HK1085124A - Method and compositions for treating anxiety - Google Patents

Description

Methods and compositions for treating anxiety

Background

Benzodiazepines are widely used in the treatment of anxiety. However, many of the side effects associated with the benzodiazepine * class limit their use in the treatment of anxiety disorders. For example, in the treatment of anxiety disorders, the benzodiazepine * class produces muscle relaxation, sedation, and amnesia, and behaviors that are generally considered undesirable. Improved compounds for the treatment of anxiety disorders are as effective as benzodiazepines * in alleviating symptoms, but without these limiting and potentially dangerous side effects. One of these types of compounds that can be used in this regard is pyridopyrazolo [1, 5-a ] pyrimidinones, which are anxiolytics disclosed in U.S. patent 4,521,422 and Vancouver et al, experimental and clinical psychopharmacology 1994, vol.2, No.3, pg.225-233. However, these compositions are difficult to administer from the standpoint of patient compliance. Because, although peak blood concentrations can be reached quickly, they are cleared more quickly from the circulating blood and require at least three daily administrations to achieve sustained therapeutically appropriate blood concentrations. Therefore, in addition to obtaining a rapid onset of action, it is important to maintain the blood concentration of the drug as therapeutic until the next time the drug is administered to exert its activity.

Summary of The Invention

Compositions and methods of using the compositions according to the present invention have been developed for administering the active ingredient 2-pyridine [7- (4-pyridine) pyrazolo [1, 5-a ] -pyrimidin-3-yl ] -methanone, or a pharmaceutically acceptable salt thereof. The active ingredient is in the form of the free base of formula I.

In accordance with the present invention, a new method and composition for administering a compound of formula I (oxepin) or a pharmaceutically acceptable salt thereof to a patient for treating anxiolytic has been developed. According to this development, when these compositions are administered to a patient, the blood concentration remains at a therapeutically suitable concentration during the administration of the compound. Thus, there is no need to repeatedly administer a compound of formula I or salt thereof to maintain its anxiolytic effect. According to the invention, the anxiolytic effect may be maintained for a given whole day by administering the compound once or twice daily. A new class of compounds, other than benzodiazepines *, has been developed for the treatment of anxiety by the methods and compounds of the present invention.

Detailed Description

In accordance with the present invention, compositions and methods have been developed for administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to treat anxiety in a patient in need of such treatment. The method comprises orally administering to a human patient a compound of formula I or a pharmaceutically acceptable salt thereof at a dose of about 0.5mg/kg to 5.0mg/kg of body weight. Treatment of anxiety is apparently achieved by using a daily dosage regimen (regiment) of about 50 to 250mg, preferably about 80mg to about 240mg, and most preferably about 100mg to 240 mg. According to a preferred embodiment of the present invention, the daily administration of a compound of formula I or a pharmaceutically acceptable salt thereof may be carried out by 1 to 3 separate administrations on a given day. Preferably once or twice daily. Each of these separate administrations comprises a portion of the compound of formula I or a salt thereof in a slow release form and the remainder of the active ingredient in a fast release form. In each of these individual administrations, the active ingredient in the fast-release form is about 1 to 4 times, preferably about 2.5 to about 3.5 times the weight of the part of the slow-release form.

According to the present invention, the compounds of formula I or pharmaceutically acceptable salts thereof may be used to treat any form of anxiety including a variety of anxiety disorders. The pyro-disorders treatable according to the methods of the present invention include Generalized Anxiety disorder (Generalized Anxiety disorder) and extreme Anxiety disorder listed in DSM-IV (sonic disorder). The active ingredient compound represented by formula I is ocilpron. According to the present invention, the aforementioned advantageous effects of the present invention are produced when the compound of formula I is administered.

To carry out the method of the invention, pharmaceutical-coated oral unit dosage forms have been developed which comprise an active ingredient divided into two compartments, a first compartment containing the active ingredient for rapid release and a pharmaceutically acceptable carrier, and a second compartment containing the active ingredient for sustained release and a carrier incorporating a hydrophilic polymeric matrix therefor. By providing such a method and unit dosage form, it is possible, on the one hand, to maintain a suitable therapeutic blood concentration of the active ingredient in the patient's circulating blood. This concentration persists throughout the day in the patient. In addition, the patient need not repeatedly administer a compound of formula I or a pharmaceutically acceptable salt thereof throughout the day.

The compounds of formula I may be administered as the free base or as a pharmaceutically acceptable salt thereof. Any conventional pharmaceutically acceptable acid salt such as hydrochloride, citrate, and the like may be used. Other salts, preferably include, for example, hydrobromide, hydroiodide, sulphate, nitrate, phosphate and malate salts.

According to the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof is administered in an oral unit dosage form. Any conventional oral unit dosage form may be used, preferably the oral unit dosage form is a tablet. The daily dose to obtain the desired anxiolytic effect by using the compound of formula I is about 50 to 250mg, preferably about 80 to about 240mg, particularly preferably about 100mg to about 240 mg. According to the invention, the total daily dose may be administered from 1 to 3 times, preferably from 1 to 2 times, respectively. It is generally preferred that these individual daily dosages be approximately equal to the amount of active ingredient administered. As an example, if a person wants to administer 50mg of the active ingredient in two separate doses during the day, about 25mg is administered separately each time. On the other hand, one would like to administer 240mg of a total daily dose to a patient in two separate doses during a day, each separate administration is preferably about 120 mg. Moreover, the two separate doses are preferably administered at about the same time period of myopia during the day (e.g., about 8 hours or 12 hours apart). However, the daily dosage time period for separate administration can be from about 6 to 14 hours, depending on the intensity of the dose, without any deleterious effects.

In the practice of the present invention, it is important that the divided dose has a slow release portion and a fast release portion, and that the weight of the fast release portion is about 1 to 4 times, preferably about 2.5 to about 3.5 times the weight of the slow release portion. Thus, in each of these two divided doses, the amount of active ingredient for the rapid release administration is 1 to 4 times the weight of the part for the slow release administration. This will give stability and sustained maintenance of the active ingredient in the blood system throughout the period of administration of the active ingredient. Generally, it is preferred that the active ingredient for rapid release administration is about 3 times the weight of the portion for slow release administration.

Of these separately administered active ingredients, the amounts of the active ingredients in the slow release form and the fast release form may be administered separately from each other or in combination. The fast-release form for a given mode of administration may be administered in a single dosage form, e.g. a capsule or a tablet or individual tablets, in which each total amount is administered by fast-release. For example, if one desires to administer 90mg of the active ingredient in a fast-release form, one can take three tablets or capsules containing different or the same amounts, which together are 90 mg. The same applies with regard to the administration of the active ingredient in a sustained release form. In any event, during each individual administration, the amount of active ingredient administered in the fast-release form is from about 1 to about 4 times the weight of the administered portion in the slow-release form. During each of these two separate administrations, the active ingredients in the fast-release and slow-release forms are administered together or even separately, but within a very short time.

According to a preferred embodiment of the present invention, there has been provided an oral unit dosage form, such as a tablet or capsule, for administering an active ingredient in a sustained and rapid release form as a single dosage unit. These oral unit dosage forms may be any conventional dosage unit, preferably a tablet. Thus, during separate administration, the patient may take one or two such unit dosage forms containing the active ingredient in both sustained and rapid release forms. According to the present invention, an oral dosage form comprising about 15 to about 250mg of a compound of formula I or a salt thereof may be prepared to have about 1 to 4 times the amount of the active ingredient in the fast-release portion as compared to the amount in the slow-release portion. A preferred oral unit dosage form is a capsule or tablet of 120mg of active ingredient, containing 30mg of active ingredient in a sustained release form and 90mg of active ingredient in a rapid release form. Another preferred oral dosage form is a capsule or tablet comprising 40mg of active ingredient, which contains 10mg of active ingredient in a sustained release form and 30mg of active ingredient in a rapid release form. Another preferred dosage form is a tablet or capsule of 240mg of active ingredient, containing 80mg of active ingredient in a sustained release form and 160mg of active ingredient in a rapid release form. This provides a simple way of administration for slow and fast release dosage forms to maintain a constant blood concentration of the compound of formula I during the treatment period.

In preparing oral unit dosage forms, preferably tablets, containing a compound of formula I as the active ingredient, the active ingredient is typically admixed with a diluent or carrier in an amount of about 40 to 75 weight percent of the immediate release composition. In slow release tablets, the diluent is typically present in an amount of 40 to 60 weight percent. Preferred diluents or carriers include lactose. Any conventional diluent may be used in accordance with the present invention. These oral dosage forms, especially tablets, typically comprise other conventional excipients, such as binders, disintegrants, lubricants or glidants, which are commonly used in formulations, such as oral unit dosage forms like tablets. The disintegrant may be one of certain modified starches or modified cellulose polymers, in particular croscarmellose sodium and crospovidone, and the binder may be any conventional binder such as vinylpyrrolidone, microcrystalline cellulose.

In preparing an extended release tablet, the active ingredient of formula I or a salt thereof is mixed with a diluent or carrier and one or more other additional formulation ingredients or excipients together, and further mixed with a hydrophilic polymeric extended release matrix which causes slow release of the active ingredient after ingestion of the tablet by a patient. The hydrophilic slow release polymers used according to the present invention typically have a viscosity of about 100cps to about 100,000 cps.

Any conventional polymeric hydrophilic sustained release matrix may be used. Including hydroxypropyl methylcellulose and other hydrophilic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxyvinyl polymers, polyvinyl alcohol, dextran, scleroglucan, mannan, xanthan gum, carboxymethyl cellulose and its derivatives, methyl cellulose, and most celluloses, cross-linked polyvinyl pyrrolidone. According to the present invention, the hydrophilic polymer matrix that produces slow release of the compound of formula I is typically incorporated into the slow release formulation in an amount of from about 20 to about 35 weight percent of the entire slow release formulation.

Tablets of the invention are prepared according to conventional tabletting procedures except that the active ingredient and carrier or diluent are ground to a particle size of less than 250 microns in diameter. Any conventional method of grinding the formulation may be used to achieve this result. The preferred method of achieving this result is to pass the active ingredient, composition with or without polymeric sustained release matrix and diluent, through a hammer mill with a 60 mesh screen at high speed to produce this reduction in particle size. For slow release formulations, the mixture passed through the hammer mill includes a slow release matrix in the composition. After granulation, the composition may be compressed into tablets containing the active ingredient in a slow release form or containing the active ingredient in a fast release form. This can be achieved by any conventional tabletting method, for example using a single layer tablet compression. On the other hand, if it is desired to obtain a bilayer unit tablet, it is possible to make both the slow release composition and the fast release composition as well as the tablet itself into a single bilayer tablet. In this method, the two components can be formulated into a single tablet using a bilayer tablet compression. Any conventional method of forming a bilayer tablet by compressing the active ingredient component compounds may be used to carry out this process.

The term "tablet" as used herein refers to a pharmaceutical dosage form comprising all shapes and particle sizes, coated or uncoated, that are compressed. Substances which may be used for coating include any conventional coating material, which may be titanium dioxide, talc, sweeteners and colorants.

The invention is further illustrated by the following examples. In the examples:

polyplasdone is polyvinylpolypyrrolidone.

Aerosil is a colloidal silica.

Kollidon 30 is polyvinylpyrrolidone.

Mag Stearate is magnesium Stearate.

Methocel K100M was hydroxypropyl methylcellulose, 1,000,000 cps.

Methocel K100LV was hydroxypropyl methylcellulose, 1,000,000 cps.

Examples

Example 1

Preparation of fast Release (RR)60MG and 90MG tablets

	In% by weight of the composition
			Substance(s)	60mg RR tablet	90mg RR tablet
Octoprone	18.6	27.1
			Fast-flow lactose	63.9	53.8
Polyplasdone	9.7	9.7
			Aerosil	0.8	0.9
Kollidon 30	3.1	4.5
			Mag Stearate	1.0	1.0
Opadry Brown	2.9	2.9

Process for preparing tablets

A. Olsimon, fast-flowing lactose, half the Polyplasdone, half the Aerosil 200 were weighed.

B. Mix in a 10L V conical stirrer for 10 minutes at 18 rpm.

C. Sieving with Fitzmill (hammers) and 60 mesh sieve; particles having a diameter of less than 250 microns are produced at high velocity.

D. Granulated in a fluidized bed system GlattGPCG-3) using PVP (7.5% w/w in water) as binder to obtain the target composition of 5% binder and 95% ground mixture.

E. The granules were mixed with the remaining Aerosil and the remaining Polyplasdone in a V-cone blender for 5 minutes, after which magnesium stearate was added and mixed for an additional 3 minutes.

F. IR tablets were prepared using a Piccola tablet press using a 9mm round, conventional concave tooling to achieve the target hardness of 160N (30%) and the necessary target weight (7%).

G. The formed tablets were coated in Vector Coater with Opadry Brown (12% w/w aqueous solution) and the weight gain was 3%.

Example 2

Preparation of 30MG Sustained Release (SR) tablet

	In% by weight of the composition
		Substance(s)	30mg SR coated tablet
Octoprone	19.4
		Methocel K100M	11.6
Methocel K100LV	17.5
		Fast-flow lactose	41.8
Aerosil	1.0
		Kollidon 30	4.8
Mag Stearate	1.0
		Opadry Brown	2.9

Process for preparing oxcarbazolone tablets

A. Olcetron, fast-flowing lactose, Methocel K100M, Methocel K100LV and half the amount of Aerosil 200 were weighed.

B. Mix in a 10L V conical stirrer at 18rpm for 10 minutes.

C. Sieving with Fitzmill (hammers) and 60 mesh sieve; particles having a diameter of less than 250 microns are produced at high velocity.

D. Granulation was carried out in a fluid bed system (GlattGPCG-3) using (7.5% w/w aqueous solution) PVP as binder to obtain the target composition of 5% binder and 95% ground mixture.

E. The remaining Aerosil was mixed for 5 minutes in a V-cone blender, after which magnesium stearate was added and mixed for an additional 3 minutes.

F. SR tablets were prepared using a Piccola tablet press using a 7mm round, conventional concave tool to achieve a target hardness of 200N (30%) and the necessary target weight (7%).

G. The formed tablets were coated in a Vector Coater with a cosmetical coating of Opadry Brown (12% w/w aqueous solution) to achieve a target weight gain of 3%.

Example 3

Preparation of bilayer tablet with 30MG SR/90MG RR

90mg of the IR composition of example 1 and 30mg of the SR composition of example 2 were used. Steps a to E of examples 1 and 2 were utilized. The compositions of examples 1 and 2 were placed in a bilayer tablet press and compressed in the press to form a single bilayer tablet. After compression, the tablets were coated in the manner as in step G of example 1.

Example 4

Procedure

The 30mg SR tablet of example 2 and the 90mg IR tablet of example 1 were used for the administration.

Placebo for this study was prepared as follows.

Substance(s)	In% by weight of the composition
		Avicel	96.6
Mag Stearate	0.5
		Opadry Brown	2.9

Preparation process

A. Avicel and magnesium stearate were weighed. Mix together in a V-cone mixer at 18 rpm.

B. Placebo was prepared using a Piccola press using either a 7mm round, conventional concave tool or a 9mm round, conventional concave tool to achieve the necessary strength (+/-30%) and the necessary weight (+/-7%).

C. The formed tablets were coated in a Vector Coater with Opadry Brown (12% w/w aqueous) cosmetic coating to achieve a target weight gain of 3%.

The actual study was carried out for 14 days. The total number of patients per treatment group was 60. There were three treatment groups. The doses of oxiprone (RR and SR combination) and comparative placebo administered were as follows:

SR(mg)/IR(mg)	SR/RR Total dose (mg)	Dosing regimens	Total daily dose (mg)
				0/60	60	Three times daily	180
30/90	120	Twice daily	240
				Placebo	0	Comparison of	0

To mask the patients, all patients were dosed three times daily, 2 tablets each time. 30/90 group of oxepin receiving placebo as one of 3 doses per day; they received two more doses containing the active ingredient.

Example 5

85. Preparation of 210, 195 and 195MG SR tablets

Tablets containing 85mg, 110mg, 195mg and 210mg were prepared with the ingredients listed in the following table. All% in the table are% by weight of the total composition.

	A	B	C	D	E
						Octoprone	29.1％	30.0％	30.0％	30.0％	30.0％
Methocel K100M	9.3％				20.4％
						Methocel K100LV	19.8％	30.0％	30.0％	30.0％	9.6％
Sodium lauryl sulfate			6.0％	6.0％	6.0％
						Lactose	32.1％	35.0％	29.0％	29.0％	29.0％
Aerosil 200	1.0％	1.0％	1.0％	1.0％	1.0％
						Kollidon 30	4.8％	3.0％	3.0％	3.0％	3.0％
Magnesium stearate	1.0％	1.0％	1.0％	1.0％	1.0％
						Opadry Brown	2.9％
Milligrams of oxepin per tablet	210mg	85mg	85mg	110mg	195mg
						Tablet size	18X 8mm elliptical conventional concave surface	7mm round conventional concave surface	7mm round conventional concave surface	Circular conventional concave surface of 9mm	18X 8mm elliptical conventional concave surface

The tablets were prepared in a manner similar to example 1, except that granulation was performed to obtain the theoretical composition of 3% binder and 97% ground blend for B-E. The tablets were not coated.

Example 6:

dissolution rate of sustained-release tablet containing oxcarbazolone

Dissolution experiments for example 2 and examples 5(A), (B), (C), (D) and (E) were performed using a USP1 instrument, a 20 mesh basket, 100rpm, 900ml of phosphate buffer pH 6.8-0.05 containing 0.5% SLS at 37 ℃. + -. 5 ℃.

The amounts of ocilpron in the samples were determined by HPLC and are listed in the table below.

	Example 2	Example 5(A)	Example 5(B)	Example 5(C)	Example 5(D)	Example 5(E)
							Time (hours)	Average release%
1	10.5	6.0	11.1	9.1	10.0	5.1
							4	48.7	29.8	45.2	46.2	44.4	27.3
8	90.9	60.9	84.0	91.0	85.2	57.7
							12	107.0	80.1	105.0	101.7	97.6	79.4
22	-	103.6	102.8	103.1	100.3	102.0

Example 7

Preparation of 30mg quick Release IR tablet

Tablets containing 30mg of oxcarbazolone were prepared according to the ingredients listed in the following table. All% in the table are by weight of the total weight% of the composition.

Substance(s)	A
		Ocinaplonin	9.4
Fast-flow lactose	74.8
		Polyplasdone	9.7
Aerosil	0.6
		Kollidon 30	1.6
Mag Stearate	1.0
		Opadry Brown	2.9
Milligrams of oxepin per tablet	30
		Tablet size	9mm round

Example 8

Preparation of 60MG and 25MG RR capsules

Tablets containing 60mg of ocilpron (a) and 25mg of active ingredient (b) were prepared using the following table materials. All% in the table are by weight% based on the total weight of the composition.

Substance(s)	A	B
			Octoprone	26.25	26.25
Avicel PH 101	20.0	20.0
			Starch 1500	10.0	10.0
Aerosil 200	0.25	0.25
			Pharmatose DCL11	42.5	42.5
Magnesium stearate	1.0	1.0

The excipients were sieved and all excipients except magnesium stearate were mixed for 15 minutes at 18rpm in a Pharmatech mixer equipped with a 10L V conical stirrer. Magnesium stearate was added and mixed for an additional 5 minutes. The mixture was manually encapsulated.

Example 9

Dissolution of fast release tablets and capsules containing oxcarbazolone

	Example 1(60mgIR tablet)	Example 1(90mgIR tablet)	Example 7(30mgIR tablet)	Example 8A (60mgIR capsule)	Example 8B (25mgIR capsule)
						0.5 hour	105.8％	96.9％	104.0％	78.3％	79.6％

Dissolution experiments for examples 1, 7, 8(A) and (B) were performed using a USP1 apparatus, 20 mesh basket, 100rpm, 0.01lN hydrochloric acid.

Claims (21)

1. A method for treating anxiety in a patient in need thereof, which comprises orally administering to said patient an anxiolytic compound of formula I, or a pharmaceutically acceptable salt thereof, as active ingredient in a daily dose of about 50 to 250mg,

said daily oral dosage comprises a first portion of the active ingredient in a fast-release form and the remainder of said active ingredient in a sustained-release form, said active ingredient being administered in a proportion of from about 1 to about 4 times the weight of the portion administered in the sustained-release form.

2. The method of claim 1 wherein the daily dose is administered in 1 to 3 administrations per day of administration.

3. The method of claim 1, wherein the active ingredient is administered as a tablet.

4. The method of claim 2, wherein in each of said separate administrations, the sustained release portion is administered in combination with the fast release portion.

5. The method of claim 4, wherein the daily dose of the anxiolytic compound is about 120 to 240 mg.

6. The method of claim 5, wherein the proportion of said active ingredient in the fast-release form in each of said administrations is from about 2.5 to about 3.5 times the weight of the slow-release portion.

7. The method of claim 3, wherein in each of said administrations, the slow release portion is administered with the fast release portion.

8. The method of claim 7, wherein in each of said administrations, the slow release portion and the fast release portion are administered in a single tablet.

9. The method of claim 8, wherein the tablet contains the active ingredient in the fast-release form in an amount about 3 times the weight of the active ingredient in the slow-release form.

10. The method of claim 9, wherein the administered tablet contains about 10mg of the active ingredient in a sustained release form and about 30mg of the active ingredient in a rapid release form.

11. The method of claim 9, wherein the administered tablet contains about 30mg of the active ingredient in a sustained release form and about 90mg of the active ingredient in a rapid release form.

12. A pharmaceutical oral unit dosage form comprising two separate compartments, each compartment containing a pharmaceutical active ingredient selected from the group consisting of a compound of formula I and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier

The composition of (a), wherein the amount of said active ingredient in the unit dosage form is from about 50 to 250mg, the amount of said active ingredient in the first compartment is from about 1 to about 4 times the weight of said active ingredient in the second compartment, the composition in the first compartment is adapted to rapidly release the active ingredient contained therein, and the composition in the second compartment has incorporated therein a hydrophilic polymeric matrix capable of causing sustained release of the active ingredient in the second compartment.

13. The unit dosage form of claim 12 wherein the oral dosage form is a tablet.

14. The unit dosage form of claim 13, wherein the composition has a particle size of less than 250 microns in diameter.

15. The unit dosage form of claim 14 wherein the polymeric matrix is hydroxypropyl methylcellulose.

16. The unit dosage form of claim 15 wherein the pharmaceutically acceptable carrier in each of said compartments is fast flow lactose.

17. The unit dosage form of claim 14 wherein the amount of active ingredient in the unit dosage form is about 80 to 240 mg.

18. The unit dosage form of claim 17 wherein the amount of active ingredient in the unit dosage form is about 120 to 240 mg.

19. The unit dosage form of claim 18 wherein the amount of active ingredient in the fast-release portion is from about 2.5 to about 3.5 times the weight of the active ingredient in the slow-release portion.

20. The unit dosage form of claim 19, wherein the tablet contains about 30mg of the active ingredient in a sustained release form and about 90mg of the active ingredient in a rapid release form.

21. The unit dosage form of claim 20 wherein the tablet contains about 10mg of active ingredient in a sustained release form and about 30mg of active ingredient in a rapid release form.