JP2003519622A - Pharmaceutical preparations - Google Patents

Abstract

  (57) [Summary] The present invention relates to pharmaceutical formulations for use in treating obesity and related conditions. More particularly, the present invention relates to pharmaceutical formulations comprising sibutramine and its analogs and bulking agents.

Description

Detailed Description of the Invention

[0001] The present invention relates to pharmaceutical formulations suitable for use in obesity and related situations. More particularly, the invention relates to pharmaceutical formulations consisting of sibutramine and its analogs and bulking agents.

Sibutramine is 5-hydroxytryptamine and is an in vivo inhibitor of noradrenaline reuptake (Buckett, WR, Thomas, PC & Luscombe,
GP (1988). Prog. Neuro-Psychopharmcol. Biol. Psychiat. 12, 575-584 and
Luscombe, GP, Hopcroft, RH, Thomas, PC & Buckett, WR (1989). Neu
ropharmacology, 28, 129-134). Studies have shown that this reduces weight through a dual mode of action. This reduces appetite by enhancing satiety (Fantino, M. & Souquet, A.-M. (1995). Int. J. Obesity, 19
, 145; Halford, JCG, Heal, DJ & Blundell, JE (1995). Brit. J. Pha
rmacol. 114, 387P; and Stricker-Krongrad, A., Souquet, A.-M. & Brurlet,
C. (1995). Int. J. Obesity, 19, 145.) and increases energy consumption by stimulating heat generation (Connoley, IP, Heal, DJ & Stock, MJ (1995).
Brit. J. Pharmacol. 114, 388P; and Connoley, IP, Frost, I. Heal, DJ.
& Stock, MJ (1996). Brit. J. Pharmacol. 117, 170P).

[0003] Bulking agents swell in the stomach when water is ingested, which increases satiety and thus reduces appetite. The combination product of sibutramine and absorbable bulking agent is considered to have an enhanced therapeutic effect in combination with a broad market appeal. A typical formulation comprises a centrally acting anorexic sibutramine plus rapidly absorbed sugar as an energy source to assist appetite suppression, and an absorbable bulking agent that hydrates and swells in contact with water. Including.

[0004]   The present invention provides formula I:

[0005]

[Chemical 3]

A pharmaceutical preparation comprising a compound containing an enantiomer and a pharmaceutically acceptable salt represented by the formula: wherein R ₁ and R ₂ independently represent H or methyl, and a bulking agent. provide.

The present invention can provide the following advantages. First, the maximum weight loss achieved is greater than that achieved by administration of either the compound of formula I or the bulking agent alone. Secondly, the weight loss obtained by the administration of the compound of formula I and the bulking agent to the first test group (eg mammal, eg rodent or human) is achieved by the same species group. And the weight loss due to administration of the bulking agent for the third test group of the same species. Thirdly, after weight loss reaches a plateau after administration of a compound of formula I or a bulking agent, administration of another compound causes further weight loss. Fourth, lower doses of compounds of Formula I and bulking agents may be used in the present invention to enhance safety action and duration of efficacy and reduce side effects associated with administration of high doses of each compound. .

Suitable bulking agents include one or more of the following agents: methylcellulose, gooseberry, wheat fiber / bran, isphagula husk, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, guar gum, xanthan. Gum, carrageenan gum, tragacanth, locust bean, agar, locust bean gum, sodium alkynate, alginic acid or Matricor.

[0009]   Advantageously, the formulation consists of: A compound of formula I 0.01-5%, Extender 10.0-90%, Excipient 5.00-89.9%.

[0010]   Advantageously, the formulation consists of: A compound of formula I 0.05-3%, Extender 40.0-80%, Excipient 17.0-59.5%.

[0011]   Most advantageously, the formulation consists of: A compound of formula I 0.1-2%, Extender 50.0-75%, Excipient 23.00-49.9%.

Excipients used are known to the person skilled in the art of pharmaceutical formulation, but are not limited to diluents, binders, disintegrants, lubricants, fragrances, colorants, sweeteners, Includes preservatives and antioxidants and mixtures thereof.

Formulations in the form of tablets, powders, capsules, oral liquids and granules optionally have one or more of the following: diluents such as lactose, microcrystalline cellulose,
Mannitol, corn starch or sorbitol; binders such as hydroxypropylmethylcellulose or polyvinylpyrrolidone; disintegrants such as croscarmellose sodium; lubricants such as magnesium stearate or stearic acid; fragrances such as orange fragrances; sweeteners such as sodium saccharin or aspartame and coloring. Agent.

Advantageously, the bulking agent is selected from methylcellulose, goshuaogiri, wheat fiber or isfagrasaya, guar gum, carrageenan gum, xanthan gum and carboxymethylcellulose. More advantageously, the bulking agent is selected from methyl cellulose, gooseberry, wheat fiber or isfagrasaya.

In another aspect, the present invention provides a method of treating obesity or a related condition, comprising administering the compound of formula I and the bulking agent simultaneously, separately or sequentially.

The preferred compounds of formula I are N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine or salts thereof, for example hydrochloric acid known as sibutramine hydrochloride. It is salt. A preferred form of this hydrochloride salt is that hydrochloride salt known as sibutramine hydrochloride monohydrate.

Preparation of the advantageous compounds of formula I such as N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine or salts thereof and their use in the treatment of depression. Are described in British Patent No. 2098602. The use of N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine or salts thereof in the treatment of Parkinson's disease is described in WO88 / 06444. ing. N- {1
-[1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N
-The use of dimethylamine and its salts in the treatment of brain function disorders is described in US Pat.
, 939,175. The use of N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine hydrochloride in obesity is described in EP-A-397831. A particularly advantageous form of this compound is N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine hydrochloride described in EP-A-230742. It is a salt monohydrate (sibutramine hydrochloride monohydrate). N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine for improving glucose tolerance in humans with impaired glucose tolerance or non-insulin dependent diabetes mellitus and its The use of salts is described in WO 95/20949.

It will be appreciated by those skilled in the art that compounds of formula I have chiral centers. Formula I
Where a compound of 1 has a single chiral center, it can exist in two enantiomers. The invention encompasses the use of individual enantiomers and mixtures of enantiomers. Enantiomers can be separated by methods known to those skilled in the art, for example by formation of enantiomeric salts or complexes which can be separated by crystallization; eg mirror images which can be separated by crystallization, gas-liquid or liquid chromatography. Via formation of an isomeric derivative; by reaction of one enantiomer with an enantiomer-specific reagent, eg enzymatic reaction or reduction, followed by separation of modified and unmodified enantiomers; or in a chiral environment, For example, it can be resolved by gas-liquid or liquid chromatography on a chiral monomer, silica with a bound chiral ligand, or in the presence of a chiral solvent. If the desired enantiomer is converted to another chemical by one of the above separation methods, another step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active substances, substrates, catalysts or solvents, or by converting one enantiomer to the other by an asymmetric rearrangement. Also, the enantiomers of the secondary amines of formula I produce the primary amine racemates, this mixture is decomposed into its individual enantiomers and then the associated optically pure primary amine enantiomers. It can be prepared by converting to the desired secondary amine product.

Preferred compounds of formula I are N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine, N- {1- [1- (4-
Chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine, and 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine, including their racemates, individual enantiomers and mixtures. And their pharmaceutically acceptable salts. The special enantiomer of formula I is (+)-N- {1- [
1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine, (-)-N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N -Dimethylamine, (R)-(+)-N- {1
-[1- (4-Chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine, (S)-(-)-N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine, (R)-(+)-1- [1
-(4-chlorophenyl) cyclobutyl] -3-methylbutylamine and (S)
-(-)-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine.

In the method of the present invention, the compound of formula I and the bulking agent can be administered together or simultaneously in the form of separate dosage units to be used simultaneously, separately or sequentially.

In another aspect, the present invention provides a compound of Formula I, which comprises an enantiomer and a pharmaceutically acceptable salt for simultaneous, separate or sequential use for treating obesity. R ₁ and R ₂ independently of each other represent H or methyl), and a bulking agent.

In yet another aspect, the invention is enantiomerically and pharmaceutically acceptable as a combined formulation for simultaneous, separate or sequential use for treating obesity. Provided are compounds of Formula I, including salts (R ₁ and R ₂ independently of each other represent H or methyl), and a bulking agent.

In another embodiment, a formula comprising an enantiomer and a pharmaceutically acceptable salt for a combined formulation for simultaneous, separate or sequential use for treating obesity A compound of I (R ₁ and R ₂ independently of each other represent H or methyl),
And a product containing a compound of formula II.

In yet another aspect, the invention provides enantiomers and pharmaceutically acceptable salts in the manufacture of a medicament for treating obesity or related conditions in a patient undergoing treatment. And a compound of formula I, wherein R ₁ and R ₂ independently of each other represent H or methyl, and a bulking agent.

In a further aspect, the present invention provides a method of treating obesity, which comprises administering to a patient in need thereof a concomitant therapeutic agent comprising a therapeutically effective amount of a compound of formula I and a bulking agent.

The present invention also provides the use of said combination of a compound of formula I and a bulking agent in the manufacture of a medicament for treating obesity and related conditions. Additionally, the present invention provides a combination for use in treating obesity.

The amount of each compound to be administered will depend on a number of factors including the age of the patient, the severity of the addiction and the patient's previous medical history, but will always be within the appropriate judgment of the administering physician. However, this is generally because the dose of formula I to be administered is in the range of 0.1 to 50 mg per day in one or more administrations, preferably 1 to 30 mg, more preferably 5 mg, 10 mg, 15 mg per day. , 20 mg, 25 mg or 30 mg, most advantageously 20 mg. The amount of bulking agent to be administered is in the range of 100 mg to 10 g, more preferably 5 or more, once or twice a day, preferably 5 times.
It is within the range of 00 mg to 8 g, most preferably within the range of 1 g to 4 g. The compound of formula I, advantageously sibutramine hydrochloride monohydrate, can be administered in any known pharmaceutical dosage form.

In an advantageous embodiment of the invention, it is administered once or twice a day, preferably first in the morning, and the bulking agent is administered twice or three times a day before meals. Advantageously, the dose of sibutramine hydrochloride monohydrate is 10 mg, 15 mg, 20 mg once or twice a day.
mg or 30 mg, and the dose of the bulking agent is 100 mg to 10 times three times before meals.
Within the range of g, for example, 100 mg, 200 mg, 300 mg, 400 mg, 500
mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 12
50 mg, 1500 mg, or 2000 mg, 3000 mg, 4000 mg, 5
000mg, 6000mg, 7000mg, 8000mg or 9000mg is administered. Advantageously, the dose of the bulking agent is administered prior to the first administration of the compound of formula I, preferably prior to the first administration of the compound of formula I, for example 30 minutes after the first administration of the compound of formula I.
1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours ago. More advantageously,
The bulking agent is administered with a compound of formula I.

Oral dosage forms are the preferred compositions for use in the present invention, and these are the known pharmaceutical forms for such administration, such as tablets, capsules, granules, liquids and aqueous solutions. Alternatively, it is an oily suspension. The excipients used in the manufacture of these formulations are well known in the pharmaceutical arts. Tablets may contain the active compound and a filler, such as microcrystalline cellulose; a disintegrant, such as corn starch; a lubricant, such as magnesium stearate; a binder, such as polyvinylpyrrolidone, and tableting the mixture by known methods. It can be made from a mixture of any of the other ingredients well known to those skilled in the art. The tablets may, if desired, be coated by known methods and excipients which may include enteric coating, for example using hydroxypropylmethylcellulose phthalate. Tablets may be prepared in a manner known to those of ordinary skill in the art to give a controlled release of the compounds according to the invention. Such tablets may, if desired, be presented with a coating, such as a film or sugar coating or enteric coating according to known methods by using a cellulose acetate phthalate. Similarly, capsules containing the active compounds with or without added excipients, for example hard or soft gelatin capsules, can also be prepared in a known manner, optionally with enteric coating. The contents of the capsule may be formulated for controlled release of the active compound using known methods. Tablets and capsules may each usually contain 1 to 50 mg of the compound of formula I and 50 to 2500 mg of filler.

Another dosage form for oral administration is, for example, a liquid or aqueous suspension containing the active compound in an aqueous medium in the presence of a nontoxic suspending agent such as carboxymethylcellulose, or a vegetable oil such as peanut. Oily suspensions containing the active compound in oil are included. The active compounds can be prepared in powders or granules with or without additional excipients. The powder or granules may be ingested directly by the patient or may be added to a suitable liquid carrier (eg water) prior to ingestion. The powder or granules may contain a disintegrating agent such as an effervescent combination formed from an acid and a carbonate or bicarbonate to facilitate dispersion in a liquid medium.

In some formulations it may be advantageous to use the compounds according to the invention in the form of particles of very small size, such as are obtained by fluid energy milling.

The pharmaceutical formulations according to the invention optionally contain one or more of the following ingredients: for example fragrances, colorants, sweeteners.

When the pharmaceutical formulation is in liquid form, it optionally contains a preservative. Advantageously, the preservative contains a benzoate or an antioxidant or an antioxidant synergist or mixtures thereof. The formulation may also include an antioxidant, or antioxidant synergist to prevent oxidative degradation. Any of the known antioxidants such as alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid, propyl gallate, sodium ascorbate or sodium metabisulfite or Those synergists such as disodium edetate can be used. More advantageously, the antioxidant is sodium metabisulfite. The level of antioxidant used should be optimized for the respective formulation, eg in the range 0.01-1.0% w / v for sodium metabisulfite, more advantageously Is 0.075 to 0.2
Within the range of% w / v.

Optionally, the liquid pharmaceutical formulation contains one or more fragrances. Advantageously, the fragrance is a fruit fragrance such as lemon, lime, apple and / or a sweetener such as sugar or aspartame.

Advantageously, the fragrance is 0.1-5% w / v of the formulation, more preferably 0.5% -1.
Present in an amount of 5% w / v.

Optionally, the liquid pharmaceutical formulation contains a pharmaceutically acceptable surfactant.
Advantageously, the surfactant is a hydrophilic nonionic surfactant. More advantageously,
Surfactant polysorbate 80, for example, Tween ^(R) 80.

Advantageously, the surfactant is 0.1-2% w / v of the formulation, more advantageously 0.2-1.
Present in an amount of% w / v.

The term “related condition” as used herein in the concept of obesity and related conditions means a medical condition known to those skilled in the art to be associated with weight loss. The term includes, but is not limited to, diabetes, including non-insulin dependent diabetes mellitus in animals, particularly humans, impaired glucose tolerance, lipid syndrome, cachexia,
Hyperglycemia and hyperlipidemia, high uric acid levels and lipid levels.

Furthermore, the present invention provides for metabolic diseases and conditions induced therefrom, such as locomotor activity fever and increased metabolic rate, weight gain associated with drug treatment, osteoarthritis and gout, cancer associated with weight gain, menstruation. It can also be used in the identification of compounds for the treatment or prevention of irregular or gallstones.

The present invention can be used in the identification of compounds for the prevention of heart disease in promoting post-pregnancy weight loss and promoting post-smoking cessation weight loss.

Pharmaceutical formulations containing both a compound of formula I and a bulking agent are an important embodiment of the invention. Such pharmaceutical preparations contain each of the compounds in a therapeutically effective amount. The respective dosage unit can contain daily doses of both compounds, or can contain a fraction of the daily dose, for example 1/3 of the dose.
Alternatively, each dosage unit may contain a total dose of one of the compounds and a fraction of the dose of the other compound. In such cases, the patient will take one of the combined dosage units and one or more units containing only the other compound.

The invention will now be illustrated by the non-limiting examples produced by methods known to those skilled in the art. The granules are prepared by blending with a suitable granulating agent using conventional wet or dry massing or by granulation. Tablets are made by compressing the granules using methods known to those of ordinary skill in the art. Powders and granules can be filled into sachets or processed into tablets.

[0043]

[Table 1]

[0044]

[Table 2]

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, C A, CH, CN, CR, CU, CZ, DE, DK, DM , DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, K E, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, R U, SD, SE, SG, SI, SK, SL, TJ, TM , TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW

Claims (8)

[Claims] 1. Formula I: A pharmaceutical preparation comprising a compound containing an enantiomer and a pharmaceutically acceptable salt represented by the formula: wherein R ₁ and R ₂ independently represent H or methyl, and a bulking agent. 2. A compound of formula I: embedded image together with a pharmaceutically acceptable diluent or carrier. A pharmaceutical preparation comprising a compound containing an enantiomer and a pharmaceutically acceptable salt represented by the formula: wherein R ₁ and R ₂ independently represent H or methyl, and a bulking agent. 3. A compound of formula I (R ₁ and R ₁ ) containing enantiomers and pharmaceutically acceptable salts for simultaneous, separate or sequential use for treating obesity and related conditions. R ₂ represents H or methyl independently of each other), and a bulking agent. 4. A formula I containing an enantiomer and a pharmaceutically acceptable salt as a combined formulation for simultaneous, separate or sequential use for treating obesity and related conditions. A compound of formula (R ₁ and R ₂ independently of each other represent H or methyl), and a compound of formula II. 5. A formula comprising an enantiomer and a pharmaceutically acceptable salt for a combined formulation for simultaneous, separate or sequential use for treating obesity and related conditions. A product containing a compound of I (R ₁ and R ₂ independently of each other represent H or methyl), and a compound of formula II. 6. A compound of formula I (R ₁ ) which comprises enantiomers and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating obesity and related conditions in a treated patient. And R ₂ independently of each other represents H or methyl) and a bulking agent. 7. A bulking agent comprising the following substances: methylcellulose, goshuaogiri, wheat fiber / bran, isfagrasaya, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, guar gum, xanthan gum, carrageenan gum, tragacanth, carob, agar,
The formulation according to claim 1 or 2, comprising one or more of locust bean gum, sodium alginate, alginic acid or matricol. 8. The formulation according to claim 7, wherein the bulking agent is selected from methylcellulose, goshuaogiri, wheat fiber or isfagrasaya.