is Other suitable polymers and methods of making them are described in U.S. Patent Nos. 5,455,044 and 5,576,018.

Polymeric formulations may be prepared, for example, by dispersing the active ingredient (e.g., an LHRH antagonist) in a liquefied polymer as described in U.S. Patent No. 4,883,666 or Odian G., Principles of Polymerization and Ring Opening Polymer, Can be prepared by methods such as bulk polymerization, interfacial polymerization and ring polymerization described in John Wiley & Sons, New York, 1981. The properties and properties of the dosage form are controlled by varying parameters such as reaction temperature, concentration of the polymer and LHRH antagonist, solvent type used, and reaction time.

LHRH antagonists comprise microcapsules, microspheres and microparticles, which are encapsulated in one or more pharmaceutically acceptable polymers and are interchangeable herein. Microcapsules, microspheres and microparticles are free-flowing constituents usually composed of spherical particles of 2 mm or less in diameter, usually 500 microns or less. Particles with diameters less than 1 micron are called nanocapsules, nanoparticles or nanospheres. In most cases, the difference between microcapsules and nanocapsules, microspheres and nanospheres or microparticles and nanoparticles is of a magnitude, and generally there is little difference between the two internal structures, even if there is a difference.

In another embodiment, the pharmaceutical acceptable dosage form comprises a lipid-based dosage form. All known lipid transport systems can be used in the present invention. (Also known as "monolayer vesicles or" SUVs ") and large monolayer plate liposomes (large vesicle liposomes, also known as" large vesicle vesicles " Monolayer vesicles or even " LUV ") can be used as long as they can continuously release the encapsulated LHRH antagonist. In one embodiment, the lipid formulation may be somewhat liposomal. Methods for the preparation of more or less liposomal drug delivery systems with controlled release are described in WO 9513796 and WO 9703652.

Compositions composed of synthetic vesicles are generally a phospholipid combination and a steroid, especially a cholesterol combination. Other phospholipids and lipids can also be used. Examples of lipids useful for the production of synthetic membrane vesicles include phosphatidyl glycerol, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingolipids, cerrebroocide, and ganglioside. Phospholipids such as egg phosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dioloylphosphatidylcholine, dipalmitoylphosphatidylglycerol and dioloylphosphatidylglycerol are preferred for use.

In the preparation of lipid vesicles containing LHRH antagonists, parameters such as the encapsulation efficiency of the LHRH antagonist, the instability of the LHRH antagonist, the ratio of the LHRH antagonist to the lipid, permeability, manufacturing instability and pharmaceutical acceptability of the formulation type Lipids, 40:89, 1986 (1986) and Hope et al. (1986), 1987, Reference).

More formulation is comprises a controlled release composition (also called "sustained release composition"), leuprolide respect to administration (under the trade name Lupron ^R) are known in the art. For example, microcapsule formulations are described in U.S. Patent Nos. 4,652,441 and 4,917,893, injectable formulations are described in U.S. Patent No. 4,849,228, lactic acid-glycolic acid copolymers useful in preparing microcapsules or injectable formulations are described in U.S. Pat. 4,677,191 and 4,728,721. Particularly preferred sustained release dosage forms comprise an insoluble complex LHRH antagonist and an anionic carrier macromolecule (in addition to the above-mentioned documents, U.S. Serial No. 08 / 762,747 and PCT Application No. PCT / US97 / 22881 ).

In addition to LHRH antagonists and pharmaceutically acceptable carriers, the pharmaceutically acceptable dosage forms employed in the methods of the invention will additionally contain pharmaceutically acceptable reagents and / or excipients. As used herein, the term " pharmaceutically acceptable reagents and / or excipients " refers to solvents and dispersion media, coatings, antibacterial agents, antifungal agents, isotonic agents (e.g., polyhydric alcohols such as sugars, mannitol, sorbitol, Absorbing agents (e. G., Monostearate and gelatin) and physiologically compatible analogs. Excipients include pharmaceutically acceptable stabilizers and disintegrating agents. It is possible to maintain adequate fluidity by using a coating such as lecithin, or by maintaining the required particle size in the case of dispersion and by using a surfactant. Uses of the active compounds in the pharmaceutical compositions of the present invention are also provided, except that not all conventional vehicles or drugs are compatible with the active compound (e.g., an LHRH antagonist).

Administration of pharmaceutical acceptable dosage forms

The LHRH antagonist is preferably administered to the subject as needed and is preferably administered continuously using sustained-release dosage forms such as osmotic pumps, implants or formulations of transdermal patches, such as LHRH antagonists and anionic Insoluble complexes comprising carrier macromolecules, sustained polymers (e.g., poly-lactide polymers, poly-glycolide polymers and poly-lactide / poly-glycolide copolymers). The sustained-release formulation is administered via a route suitable for continuous release of the drug from the subject, that is, by subcutaneous injection or implantation. Pharmaceutically acceptable formulation forms are readily suspended in aqueous vehicles and injected using conventional injection needles or infusion pumps. Prior to injection, the formulation is sterilized by gamma irradiation or electron beam sterilization as described in U.S. Patent No. 436,742. To be able to inject LHRH antagonist formulations, it is formulated into a physiologically compatible buffer, such as a liquid solution, preferably a lactose or Ringer's solution. In addition, the LHRH antagonist formulations are formulated in a solid form, e. G., Lyophilized, and dissolved or suspended immediately prior to use. Injection of the LHRH antagonist is achieved, for example, by continuous infusion in the form of large pills or infusion pumps.

When the LHRH antagonist is suitably formulated, it may be orally administered, for example, together with an inert diluent or an assimilable edible carrier. The LHRH antagonist (and other ingredients) may be wrapped in a rigid external gelatin capsule or a soft external gelatin capsule, compressed into tablets, or mixed directly into the subject's food. When the LHRH antagonist is orally administered for therapeutic purposes, it can be administered in the form of tablets, oral tablets, capsules, xylitol, suspensions, syrups, ovlaatos and the like, which can be administered and ingested together with excipients. The percentage of LHRH antagonist present in the composition and formulation will vary from case to case. A suitable dosage can be calculated as the amount of LHRH antagonist present in the therapeutically useful composition.

In order to administer the LHRH antagonist by any other parenteral administration method, the compound must be coated or administered together with the substance as a substance to prevent its inactivation.

One of the methods of the present invention is to administer the LHRH antagonist (generally a pharmaceutical formulation) alone to the subject. In another embodiment, the methods of the invention comprise administering an LHRH antagonist in combination with one or more other therapeutic agents. Examples of other therapeutic agents in combination with LHRH antagonist therapy include anti-estrogens (e.g., used in the treatment of estrogen-dependent cancers or female mammogra- phy), anti-androgens, LHRH agonists or inhibitors involved in sex- do. When an adrenal-steroid biosynthesis inhibitor is used, it is preferable to administer the hydrocortisone in an amount sufficient to maintain a normal amount of glucocorticoid concurrently with the patient.

Duration and Dose

In another embodiment of the present invention, the pharmaceutical acceptable dosage form provides for sustained delivery, e. G., &Quot; slow release " LHRH antagonist to the subject. Preferably, the LHRH antagonist is delivered continuously for at least one week, more preferably at least two weeks, or at least one month after administration of the pharmaceutical acceptable dosage form to the subject. In various embodiments, the subject is eligible for treatment with an LHRH antagonist for at least one month, three months, or six months.

As used herein, the term " sustained transport " means that the LHRH antagonist is constantly transported in vivo over a period of time after administration. Continuous delivery of the LHRH antagonist can be seen, for example, as a sustained therapeutic effect of the LHRH antagonist over a period of time (e.g., sustained delivery of the LHRH antagonist inhibits transient fever or female gynecomastia over a period of time) . Alternatively, whether or not the LHRH antagonist is continuously delivered can be confirmed by detecting the presence or absence of the LHRH antagonist for a certain period of time in vivo.

Pharmaceutical formulations used in the methods of the present invention contain a therapeutically effective amount of an LHRH antagonist. &Quot; Therapeutically effective amount " refers to the amount of time and dosage effective to achieve the desired result. A therapeutically effective amount of an LHRH antagonist will depend on such factors as the condition of the disease, the age and weight of the subject, and the ability of the LHRH antagonist (alone or in combination with one or more other therapeutic agents) to elicit the desired response in the subject. The dosage regimen is adjusted to provide the optimal therapeutic response. A therapeutically effective amount also refers to that amount when the therapeutic effect of the LHRH antagonist is much greater than the result of toxicity or harmfulness. The therapeutically effective amount of the LHRH antagonist is in the range of 0.01 μg / kg to 10 mg / kg, preferably about 0.01 to 5 mg / kg, and is not limited to this range. In a preferred embodiment, the dose of the LHRH antagonist is about 15-300 占 퐂 / kg / day, more preferably about 15-200 占 퐂 / kg / day, more preferably about 15-100 占 퐂 / kg / day . Preferred dosages are 30 [mu] g / kg / day, 50 [mu] g / kg / day, or 100 [mu] g / kg / day. It is also noted that the dose depends on the severity of the condition being treated. Also, for each individual patient, the specific dosage regimen is given for a period of time, depending on the needs of the individual and the professional judgment of the LHRH antagonist or manager, and the dosage ranges set forth herein are illustrative only , It is to be understood that the invention is not intended to limit the invention to the aspects or implementations claimed.

Dosage regimens are adjusted to induce optimal therapeutic response. For example, one large pill can be administered or divided into several cycles to be administered over a period of time, or gradually reduced or increased considering the urgency of the treatment. It is preferable to formulate the parenteral composition as a unit dosage form so as to facilitate administration or to formulate the parenteral composition at a uniform dose. As used herein, the term " unit dosage form " means separated into units that can be administered once to a mammalian subject being treated; Each unit containing the determined amount of LHRH antagonist is calculated to have the desired therapeutic effect with the required pharmaceutical carrier. Specific aspects of the unit dosage forms of the present invention include: (a) the characteristics of the particular LHRH antagonist used and the particular therapeutic effect used; and (b) an indication of the combination of such LHRH antagonist to treat a transient hot sensation or female & It is governed by the inherent limitations of the field.

The present invention will be described in more detail by means of the following examples, which are not intended to be limiting. The contents of all citations, patent applications and open patent applications cited in this application are hereby incorporated herein by reference.

Example 1

In this example, patients with increased prostate-specific antigen (PSA) levels after radiotherapy, radical prostatectomy, or other topical treatments, or patients with stage D1 or D2 metastatic prostate cancer are continuously (eg, 14 days or 28 days) Day) at a dose of 30 mg / kg / day or 50 mg / kg / day. Other patients were treated with either the LHRH antagonists proline or both PPI-149 and leuprolide.

Patients completed an endocrine-related questionnaire on whether symptoms associated with changes in male sex hormone levels, including the occurrence of transient hot flashes during the treatment period (other symptoms include fatigue, loss of libido, decreased sexual function, , Body change or thinning, decrease in muscle mass, decrease in muscle tension, weight gain or decrease, frequent urination, urinary incontinence, urinary difficulties, and nocturnal enuresis). The following table summarizes the results of transient hyperthermia for patients treated with PPI-149 alone, or patients treated with leuprolide alone or in combination with PPI-149 with leuprolide:

This data suggests that transient hyperthermia occurred in more than half of the patients treated with the LHRH-active medicament, while transient hyperthermia did not occur in patients treated with PPI-149 alone, the LHRH antagonist. Although not intended to be limited by the mechanism, the occurrence of transient hot sensation is due, at least in part, to a change in the circulating amount of luteinizing hormone (LH) and / or FSH (hormone), and thus the use of LHRH antagonists Inhibit LHRH receptor activity without a slight increase in the amount of LH and / or FSH), regardless of whether it occurs at a clinically time point (e. G., When a woman with transient hyperthermia is in menopause or after menopause Or other patient population) to prevent or inhibit changes in the amount of LH and / or FSH.

Example 2

Patients who are being treated with the LHRH antagonist PPI-149 as described in Example 1 and who have increased prostate-specific antigen (PSA) levels after radiation therapy, radical prostatectomy or other topical treatment, or patients with stage D1 or D2 metastatic prostate cancer Patients were examined for female gynecomastia. The results were compared with data obtained from patients treated with LHRH-active drug rheumrolide. As a result, patients treated with PPI-149 experienced relatively mild female pneumonias compared to patients treated with leuprolide reservoirs.

Example 3

In order to prepare a sustained release LHRH antagonist form, 100 mL of the LHRH antagonist PPI-149 solution was prepared by dissolving 6.25 mg / mL of PPI-149 in water. The same sample (at least 100 ml) of USP carboxymethylcellulose sodium (CMC) (low viscosity, purchased from Hercules Chemical Company) is made up to 0.125% w / v and mixed until dissolved. The same portions of PPI-149 and CMC solution were equally mixed to yield a solid material [ratio of CMC: peptide = 0.2: 1 (w / w)]. The solid material was stirred overnight and then collected by filtration through a 0.45 micron nylon filter. It was confirmed by HPLC that at least 95% of the PPI-149 compound was converted to a solid complex, and the filtrate was removed from the solution. The recovered white plate is washed twice with water, then transferred to a vial and vacuum dried. After drying for 72 hours, 633 mg of white powder was obtained. Crush the solid material with mortar and mortar. It was confirmed that 57% of the peptide was contained in the complex by the basic analysis method.

Example 4

In this example, patients with increased prostate-specific antigen (PSA) levels after radiotherapy, radical prostatectomy or other localized treatment, or patients with stage D1 or D2 metastatic prostate cancer, Week or 85 days), the LHRH antagonist PPI-149 treatment was administered at a dose of 50 mg or 50-100 mg continuously. Other patients underwent LHRH-active drug treatment (LUPRON ^TM ) treatment with or without anti-androgen.

During the course of the treatment, the patients filled out a questionnaire about symptoms such as frequency, severity and duration of transient hot flashes. Results for transient hyperthermia in patients who received 4 weeks PPI-149 alone or in patients treated with leuprolide with anti-androgen are summarized in Table I below:

The following table summarizes the severity of the transient hyperthermia in patients who received 4 weeks PPI-149 alone or in patients treated with leuprolide with anti-androgen:

The results for the transient hyperthermia period in patients who received 4 weeks PPI-149 alone or in patients treated with leuprolide with anti-androgens are summarized in Table III below:

These data demonstrate that patients treated with the LHRH antagonist PPI-149 alone during the first four weeks of treatment had less frequent transient fever than patients treated with leuprolide and anti-androgen. In addition, the transient hyperthermia that occurred in patients treated with PPI-149 alone was much milder and shorter in duration than those with transient hyperthermia treated with leuprolide and anti-androgen.

Equivalent

Those skilled in the art will recognize, or be able to ascertain, using routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are included in the claims of the present invention.

Claims (26)

A method for inhibiting transient hot sensation in a subject comprising administering to the subject an LHRH antagonist to inhibit transient hot sensation. A method of treating a transient hot sensation comprising the steps of: (a) screening subjects who require transient hottherapy; (b) Treat transient hyperthermia by administering an LHRH antagonist to the subject. A method for treating menopausal-related transient hot sensations comprising the steps of: (a) screening subjects in need of postmenopausal-related transient hyperthermia treatment; (b) Treating menopausal-related transient hot sensations by administering an LHRH antagonist to the subject. The method according to any one of claims 1, 2, 3, LHRH antagonists method characterized by having the following ^{structure: Ac-D-Nal 1,} 4-Cl-D-Phe 2, D-Pal 3, N -Me-Tyr ⁵ , D-Asn ⁶ , Lys (iPr) ⁸ , D-Ala ¹⁰ -LHRH. The method according to any one of claims 1, 2 and 3, wherein the subject is a human. 3. The method according to claim 1 or 2, wherein the transient hot sensation is due to menopause. 3. The method according to claim 1 or 2, wherein the transient hot sensation is by treatment with tamoxifen acetate. 3. The method according to claim 1 or 2, wherein the transient hot sensation is by prostate cancer treatment. 3. The method according to claim 1 or 2, wherein the transient hot sensation is due to an alcohol dehydrogenase deficiency. 3. The method according to claim 1 or 2, wherein the transient hot sensation is due to carcinoid syndrome / chromaffin cell tumor. 4. A method according to any one of claims 1, 2 or 3, wherein the LHRH antagonist is administered to the subject via a parenteral route. 4. A method according to any one of claims 1, 2 or 3, wherein the LHRH antagonist is administered to the subject by intramuscular, intradermal or subcutaneous injection. 4. A method according to any one of claims 1, 2 or 3, wherein the LHRH antagonist is administered to the subject in a pharmaceutically acceptable formulation. 14. The method of claim 13, wherein the pharmaceutically acceptable formulation is a lipid-based formulation. 14. The method of claim 13, wherein the pharmaceutically acceptable dosage form comprises a polymeric substrate. 14. The method of claim 13, wherein the pharmaceutically acceptable dosage form comprises an insoluble complex LHRH antagonist and an anionic carrier macromolecule. The method of any one of claims 1, 2, 3, wherein the LHRH antagonist is administered at a dosage of about 15-300 占 퐂 / kg / day. The method of any one of claims 1, 2, 3, wherein the LHRH antagonist is administered at a dosage of about 15-200 g / kg / day. The method according to any one of claims 1, 2, 3, wherein the LHRH antagonist is administered at a dose of about 15-100 占 퐂 / kg / day. 4. A method according to any one of claims 1 to 3, characterized in that the LHRH antagonist is continuously administered using a sustained release formulation. 4. A method according to any one of claims 1 to 3, characterized in that the LHRH antagonist is administered together with at least one other therapeutic agent. A method for inhibiting female < RTI ID = 0.0 > embryonic < / RTI > disorder, comprising administering to a subject an LHRH antagonist to inhibit the subject's female ' s disease. A method for treating female mammograms comprising the steps of: (a) screening subjects who require treatment for female gynecomastia; (b) Treating female mammogia by administering an LHRH antagonist to the subject. 24. The method according to claim 22 or 23, wherein the female mammogram is due to hormone imbalance. 24. The method of claim 22 or 23, wherein the LHRH antagonist has the structure: Ac-D-Nal ¹ , 4-Cl-D-Phe ² , D-Pal ³ , N-Me-Tyr ⁵ , D-Asn ⁶ , Lys (iPr) ⁸ , D-Ala ¹⁰ -LHRH. 24. The method of claim 22 or 23, wherein the LHRH antagonist has the structure: Ac-D-Nal ¹ , 4-Cl-D-Phe ² , D-Pal ³ , Tyr ⁵ , D-Asn ⁶ , Lys (iPr) ⁸ , D-Ala ¹⁰ -LHRH.