KR100484994B1 - Pharmacy Composition - Google Patents

Abstract

The present invention relates to 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable thereof. A sustained release formulation comprising a salt, a method for treating a psychotic state and hyperactivity using the sustained release formulation, and a method for preparing the sustained release formulation.

Description

Pharmaceutical composition

The present invention relates to pharmaceutical compositions, more specifically 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or It relates to a sustained release pharmaceutical composition comprising a pharmaceutically acceptable salt thereof.

For the treatment of many diseases in both aspects of treatment and prevention, it is desirable to provide the active pharmaceutical ingredient in a sustained release form. Preferably the sustained release generally provides a uniform and constant release rate over a long time, whereby a stable desired blood (plasma) concentration of the active ingredient is achieved without the need for frequent administration of the medicament.

Although there are a number of sustained release formulations known in the art that utilize gelling agents such as hydroxypropyl methylcellulose, it is difficult to formulate sustained release formulations consisting of soluble agents and gelling agents such as hydroxypropyl methylcellulose. It turned out. First and foremost, water-soluble active ingredients tend to yield sustained-release products that are sensitive to a phenomenon known as drug dumping. That is, the release of the active ingredient is delayed for a period of time, but once the release begins to occur the release rate becomes very high. In addition, fluctuations in the plasma concentration of the active ingredient tend to increase the likelihood of toxicity. In addition, some changes in the plasma concentrations of the active ingredient were observed daily. Finally, it has been found difficult to achieve the desired degradation profile or to control the rate of release of soluble drugs.

Thus, it is possible to overcome or at least alleviate one or more of the difficulties described above and furthermore to administer the active agent less frequently, eg once daily, but more frequently, for example, in smaller doses of the drug. Soluble agents, such as 11- [4- [2- (2-hydroxyethoxy) ethyl] -1, that provide advantageous properties that can achieve similar blood (plasma) concentrations as obtained by twice daily administration There is a need for sustained-release preparations of piperazinyl] dibenzo [b, f] [1,4] thiazepine or pharmaceutically acceptable salts thereof.

1 shows a suitable tablet obtained by dipping in 750 ml of 0.1 N HCl at 100 rpm for 2 hours at 37 ° C., followed by the addition of 250 ml of 0.2 M sodium phosphate buffer to the digestion medium to pH 6.2. Examples 8, 9 And the release (decomposition) profile of the sustained release formulation of 10.

FIG. 2 shows the plasma concentration versus time profile of the active ingredient in the sustained release formulations of Examples 1 and 2 and the immediate release formulation of Example 12.

Compound 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] -dibenzo [b, f] [1,4] thiazepine (see Formula I below) and its Pharmaceutically acceptable salts show useful antidopaminergic activity, for example as an antipsychotic agent (eg, an antipsychotic agent for the control of mental disease manifestations) or hyperactivity. It can be used as a therapeutic for. The compound substantially reduces the possibility of causing side effects that may occur by using other antipsychotics or neuroleptics, such as acute dystonia, acute dyskinesia, pseudo-Parkinson's disease, and spontaneous dyskinesia. This is very important because it can be used as an antipsychotic.

[Formula I]

Preparation of 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine and its pharmaceutically acceptable salts, Physical and beneficial pharmacological properties are described in European Patent Publication Nos. 240,236 and 282,236 as well as US Pat. No. 4,879,288, the entire contents of which are incorporated herein by reference.

The present invention provides a gelling agent, preferably hydroxypropyl methylcellulose and 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1, 4] Provided a sustained release formulation comprising thiazine or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients. Preferably, the sustained release preparation is a gelling agent, preferably hydroxypropyl methylcellulose and 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients.

As used herein, the term gelling agent refers to any substance which forms a gel when in contact with water, in particular a hydrophilic substance, examples of which are hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydride Hydroxyethyl cellulose, hydroxypropyl ethyl cellulose, methyl cellulose, ethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, carbomer, sodium carboxymethyl cellulose, polyvinylpyrrolidone and the like or a mixture thereof. . The gelling agent is preferably hydroxypropyl methylcellulose.

The amount of gelling agent, preferably hydroxypropyl methylcellulose, is such that the active ingredient is released from the formulation in a controlled manner over a period of at least 4 hours, preferably at least 8 hours, in particular 8 to 24 hours, ie It is preferred to select at least 60% of the active ingredient to be released by the second half.

The gelling agent, preferably hydroxypropyl methylcellulose, is easily from about 5% to 50% by weight, more easily from about 5% to 40% by weight, most preferably from about 8% to 30% by weight, Especially from about 10% to 35% by weight. In general, the gelling agent, preferably hydroxypropyl methylcellulose, is preferably present at about 10% to 30% by weight, more preferably at about 15% to 30% by weight.

Hydroxypropyl methylcellulose may contain one or more grades of polymers, and several trade names, such as METHOCELL E, F, J and K (product of Dow Chemical Company, USA) and metallo It is marketed by OSU (METALOSE: brand name) SH (product of Shin-Etsu Limited, Japan). The various grades available under the trade name differ in viscosity as well as methoxy content and hydroxypropoxy content. The methoxy content ranges from 16.5% to 30% by weight, the hydroxypropoxy content ranges from 4% to 32% by weight, and the viscosity of the 2% aqueous solution at 20 ° C. ranges from 3 cps to 100,000 cps. For example, hydroxypropyl methylcellulose has (a) a viscosity of about 40 cps to 60 cps (particularly about 50 cps), a methoxy content of about 28% to 30% by weight, and a hydroxypropoxy content of A polymer having from about 7 wt% to less than 9 wt%, or (b) a viscosity of about 3,500 cps to 5,600 cps (particularly about 4,000 cps), a methoxy content of about 28 wt% to 30 wt%, and hydroxypropoxy A polymer having a content of about 7 wt% to 12 wt%, or (c) a viscosity of about 80 cps to 120 cps (particularly 100 cps), a methoxy content of about 19 wt% to 24 wt%, and hydroxypro A polymer having a foxy content of about 7% to less than 9% by weight, or (d) a viscosity of about 3,500 cps to 5,600 cps (particularly about 4,000 cps), a methoxy content of about 19% to 24% by weight, and It is preferred to include polymers having a oxypropoxy content of about 7% to 12% by weight, or mixtures thereof. The hydroxypropoxy methyl cellulose is preferably selected from the group consisting of the above-mentioned (a) to (d) or mixtures thereof, provided that the formulation contains hydroxypropyl methylcellulose as described in (d) above. The total amount of hydroxypropyl methylcellulose present should be at least 25.8% by weight.

In one embodiment, the hydroxypropyl methylcellulose comprises 8% to 12%, preferably about 5% to 10%, of a polymer having a viscosity of about 4,000 cps. In another embodiment, the hydroxypropyl methylcellulose comprises 10% to 35%, preferably about 10% to 15%, of a polymer having a viscosity of about 50 cps.

In certain embodiments, hydroxypropyl methylcellulose comprises 15% of a polymer having a viscosity of about 50 cps and optionally about 5% of hydroxypropyl methylcellulose polymer having a viscosity of about 4,000 cps.

In particular 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable salt thereof ( Preferably the hemifumarate salt) is about 10% to 90% by weight, preferably about 20% to 80% by weight, more preferably about 35% to 65% by weight, most preferably about 40% by weight % To 60% by weight, in particular about 43.2% to 57.6% by weight.

In general, formulations contain one or more excipients. Such excipients are diluents, for example, lactose, microcrystalline cellulose, dextose, mannitol, sucrose, sorbitol, gelatin, acacia, calcium dihydrogen phosphate, calcium phosphate, calcium dihydrogen phosphate, sodium phosphate, sodium carbonate and the like, preferably Are lactose and microcrystalline cellulose; Glidants such as stearic acid, zinc stearate, calcium stearate, magnesium stearate and the like, preferably magnesium stearate; Binders such as sucrose, polyethylene glycol, povidone (polyvinylpyrrolidone), corn or maise starch, pregelatinized starch and the like, preferably povidone (polyvinylpyrrolidone); Colorants such as iron oxides, FD & dyes, lakes and the like; Spice; And suitable organic acids or alkali metal (eg lithium, sodium or potassium) salts thereof, such as benzoic acid, citric acid, tartaric acid, succinic acid, adipic acid and the like or their corresponding alkali metal salts, preferably the above PH adjusting agents including alkali metal salts of acids, in particular sodium salts of citric acid (ie sodium citrate). Generally, the excipient (s) is about 10% to 90% by weight, preferably about 20% to 80% by weight, more preferably about 20% to 45% by weight, most preferably about 20% by weight To 40% by weight, especially about 22.4% to 36.8% by weight. The formulation may preferably contain one or more pharmaceutically acceptable excipients selected from the group consisting of microcrystalline cellulose, lactose, magnesium stearate, sodium citrate and povidone. In particular, the formulation comprises (a) preferably microcrystalline cellulose in an amount of about 4% to 20% by weight, (b) preferably lactose in an amount of about 5% to 20% by weight, (c) preferably about Magnesium stearate in an amount of 1% to 3% by weight, (d) sodium citrate in an amount of about 10% to 30% by weight, preferably about 12.5% to 25% by weight, in particular about 12.5% by weight, and (e ) At least one of povidone (polyvinylpyrrolidone) in an amount of about 1% to 15% by weight, preferably about 4% to 6% by weight, in particular about 5% by weight.

The present invention also provides a gelling agent, preferably hydroxypropyl methylcellulose and 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [ 1,4] S sustained release formulations comprising thiatiazepine or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients, one of which is a pH adjusting agent.

The present invention also provides 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or an active ingredient thereof as an active ingredient. It provides a sustained release formulation comprising a pharmaceutically acceptable salt and 5% to 40% by weight of hydroxypropyl methylcellulose together with one or more pharmaceutically acceptable excipients.

The present invention also provides 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or an active ingredient thereof as an active ingredient. Provided is a sustained release formulation comprising about 35% to 65% by weight of a pharmaceutically acceptable salt and 5% to 40% by weight of hydroxypropyl methylcellulose together with one or more excipients.

The present invention also provides 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or an active ingredient thereof as an active ingredient. About 35% to 65% by weight of a pharmaceutically acceptable salt and about 15% to 30% by weight of hydroxypropyl methylcellulose together with about 20% to 45% by weight of one or more pharmaceutically acceptable excipients A sustained release formulation is provided.

The present invention also provides 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or an active ingredient thereof as an active ingredient. Pharmaceutically acceptable salts of about 35% to 65% by weight, about 5% to 40% by weight of hydroxypropyl methylcellulose, about 4% to 12% by weight of microcrystalline cellulose, about 8% to 20% by weight of lactose And the remaining weight percent of one or more pharmaceutically acceptable additional excipients. The additional excipient may include ingredients (eg, magnesium stearate) that act as glidants during preparation of the formulation or dosage form.

In addition, the present invention (a) hydroxypropyl having a viscosity of about 40 cps to 60 cps, a methoxy content of about 28% to 30% by weight, and a hydroxypropoxy content of about 7% to less than 9% by weight. Methylcellulose, (b) hydroxypropyl methylcellulose having a viscosity of about 3,500 cps to 5,600 cps, a methoxy content of about 28% to 30% by weight, and a hydroxypropoxy content of about 7% to 12% by weight (c) hydroxypropyl methylcellulose having a viscosity of about 80 cps to 120 cps, a methoxy content of about 19% to 24% by weight, and a hydroxypropoxy content of about 7% to less than 9% by weight; d) from the group consisting of hydroxypropyl methylcellulose having a viscosity of about 3,500 cps to 5,600 cps, a methoxy content of about 19% to 24% by weight, and a hydroxypropoxy content of about 7% to 12% by weight. Selected Hydroxypropyl Meth Cellulose or from about 5% to 40% by weight mixtures thereof; 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable salt thereof Weight percent to 65 weight percent; And about 20% to 45% by weight of one or more pharmaceutically acceptable excipients, provided that the formulation comprises hydroxypropyl methylcellulose as described in (d) above The total amount of hydroxypropyl methylcellulose present should be at least 25.8% by weight.

Other agents within this class include (a) a viscosity of about 40 cps to 60 cps, a methoxy content of about 28% to 30% by weight, and a hydroxypropoxy content of about 7% to 9% by weight. Hydroxypropyl methylcellulose less than%, (b) viscosity of about 3,500 cps to 5,600 cps, methoxy content of about 28% to 30% by weight, hydroxypropoxy content of about 7% to 12% by weight Hydroxypropyl methylcellulose, (c) hydroxy having a viscosity of about 80 cps to 120 cps, a methoxy content of about 19% to 24% by weight, and a hydroxypropoxy content of about 7% to less than 9% by weight Propyl methylcellulose and (d) hydroxypropyl methyl having a viscosity of about 3,500 cps to 5,600 cps, a methoxy content of about 19% to 24% by weight, and a hydroxypropoxy content of about 7% to 12% by weight. From the group consisting of cellulose About 8% to 35% by weight of selected hydroxypropyl methylcellulose or mixtures thereof; 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable salt thereof Weight percent to 65 weight percent; And about 20% to 45% by weight of one or more pharmaceutically acceptable excipients.

Other agents within the scope of this class include about 10% to 30% by weight of hydroxypropyl methylcellulose or mixtures thereof selected from the group consisting of (a) to (d) above; 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable salt thereof Weight percent to 60 weight percent; And about 20% to 40% by weight of one or more pharmaceutically acceptable excipients.

Preferred agents falling within the scope of this class include from about 15% to 30% by weight of hydroxypropyl methylcellulose or mixtures thereof selected from the group consisting of (a) intrinsic (d) above; 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine, or a pharmaceutically acceptable salt thereof, about 43.2 Weight percent to 57.6 weight percent; And about 22.4% to 36.8% by weight of one or more pharmaceutically acceptable excipients.

Particularly preferred agents falling within the scope of this class include about 15% to 30% by weight of hydroxypropyl methylcellulose or mixtures thereof selected from the group consisting of (a) to (d) above: 11- [4- [2 -(2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable salt thereof from about 43.2% to 57.6% by weight; And (a) about 4% to 12% by weight of microcrystalline cellulose, (b) about 5% to 20% by weight of lactose, (c) about 1% to 3% by weight of magnesium stearate, (d) sodium citrate About 22.4% to 36.8% by weight of at least one pharmaceutically acceptable excipient selected from the group consisting of about 10% to 30% by weight and (e) about 1% to 15% by weight of povidone (polyvinylpyrrolidone) There are things that include.

In the formulations described above, 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine has a temperature of 20 ° C. It is preferred that it is in the form of a hemifumarate salt with an equilibrium solubility in water of 3.29 mg / ml.

Particularly important formulations include those described in the examples which follow, wherein the formulations as described in the examples which follow substantially provide further features of the invention.

As described above, compound 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine and its pharmaceuticals Salts that exhibit useful antidopaminergic activity, and can be used, for example, as antipsychotics (eg antipsychotics for the control of mental disease manifestations) or as therapeutics for hyperactivism. Therefore, the present invention also provides a method of treating a psychotic condition, such as psychosis, in a warm blooded animal, comprising administering an effective amount of a formulation of the invention to a warm blooded animal such as a human.

The present invention also provides a method of treating hyperactivity in a warm blooded animal comprising administering to the warm blooded animal an effective amount of a formulation of the invention.

The formulations of the present invention can be prepared by conventional techniques well known to those skilled in the art, such as wet granulation, direct compression, dry consolidation (slugging) and the like. Thus, for example, the active ingredient 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutical thereof Sustained release formulations of the invention are prepared by mixing together an acceptable salt, gelling agent, preferably hydroxypropyl methylcellulose and other excipients. Preferably, the active ingredient 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutical thereof Acceptable salts, gelling agents, preferably hydroxypropyl methylcellulose and other excipients are mixed together to form a mixture suitable for compression into tablets, which are then compressed into tablets or filled into capsules.

The mixing process mixes the components and granulates the mixed components, then the mixture is dried and the dried mixture is ground, then the mixture is mixed with a lubricant, for example magnesium stearate and the mixture is compressed Preferably by preparing tablets or by filling the mixed mixture into capsules.

Preferred methods for preparing the formulations of the invention

(a) 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable thereof Mixing a salt, a gelling agent, preferably hydroxypropyl methylcellulose and other excipients,

(b) wet granulating the mixed components,

(c) drying the mixture,

(d) grinding the dried mixture,

(e) mixing the mixture with a lubricant such as magnesium stearate, and

(f) pressing the mixed mixture to form a tablet

It includes.

The formulation may be one or more coatings, as is well known in the art, for example shellac, zein, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, polymethacrylate, polyvinyl acetate phthalate, Coating with cellulose acetate phthalate, triacetin, dibutyl sebacate, and mixtures of polyethylene glycol, titanium dioxide and hydroxypropyl methylcellulose.

Sustained release properties of the formulations of the invention can be demonstrated by monitoring the degree of degradation of the active ingredient. Degradation of the active ingredient is a standard procedure well known to those skilled in the art (e.g., Rotating Basket Method (Device I) or Paddle Method (Device II) as disclosed in USP). Can be monitored using a dissolution test procedure such as Such procedures include procedures for impregnating the formulation in an aqueous medium, such as water or hydrochloric acid, and recovering a aliquot of the medium at various time points over 24 hours. This subsample is analyzed by high pressure liquid chromatography (HPLC) with UV detection by measuring the concentration of the active ingredient degraded by standard techniques. In one particular embodiment, the tablet is impregnated in about 900 ml of water and the degradation profile is measured. In another specific embodiment, the dissolution profile is a spinning basket method wherein the tablets are immersed in 750 ml of 0.1 N HCl for 2 hours at 100 rpm speed and then 250 ml of 0.20 M phosphate buffer is added to the dissolution medium to yield a pH 6.2 ( Rotating Basket Method).

The formulation is preferably released in a controlled manner over a period of up to about 8 hours or more. For example, the formulations described in Example 2 below release about 90% of the active ingredient over a period of 16 hours and the formulations described in Example 1 show that about 90% of the active ingredient over a period of 8 hours Is released.

The plasma concentration versus time profile of the active ingredient shown in FIG. 2 was obtained using the following procedure. Thirty-two patients were divided into group A and group B by 16 patients in each group. After 2 days (day 1 and day 2) without drug administration, all patients received oral dosages of the immediate release formulations of Example 12 from 25 mg to 200 mg in a fixed step manner, 2 days a day. Each dose was administered for 9 days (3 to 11 days). On the 12th day of initiation, a randomized treatment sequence was performed for patients in each group (Groups A and B). Patients in group A were treated with a randomized sequence of administration of either of the following active ingredient formulations: two 100 mg tablets, the immediate release formulation of Example 12, administered every 12 hours while fasting ( Treatment 1), one 400 mg tablet (treatment 2), which is the formulation of Example 2 administered while fasting, and one 400 mg tablet (treatment 3), which is the formulation of Example 2, administered while eating. Patients in group B were treated with a randomized sequence of administration of either of the following active ingredient formulations: two 100 mg tablets, the immediate release formulation of Example 12, administered every 12 hours while fasting ( Treatment 1), one 400 mg tablet (Treatment 4), which is the formulation of Example 1 administered while fasting, and one 400 mg tablet (Treatment 5), which is the formulation of Example 1, administered while eating. On day 12, day 16 and day 20, patients were tested in the order of treatment assigned to the patients. At night on days 13 and 17, 200 mg of the immediate release formulation of Example 12 was administered to the patient, and on day 14, 15, 18 and 19 the dose 200 mg of the immediate release formulation of Example 12 was administered to the patient. Was administered to the patient twice daily. Blood samples were taken from each patient on day 3, 10, 11, 14, 15, 18 and 19 before the dose was administered in the morning. At 12, 16 and 20 days, blood samples from each patient immediately before administration and at specified time intervals from immediately after administration to 36 hours after administration Was taken. The concentration of active ingredient in the blood sample was measured using liquid-liquid extraction and high performance liquid chromatography with ultraviolet absorbance detection. For the formulations of Example 1 (n = 11), Example 2 (n = 10) and Example 12 (n = 10 for group A, n = 12 for group B and n = 12), the active ingredient concentration versus time profile is shown in FIG. 2. The mean area under the curve (AUC) value and the mean maximum blood concentration (C _max ) values for each 24 hour dosing interval for each example are summarized in Table A below.

TABLE A

Dosages of the compounds of the present invention to be administered are well known in the art, taking into account the route of administration, duration of treatment, severity of the psychotic state, the size and age of the patient, the efficacy of the active ingredient and the patient's responsiveness to the active ingredient. It is necessary to change according to. Thus, the effective dosage of the active ingredient can be readily determined by the physician taking into account all criteria and making the best judgment for the patient. Generally, such compounds are administered to warm-blooded animals (eg, humans) at daily dosages usually in the range of about 0.01 mg / kg body weight to about 40 mg / kg body weight so that an effective dosage is administered.

For example, when administered orally, the compound is typically administered in the range of about 0.1 mg / kg body weight to about 40 mg / kg body weight. The compounds of the invention are preferably administered at doses of about 25 mg, 50 mg, 200 mg, 300 mg and 400 mg.

In general, the formulations of the invention are in the form of unit dosage forms, in particular in the form of tablets.

It is apparent to those skilled in the art that the formulations of the present invention may be administered with other therapeutic or prophylactic drugs and / or agents which are not medicinally incompatible with each other. In general, the formulations of the present invention show no pronounced toxicity in laboratory test animals even at doses that are multiples of the minimum effective dose of the active ingredient.

In the following, the present invention is illustrated by the following examples, but is not limited to these examples. In the examples described below, the temperature is expressed in degrees Celsius. 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine and its pharmaceutically acceptable salts are European It may be prepared as described in patent publications 240,228 or 282,236 as well as US Pat. No. 4,879,288, the entire contents of which are incorporated herein by reference.

Example 1

Tablets having the composition as defined in Table 1 below were prepared using the following procedure.

11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepinehememifumarate (3453.8 g), lactose (1144.7 g), microcrystalline cellulose (381.5 g) and Methocel® E50L V (900 g) were mixed for about 3 minutes in an oily peristaltic mixer.

The mixture was wet granulated with purified water in an oily peristaltic mixer. The wet granules were dried in a fluid bed drier at about 65 ° C. until the loss due to drying was less than about 3% as measured by moisture balance.

The dried granules were ground using a hammer-type or similar mill equipped with a suitable screen (eg, 20 mesh to 40 mesh) and running at high speed in front of the blade.

Magnesium stearate was passed through a suitable screen (eg, 20 to 40 mesh).

The dried granulated material was mixed with the magnesium stearate screened for 3 minutes in a conventional mixer (eg, Patterson-Kelley Twin Shell).

This mixed mixture was compressed into tablets using a conventional rotary tablet press (eg, Kilian LX-21).

TABLE 1

(a) The active ingredient is 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate.

(b) Methocel® E50LV Premium (Premium) has a viscosity of 40 cps to 60 cps, a methoxy content of 28% to 30% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Phosphorus hydroxypropyl methylcellulose (commercially available from Dow Chemical Company, Michigan). This product meets specifications for the HPMC 2910 USP. It should be noted that the particular Methocel® E50LV Premium used in this example has a viscosity of 48 cps, a methoxy content of 28.9 weight percent, and a hydroxypropoxy content of less than 9.0 weight percent (i.e. 8.0 weight). %).

(c) added, but not retained.

The plasma concentration versus time profile of the active ingredient for the formulation of Example 1 is shown in FIG. 2.

Example 2

The procedure described in Example 1 was repeated using Methocel® E50LV and Methocel® E4M instead of Methocel® E50LV to provide a tablet having the composition of Table 2 below.

TABLE 2

(a) The active ingredient is 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate.

(b) Methocel® E50LV Premium is a hydroxy having a viscosity of 40 cps to 60 cps, a methoxy content of 28% to 30% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Propyl methylcellulose (commercially available from Dow Chemical Company, Michigan). This product meets specifications for the HPMC 2910 USP. Note that the particular Methocel® E50LV Premium used in this example has a viscosity of 48 cps, a methoxy content of 28.9 weight percent, and a hydroxypropoxy content of 9.0 weight percent or less (i.e. 8.0 weight). %).

(c) added, but not retained.

(d) Methocel® E4M Premium CR has a viscosity of 3,500 cps to 5,600 cps, a methoxy content of 28% to 30% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Oxypropyl methylcellulose (commercially available from Dow Chemical Company, Michigan). This product meets specifications for the HPMC 2910 USP. Note that the particular methocel® E4M Premium CR used in this example had a viscosity of 4364 cps, a methoxy content of 28.5 weight percent, and a hydroxypropoxy content of 7.8 weight percent.

The plasma concentration versus time profile of the active ingredient for the formulation of Example 2 is shown in FIG. 2.

Example 3

Tablets having the compositions in Table 3 were prepared using procedures similar to those described in Example 1.

TABLE 3

(a) The active ingredient is 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate.

(b) Methocel® K100LV Premium CR has a viscosity of 80 cps to 120 cps, a methoxy content of 19% to 24% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Roxypropyl methylcellulose (available from Dow Chemical Company, Michigan, USA) This product meets specifications for the HPMC 2208 USP. Note that the particular Methocel® K100LV Premium CR used in this example should have a hydroxypropoxy content of less than 9.0 wt%.

(c) Methocel® K4M Premium CR has a viscosity of 3,500 cps to 5,600 cps, a methoxy content of 19% to 24% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Oxypropyl methylcellulose (commercially available from Dow Chemical Company, Michigan). This product meets specifications for the HPMC 2208 USP.

(d) added, but not retained.

Example 4

Tablets having the compositions in Table 4 were prepared using procedures similar to those described in Example 1.

TABLE 4

(a) The active ingredient is 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate.

(b) Methocel® K100LV Premium CR has a viscosity of 80 cps to 120 cps, a methoxy content of 19% to 24% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Oxypropyl methylcellulose (available from Dow Chemical Company, Michigan, USA). This product meets specifications for the HPMC 2208 USP. Note that the particular Methocel® K100LV Premium CR used in this example should have a hydroxypropoxy content of less than 9.0 wt%.

(c) Methocel® E4M Premium CR has a viscosity of 3,500 cps to 5,600 cps, a methoxy content of 28% to 30% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Oxypropyl methylcellulose (commercially available from Dow Chemical Company, Michigan). This product meets specifications for the HPMC 2190 USP.

(d) added, but not retained.

Example 5

Tablets having the compositions in Table 5 were prepared using procedures similar to those described in Example 1.

TABLE 5

(a) The active ingredient is 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate.

(b) Methocel® K100LV Premium CR has a viscosity of 80 cps to 120 cps, a methoxy content of 19% to 24% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Oxypropyl methylcellulose (commercially available from Dow Chemical Company, Michigan). This product meets specifications for the HPMC 2208 USP. Note that the particular Methocel® K100LV Premium CR used in this example should have a hydroxypropoxy content of less than 9.0 wt%.

(d) added, but not retained.

Example 6

Tablets having the compositions in Table 6 were prepared using procedures similar to those described in Example 1.

TABLE 6

(a) The active ingredient is 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate.

(b) Povidone USP is a polyvinylpyrrolidone polymer with a K value of 29 to 32, marketed under the trade name Plasdon® K-29 / 32 (ISP Technologies, Inc., Wayne, NJ). Available from Ratings). This product meets the specifications for Povidone USP.

(c) Methocel® E50LV Premium is a hydroxy having a viscosity of 40 cps to 60 cps, a methoxy content of 28% to 30% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Propyl methylcellulose (commercially available from Dow Chemical Company, Michigan). This product meets specifications for the HPMC 2910 USP. Note that the particular Methocel® E50LV Premium used in this example should have a hydroxypropoxy content of less than 9.0% by weight.

(d) Methocel® E4M Premium CR has a viscosity of 3,500 cps to 5,600 cps, a methoxy content of 28% to 30% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Oxypropyl methylcellulose (commercially available from Dow Chemical Company, Michigan). This product meets specifications for the HPMC 2910 USP.

(e) added, but not retained.

Example 7

Tablets having the compositions in Table 7 were prepared using procedures similar to those described in Example 1.

TABLE 7

(a) The active ingredient is 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate.

(b) Povidone USP is a K value 90 polyvinylpyrrolidone polymer sold under the trade name Plasdon® K-90 (commercially available from ISP Technologies Inc., Wayne, NJ). This product meets the specifications for Povidone USP.

(c) Methocel® E50LV Premium is a hydroxy having a viscosity of 40 cps to 60 cps, a methoxy content of 28% to 30% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Propyl methylcellulose (commercially available from Dow Chemical Company, Michigan). This product meets specifications for the HPMC 2910 USP. Note that the particular Methocel® E50LV Premium used in this example should have a hydroxypropoxy content of less than 9.0% by weight.

(d) Methocel® E4M Premium CR has a viscosity of 3,500 cps to 5,600 cps, a methoxy content of 28% to 30% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Oxypropyl methylcellulose (commercially available from Dow Chemical Company, Michigan). This product meets specifications for the HPMC 2910 USP.

(e) added, but not retained.

Examples 8, 9 and 10

Tablets having the composition of Table 8 were prepared using a procedure similar to that described in Example 1.

TABLE 8

(a) The active ingredient is 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate.

(b) Methocel® K100LV Premium CR has a viscosity of 80 cps to 120 cps, a methoxy content of 19% to 24% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Oxypropyl methylcellulose (available from Dow Chemical Company, Michigan, USA). This product meets specifications for the HPMC 2208 USP. Note that the particular Methocel® K100LV Premium CR used in this example should have a viscosity of 90 cps, a methoxy content of 22.7 weight percent, and a hydroxypropoxy content of less than 8.5 weight percent.

(c) Methocel® K4M Premium CR has a viscosity of 3,500 cps to 5,600 cps, a methoxy content of 19% to 24% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Oxypropyl methylcellulose (commercially available from Dow Chemical Company, Michigan). This product meets specifications for the HPMC 2208 USP. It should be noted that the particular Methocel® K4M Premium CR used in this example should have a viscosity of 4105 cps, a methoxy content of 22.3 weight percent, and a hydroxypropoxy content of less than 9.7 weight percent.

(d) added, but not retained.

The release degradation profiles of the formulations of Examples 8, 9 and 10 are shown in FIG. 1.

Example 11

Tablets having the compositions in Table 9 were prepared using procedures similar to those described in Example 1.

TABLE 9

(a) The active ingredient is 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate.

(b) Povidone USP is a K value 90 polyvinylpyrrolidone polymer sold under the trade name Plasdon® K-90 (commercially available from ISP Technologies Inc., Wayne, NJ). This product meets the specifications for Povidone USP.

(c) Methocel® E4M Premium CR has a viscosity of 3,500 cps to 5,600 cps, a methoxy content of 28% to 30% by weight, and a hydroxypropoxy content of 7% to 12% by weight. Oxypropyl methylcellulose (commercially available from Dow Chemical Company, Michigan). This product meets specifications for the HPMC 2910 USP. Note that the particular methocel® E4M Premium CR used in this example had a viscosity of 4364 cps, a methoxy content of 28.5 weight percent, and a hydroxypropoxy content of 7.8 weight percent.

(e) added, but not retained.

Example 12

TABLE 11

(a) The active ingredient is 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate.

(b) Povidone USP is a K-29-32 polyvinylpyrrolidone polymer available under the trade name Plasdon® K-29 / 32 (available from ISP Technologies Inc., Wayne, NJ). Yes). This product meets the specifications for Povidone USP.

(c) added, but not retained.

(d) The hydroxypropyl methylcellulose used in this example is Pharmacoat® PHARMACOAT 606 (product of Shin-Etsu Limited, Japan), having a viscosity of 4.5 cps to 8.0 cps and a methoxy content of 28% by weight to 30 weight percent and hydroxypropoxy content of 7 weight percent to 12 weight percent.

The above-mentioned immediate release composition was prepared by the following process: Mixer-granulator (eg, Littleford MGT) with the active ingredient, povidone, calcium dihydrogen phosphate dihydrate and some microcrystalline cellulose and sodium starch glycolate ) For about 5 minutes. Purified water was added while mixing until suitable granules were obtained. The wet granules are passed through a cone grinder equipped with a suitable screen (6.35 mm) and then dried in a fluid bed dryer at a temperature of approximately 65 ° C. until the loss on drying is less than 2.5% w / w. Dried. The dried granules were then passed through a suitable grinder equipped with a suitable screen (eg # 20 mesh for hammer mill). The granulate was combined with lactose and the remaining microcrystalline cellulose and sodium starch glycolate in a mixer (eg V-mixer) and mixed for about 5 minutes. Magnesium stearate was passed through a suitable mill equipped with a suitable screen (eg 40 mesh), then added to the dried granular material and mixed for about 3 minutes. The mixed mixture was then compressed into tablets using a conventional rotary compaction apparatus. The tablets were then film coated using conventional drum coating equipment with an aqueous suspension of film coating components (ie, hydroxypropyl methylcellulose, propylene glycol 400, yellow iron oxide and titanium dioxide).

Claims (14)

Gelling agent and 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable thereof Sustained release formulations comprising salts with one or more pharmaceutically acceptable excipients. The sustained release preparation of claim 1, wherein the gelling agent is hydroxypropyl methylcellulose. 3. A hydroxy compound according to claim 2 wherein (a) a hydroxy having a viscosity of about 40 cps to 60 cps, a methoxy content of about 28% to 30% by weight, and a hydroxypropoxy content of about 7% to less than 9% by weight. Propyl methylcellulose, (b) hydroxypropyl methyl having a viscosity of about 3,500 cps to 5,600 cps, a methoxy content of about 28% to 30% by weight, and a hydroxypropoxy content of about 7% to 12% by weight Cellulose, (c) hydroxypropyl methylcellulose having a viscosity of about 80 cps to 120 cps, a methoxy content of about 19% to 24% by weight, a hydroxypropoxy content of about 7% to less than 9% by weight, and (d) a group consisting of hydroxypropyl methylcellulose having a viscosity of about 3,500 cps to 5,600 cps, a methoxy content of about 19% to 24% by weight, and a hydroxypropoxy content of about 7% to 12% by weight Hydroxypropyl Meth selected from From about 5% to 50% by weight of cellulose or a mixture thereof, provided that the total amount of hydroxypropyl methylcellulose present in the formulation is 25.8 weight if the formulation contains hydroxypropyl methylcellulose as described in (d) above. Sustained release formulation which should be at least%. The sustained-release preparation according to claim 3, comprising about 5 wt% to 40 wt% of hydroxypropyl methylcellulose or a mixture thereof selected from the group consisting of (a) to (d). The sustained-release preparation according to claim 4, comprising about 8% to 35% by weight of hydroxypropyl methylcellulose or a mixture thereof selected from the group consisting of (a) to (d). The sustained-release preparation according to claim 5, comprising about 10% to 30% by weight of hydroxypropyl methylcellulose or a mixture thereof selected from the group consisting of (a) to (d). The sustained-release preparation according to claim 6, comprising about 15% to 30% by weight of hydroxypropyl methylcellulose or a mixture thereof selected from the group consisting of (a) to (d). 8. The sustained release of claim 1, wherein the one or more pharmaceutically acceptable excipients is selected from the group consisting of microcrystalline cellulose, lactose, magnesium stearate, sodium citrate and povidone. Sex preparations. The method of claim 8, wherein the one or more pharmaceutically acceptable excipients are: (a) about 4% to 20% by weight of microcrystalline cellulose, (b) about 5% to 20% by weight of lactose, (c) magnesium stearate A sustained release formulation selected from the group consisting of about 1% to 3% by weight, (d) about 10% to 30% by weight sodium citrate, and (e) about 1% to 15% by weight of povidone. The method of claim 1, wherein 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine is hemifumarate. Sustained release formulations in the form of salts. The sustained release preparation according to any one of claims 1 to 7, wherein one of the one or more pharmaceutically acceptable excipients is a pH adjusting agent. The sustained release preparation of claim 11, wherein the pH adjusting agent is sodium citrate. 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable salt, gel thereof A process for preparing the formulation of claim 1, comprising mixing a topical agent and other excipients. (a) 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable thereof Mixing salts, gelling agents and other excipients, (b) wet granulating the mixed components, (c) drying the mixture, (d) grinding the dried mixture, (e) mixing the mixture with a lubricant, and (f) pressing the mixed mixture to form a tablet A method for producing the formulation according to claim 1 or 2, including.