HK1109063A - Pharmaceutical compositions - Google Patents
Pharmaceutical compositions Download PDFInfo
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- HK1109063A HK1109063A HK07114257.2A HK07114257A HK1109063A HK 1109063 A HK1109063 A HK 1109063A HK 07114257 A HK07114257 A HK 07114257A HK 1109063 A HK1109063 A HK 1109063A
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Description
The application is a divisional application with the application number of CN 200410003379.8. The filing date of this parent application is 27/5/1997; the invention relates to a medicinal composition.
Technical Field
The present invention relates to pharmaceutical compositions, particularly sustained release pharmaceutical compositions, comprising 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine (thiazepine) or a pharmaceutically acceptable salt thereof.
Background
In the treatment (treatment and prevention) of some diseases, it is desirable to provide the active pharmaceutical ingredient in a sustained release dosage form. The desired sustained release provides a generally uniform and constant release rate over an extended period of time, thereby achieving stable and desirable blood (plasma) levels of the active ingredient without the need for frequent administration.
Although there are many sustained release dosage forms known in the art that use gelling agents such as hydroxypropyl methylcellulose, it has been found difficult to make sustained release formulations of soluble drugs and gelling agents such as hydroxypropyl methylcellulose for several reasons. Firstly, soluble active ingredients in water tend to give sustained release products which tend to give rise to the known phenomenon of dose accumulation (dosedumping). That is, the release of the active ingredient is delayed for a period of time, but once release begins, the rate of release is very high. Furthermore, the plasma concentration of the active ingredient may fluctuate, which increases the likelihood of toxicity. Furthermore, some degree of diurnal variation in the plasma concentration of the active ingredient was observed. Finally, it has been found difficult to obtain the desired dissolution profile or control the release rate of the soluble drug.
Thus, sustained release dosage forms of water-soluble drugs such as 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof are needed to overcome or at least ameliorate one or more of the above difficulties, thereby further providing superior performance such that the frequency of administration of the active agent is reduced, such as once a day, while achieving blood (plasma) levels achieved at lower doses, more frequent administration, such as twice or more a day.
The compound 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiaheptine (see formula I below) and pharmaceutically acceptable salts thereof exhibit useful anti-dopaminergic activity and are useful, for example, as antipsychotic agents (e.g., to treat manifestations of psychotic disorders) or in the treatment of hyperactivity. It is a particularly important compound because it has a tendency to actually reduce the side effects caused, such as acute dystonia, acute dyskinesia, pseudo-Parkinson's syndrome, and tardive dyskinesia, as an antipsychotic, which may be caused by the use of other antipsychotics.
The preparation, physical properties and beneficial pharmacological properties of 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine and pharmaceutically acceptable salts thereof are disclosed in European patents EP240,228 and 282,236 and U.S. Pat. No. 4,879,288, the entire contents of which are incorporated herein by reference.
According to the present invention there is provided a sustained release formulation comprising a gelling agent, preferably hydroxypropylmethylcellulose, and 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Preferably, the sustained release formulation comprises a hydrophilic matrix comprising a gelling agent, preferably hydroxypropylmethylcellulose, and 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
The term gelling agent as used herein denotes any substance which forms a gel on contact with water, in particular a hydrophilic substance, and thus includes substances such as: hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl ethylcellulose, methylcellulose, ethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, carbopol preparations (carbomers), sodium carboxymethyl cellulose, polyvinylpyrrolidone, and the like, or mixtures thereof. The gelling agent is preferably hydroxypropyl methylcellulose.
Preferably the amount of gelling agent (preferably hydroxypropylmethylcellulose) is such that the active ingredient is released from the formulation in a controlled release form for more than 4 hours or more, preferably for more than 8 hours or more, particularly preferably for more than 8 to 24 hours, and at the end of this period of time such that at least 60% of the active ingredient has been released.
The gelling agent, preferably hydroxypropyl methylcellulose, is suitably present in an amount of about 5 to 50% by weight, more suitably about 5 to 40%, most suitably about 8 to 35%, especially about 10 to 35%. It is generally preferred that the gelling agent (preferably hydroxypropyl methylcellulose) be present in an amount of about 10-30%, more preferably about 15-30%.
Hydroxypropyl methylcellulose may contain more than one grade of polymer and is commercially available under several trademarks, such as METHOCEL, available from the Dow Chemical Company, u.s.a®E. F, J and K and METALOSE from Shin-Etsu, Ltd., JapanTMAnd (5) SH. Various grades under the given trade mark indicate the content of methoxy and hydroxypropoxy groups toAnd the viscosity is different. The content of methoxy group is in the range of 16.5-30% by weight, the content of hydroxypropoxy group is in the range of 4-32% by weight, and the viscosity of a 2% aqueous solution is in the range of 3cps-100,000cps at 20 ℃. For example, the hydroxypropyl methylcellulose preferably comprises (a) a polymer having a viscosity of about 40 to about 60cps (particularly about 50cps), a methoxyl content of about 28 to about 30% by weight, and a hydroxypropoxyl content of about 7 to less than 9% by weight; or (b) a polymer having a viscosity of about 3500-; or (c) a polymer having a viscosity of about 80 to about 120cps (particularly about 100cps), a methoxy content of about 19 to about 24% by weight, and a hydroxypropoxy content of about 7 to less than 9% by weight; or (d) a polymer or mixture thereof having a viscosity of about 3500-. More preferably, the hydroxypropyl methylcellulose is selected from (a) - (d) above or mixtures thereof, with the proviso that if the formulation contains hydroxypropyl methylcellulose under (d) above, then the total amount of hydroxypropyl cellulose present in the formulation must be greater than 25.8% by weight.
In one embodiment, the hydroxypropyl methylcellulose contains 8-12% polymer, preferably about 5-10% polymer, having a viscosity of about 4000 cps. In another embodiment, the hydroxypropyl methylcellulose contains 10-35% polymer, preferably about 10-15% polymer, having a viscosity of about 50 cps.
In a particular embodiment, the hydroxypropyl methylcellulose contains 15% polymer having a viscosity of about 50cps, and optionally about 5% hydroxypropyl methylcellulose polymer having a viscosity of about 4000 cps.
In particular, 11- [4- [2- (2-hydroxyethoxy) -ethyl ] -1-piperazinyl ] -dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof (preferably, hemifumarate) is present in an amount of about 10 to about 90% by weight, preferably about 20 to about 80% by weight, more preferably about 35 to about 65% by weight, most preferably about 40 to about 60% by weight, and particularly preferably about 43.2 to about 57.6% by weight.
Generally, the formulations contain one or more excipients. Such excipients include diluents such as lactose, microcrystalline cellulose, dextran, mannitol, sucrose, sorbitol, gelatin, acacia, dicalcium phosphate, tricalcium phosphate, monocalcium phosphate, sodium carbonate, and the like, preferably lactose and microcrystalline cellulose; lubricants such as stearic acid, zinc stearate, calcium stearate, or magnesium stearate, etc., preferably magnesium stearate; binders such as sucrose, polyethylene glycol, povidone (polyvinylpyrrolidone), corn starch, pregelatinized starch, and the like, preferably povidone (polyvinylpyrrolidone); colorants such as iron oxide, FD & C dyes, lakes, etc.; a flavoring agent; pH adjusting agents comprising suitable organic acids or alkali metal (e.g. lithium, sodium or potassium) salts thereof, such as benzoic acid, citric acid, tartaric acid, succinic acid, adipic acid and the like or the corresponding alkali metal salts thereof, preferably alkali metal salts of such acids, especially the sodium salt of citric acid (i.e. sodium citrate). In general, the excipient is present in an amount of 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 to 40% by weight, and particularly preferably about 22.4 to 36.8% by weight. The formulation preferably contains one or more pharmaceutically acceptable excipients selected from the group consisting of: microcrystalline cellulose, lactose, magnesium stearate, sodium citrate, or povidone. In particular, the formulation may contain one or more of (a) microcrystalline cellulose, preferably present in about 4-20% by weight, (b) lactose, preferably present in about 5-20% by weight, (c) magnesium stearate, preferably present in about 1-3% by weight, (d) sodium citrate in about 10-30% by weight, preferably about 12.5-25% by weight, particularly preferably about 12.5% by weight, and (e) povidone (polyvinylpyrrolidone) in about 1-15% by weight, preferably about 4-6% by weight, particularly preferably about 5% by weight.
According to the present invention there is also provided a sustained release formulation comprising a gelling agent, preferably hydroxypropylmethylcellulose, and 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein one of said excipients is a pH adjusting agent.
According to the present invention there is also provided a sustained release formulation comprising 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof as the active ingredient, and 5-40% hydroxypropylmethylcellulose and one or more pharmaceutically acceptable excipients.
According to the present invention there is also provided a sustained release formulation comprising 35 to 65% of 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof as the active ingredient, and about 5 to 40% by weight of hydroxypropylmethylcellulose and one or more pharmaceutically acceptable excipients.
According to the present invention there is also provided a sustained release formulation comprising about 35-65% of 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof and about 15-30% of hydroxypropylmethylcellulose and about 20-45% of one or more pharmaceutically acceptable excipients as active ingredients.
According to the present invention there is also provided a sustained release formulation comprising as active ingredient about 35-65% 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof, about 5-40% by weight of hydroxypropylmethylcellulose, about 4-12% microcrystalline cellulose, about 8-20% lactose and the balance one or more other pharmaceutically acceptable excipients. Such other excipients may include components that act as lubricants (e.g., magnesium stearate) during the manufacture of the formulation or dosage form.
According to the present invention, there is also provided a sustained release formulation comprising about 5 to 40% by weight of hydroxypropyl methylcellulose selected from the group consisting of: (a) hydroxypropyl methylcellulose having a viscosity of about 40-60cps, a methoxy content of about 28-30% by weight, and a hydroxypropoxy content of about 7% to less than 9% by weight, (b) hydroxypropyl methylcellulose having a viscosity of about 3500-5600cps, a methoxy content of about 28-30% by weight, and a hydroxypropoxy content of about 7-12% by weight, (c) hydroxypropyl methylcellulose having a viscosity of about 80-120cps, a methoxy content of about 19-24% by weight, and a hydroxypropoxy content of about 7-less than 9% by weight, and (d) hydroxypropylmethylcellulose having a viscosity of about 3500-; about 35% to about 65% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof; and about 20-45% by weight of one or more pharmaceutically acceptable excipients; with the proviso that if the preparation contains hydroxypropylmethylcellulose according to item (d) above, the total amount of hydroxypropylmethylcellulose present in the preparation must be greater than 25.8% by weight.
Other agents included in this latter group are those containing about 8-35% by weight of hydroxypropyl methylcellulose selected from the group consisting of: (a) hydroxypropyl methylcellulose having a viscosity of about 40-60cps, a methoxy content of about 28-30% by weight, and a hydroxypropoxy content of about 7% to less than 9% by weight, (b) hydroxypropyl methylcellulose having a viscosity of about 3500-5600cps, a methoxy content of about 28-30% by weight, and a hydroxypropoxy content of about 7-12% by weight, (c) hydroxypropyl methylcellulose having a viscosity of about 80-120cps, a methoxy content of about 19-24% by weight, and a hydroxypropoxy content of about 7-less than 9% by weight, and (d) hydroxypropylmethylcellulose having a viscosity of about 3500-; about 35% to about 65% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof; and about 20-45% by weight of one or more pharmaceutically acceptable excipients.
Other formulations included in the latter group are those comprising about 10-30% by weight of hydroxypropyl methylcellulose selected from groups (a) - (d) above or mixtures thereof; about 40% to about 60% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof; about 20-40% by weight of one or more pharmaceutically acceptable excipients.
Preferred formulations included in the latter group are those containing about 15 to 30% by weight of hydroxypropyl methylcellulose selected from groups (a) to (d) above or mixtures thereof; about 43.2% to about 57.6% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof; and about 22.4% to about 36.8% by weight of one or more pharmaceutically acceptable excipients.
Particularly preferred formulations included in the latter group are those containing about 15 to 30% by weight of hydroxypropyl methylcellulose selected from groups (a) to (d) above or mixtures thereof; about 43.2% to about 57.6% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof; and about 22.4% to about 36.8% by weight of one or more pharmaceutically acceptable excipients selected from the group consisting of: (a) about 4% to about 12% by weight microcrystalline cellulose; (b) about 5-20% by weight lactose, (c) about 1-3% by weight magnesium stearate, (d) about 10-30% by weight sodium citrate and (e) about 1-15% by weight povidone (polyvinylpyrrolidone).
In the above formulation, 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine is preferably present in the form of the hemifumarate salt, which has an equilibrium solubility in water of 3.29mg/ml at 20 ℃.
Formulations of particular interest include those described in the accompanying examples, provided as a further aspect of the invention substantially as described in the accompanying examples.
As described above, the compound 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine and pharmaceutically acceptable salts thereof exhibit useful anti-dopaminergic activity and are therefore useful, for example, as antipsychotics (e.g., for the management of symptoms of psychiatric disorders) or as a treatment for hyperactivity. Accordingly, the present invention also provides a method of treating a psychotic disorder, e.g. psychosis, in a warm-blooded animal, such as man, which comprises administering to said warm-blooded animal an effective amount of a formulation of the invention.
The invention also provides a method of treating hyper-function 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 may be prepared by conventional techniques well known to those skilled in the art, such as wet granulation, direct compression, dry compression (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 pharmaceutically acceptable salt thereof, a gelling agent (preferably hydroxypropylmethylcellulose), and other excipients may be mixed together to form the sustained-release formulation of the present invention. Preferably, the active ingredient 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof, a gelling agent (preferably hydroxypropyl methylcellulose), and other excipients are mixed together to form a mixture suitable for tableting, and then the mixture is compressed to form tablets or filled into capsules.
The mixing process is preferably carried out by the following procedure: mixing the ingredients, wet granulating the mixed ingredients, drying the mixture, grinding the dried mixture, mixing the mixture with a lubricant such as magnesium stearate, compressing the mixed mixture to form tablets or filling the mixed mixture into capsules.
A preferred method of preparing the formulation of the present invention comprises the steps of:
(a) mixing 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof, a gelling agent (preferably hydroxypropylmethylcellulose), and other excipients;
(b) wet granulating the mixed components;
(c) drying the mixture;
(d) grinding the dried mixture;
(d) mixing the mixture with a lubricant such as magnesium stearate; and are
(f) The blended mixture is compressed to form tablets.
The dosage form may be coated with one or more coatings well known in the art, such as shellac, zein, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, polyacrylates, polyvinyl acetate phthalate, cellulose acetate phthalate, triacetin, dibutyl sebacate, mixtures of polyethylene glycols, titanium dioxide, and hydroxypropyl methyl cellulose, and the like.
The sustained release properties of the formulations of the invention can be demonstrated by monitoring the dissolution of the active ingredient. Dissolution of the active ingredient can be monitored using standard methods well known to those skilled in the art [ e.g., dissolution testing methods, such as the rotary basket Method (apparatus I) or the Paddle Method (apparatus II), disclosed in the United States Pharmacopeia (USP) ]. Such methods include steps in which the formulation is immersed in an aqueous medium, such as water or hydrochloric acid, and the medium is sampled at various time points over a 24 hour period. The samples were analyzed by High Pressure Liquid Chromatography (HPLC) with UV detection to determine the concentration of the dissolved active ingredient by standard methods. In a specific example, the tablet is immersed in about 900ml of water and the dissolution profile is determined. In another specific example, the dissolution profile was determined by immersing the tablets in 750ml of 0.1N HCl for 2 hours at a rate of 100rpm by a basket method, and then adding 250ml of 0.2M phosphate buffer to the dissolution medium to obtain a solution of pH 6.2.
Preferably, the formulation releases the active ingredient in a controlled manner for up to about 8 hours or more. For example, the formulation described in example 2 below released about 90% of the active ingredient over 16 hours, and the formulation described in example 1 released about 90% of the active ingredient over 8 hours.
The following procedure was used to obtain the plasma concentration versus time curves for the active ingredient shown in figure 2. The 32 patients were divided into groups a or B, each of 16 patients. All patients were given an oral dose of the immediate release formulation of example 12 twice daily for 9 consecutive days (days 3-11) after 2 days (days 1 and 2) of no drug administration, with a fixed gradual dose increase from 25 to 200 mg. Patients were treated by a randomized treatment sequence in their respective groups (group a or group B) starting on day 12. Group A patients were treated according to the following treatment sequence, which included administering each of the following formulations of active ingredients according to a randomized sequence: two 100mg of the immediate release formulation of example 12 (treatment 1) were administered every 12 hours under starvation conditions, one 400mg of the formulation of example 2 (treatment 2) were administered under starvation conditions and one 400mg of the formulation of example 2 (treatment 3) were administered at the time of feeding. Group B patients were randomized according to the following treatment sequence, which included administering each of the following formulations of active ingredients according to a randomized sequence: two 100mg of the immediate release formulation of example 12 (treatment 1) were administered every 12 hours under starvation conditions, one 400mg of the formulation of example 1 (treatment 4) were administered under starvation conditions and one 400mg of the formulation of example 1 (treatment 5) were administered at the time of feeding. On days 12, 16 and 20, patients received their experimental treatment in the indicated treatment sequence. On days 13 and 17 evening, the patient received a 200mg dose of the immediate release formulation of example 12, and on days 14, 15, 18 and 19, the patient received a 200mg dose of the immediate release formulation of example 12 twice daily. Blood samples were taken from each subject prior to the morning dose on days 3, 10, 11, 14, 15, 18 and 19. On days 12, 16 and 20, blood samples were taken from each subject immediately prior to dosing and at specified time intervals from post-dose to 36 hours post-dose. The concentration of the active components in the blood sample was quantified by liquid-liquid extraction and high performance liquid chromatography and detected by UV absorption. The plasma concentration curves of the active ingredient versus time for the formulations of example 1 (n-11), example 2 (n-10) and example 12 (group a, n-10; group B, n-12) are illustrated in figure 2, and table a summarizes the mean area under the curve (AUC) and mean maximum plasma concentration value (C) for the dosing interval over 24 hours for each examplemax)。
TABLE A
| Example No. 2 | Group A | Group B | ||
| AUC0-24 | Cmax | AUC0-24 | C-max | |
| 1212 | -56095347 | -433703 | 4886-4818 | 565-563 |
The dosage of the compounds of the invention to be administered may vary according to principles well known in the art, such as the route of administration, the duration of the treatment, the severity of the psychotic disorder, the weight and age of the patient, the potency of the active ingredient and the response of the patient. The effective dose of the active ingredient can therefore be readily determined by the clinician after taking into account all criteria and taking into account his best judgment on the patient. Generally, the compounds are administered to a warm-blooded animal (e.g., a human) in order to obtain an effective dose, generally, a daily dose in the range of about 0.01 to about 40mg/kg body weight. For example, when administered orally, the range of administration is generally from about 0.1 to about 40mg/kg body weight. Preferably, the compounds of the invention are administered in a dose of about 25, 50, 200, 300 or 400 mg.
In general, the formulations of the present invention are in unit dosage form, particularly in the form of tablets.
It will be apparent to those skilled in the art that the formulation may be administered in combination with other therapeutic or prophylactic agents and/or medicaments with which it is medically compatible. In general, the formulations of the invention generally do not exhibit significant toxicity in experimental animals at several fold the minimum effective dose of the active ingredient.
Drawings
FIG. 1 is a release (dissolution) profile of the sustained-release preparations of examples 8, 9 and 10, which was obtained by: the appropriate tablets were immersed in 750ml of 0.1N HCl at 37 ℃ for 2 hours at 100rpm, and the dissolution medium pH was adjusted to 6.2 by adding 250ml of 0.2M sodium phosphate buffer.
FIG. 2 is a plot of plasma concentration versus time for the active ingredient in the immediate release formulation of example 12 and the extended release formulations of examples 1 and 2.
Detailed Description
The invention is further illustrated by the following non-limiting examples in which temperatures are expressed in degrees Celsius. The compound 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine and pharmaceutically acceptable salts thereof may be prepared according to the procedures described in published European patent EP240228 or 282236 and U.S. Pat. No. 4879288, the entire contents of which are incorporated herein by reference.
Example 1
Tablets having the composition defined in table 1 were prepared by the following method.
Reacting 11- [4- [2- (2-hydroxyethoxy) ethyl]-1-piperazinyl]Dibenzo [ b, f ]][1，4]Thidiazene hemifumarate (3453.8g), lactose (1144.7g), microcrystalline cellulose (381.5g) and METHOCEL®E50LV (900g) was mixed in a planetary mixer for about 3 minutes.
The mixture was wet granulated with purified water in a planetary mixer. The wet mass was dried in a fluid bed dryer at about 65 ℃ to a loss on drying of less than about 3% as determined by a humidity balance.
The dried granules are milled at high speed using a hammer type or similar mill and passed through a suitable screen (e.g. 20-40 mesh).
The magnesium stearate is passed through a suitable screen (e.g., 20-40 mesh).
The dried granular material is mixed with the sieved magnesium stearate in a conventional mixer (e.g., Patterson-Kelley Twin Shell) for about 3 minutes.
The blended mixture is compressed into tablets using a conventional rotary tablet press (e.g., Kilian LX-21).
TABLE 1
mg/tablet
All-in-one tablets
| Active component (a) | 460.51 | 57.6 |
| Lactose NF | 152.62 | 19.1 |
| Microcrystalline cellulose NF | 50.87 | 6.3 |
| METHOCEL®E50LV Premium(b) | 120.00 | 15.0 |
| Pure water (c) | Proper amount of | - |
| Magnesium stearate NF | 16.0 | 2.0 |
(a) The active component is 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine hemifumarate
(b)METHOCEL®E50LV Premium is a hydroxypropyl methylcellulose having a viscosity of 40-60cps, a methoxyl content of 28-30% by weight, and a hydroxypropoxyl content of 7-12% by weight, available from The Dow Chemical Company, Michigan, USA. This product met the criteria for HPMC 2910 USP. Note the specific METHOCEL used in this example®The E50LV Premium had a viscosity of 48cps, a methoxy content of 28.9% by weight, and a hydroxypropoxy content of less than 9.0% by weight (i.e., 8.0%).
(c) Added but not retained.
Figure 2 shows the plasma concentration versus time curve of the active ingredient of the formulation of example 1.
Example 2
By METHOCEL®E50LV and METHOCEL®E4M substituted for METHOCEL®E50LV the process described in example 1 is repeated to give tablets of the following composition.
TABLE 2
mg/tablet
% tablet
| Active component (a) | 460.51 | 57.6 |
| Lactose NF | 81.74 | 10.2 |
| Microcrystalline cellulose NF | 81.75 | 10.2 |
| METHOCEL®E50LV Premium(b) | 120.00 | 15.0 |
| METHOCEL®E4M Premium CR(d) | 40.00 | 5.0 |
| Pure water (c) | Proper amount of | - |
| Magnesium stearate NF | 16.0 | 2.0 |
(a) The active component is 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine hemifumarate
(b)METHOCEL®E50LV Premium is a hydroxypropyl methylcellulose having a viscosity of 40-60cps, a methoxyl content of 28-30% by weight, and a hydroxypropoxyl content of 7-12% by weight, available from The Dow Chemical Company, Michigan, USA. This product met the criteria for HPMC 2910 USP. Note the specific METHOCEL used in this example®The E50LV Premium had a viscosity of 48cps, a methoxy content of 28.9% by weight, and a hydroxypropoxy content of less than 9.0% by weight (i.e., 8.0%).
(c) Added but not retained.
(d)METHOCEL®E4M Premium CR is a hydroxypropyl methylcellulose having a viscosity of 3500-. This product met the criteria for HPMC 2910 USP. Note the specific METHOCEL used in this example®E4M Premium CR had a viscosity of 4364cps, a methoxy content of 28.5% by weight and a hydroxypropoxy content of 7.8% by weight.
Figure 2 shows the plasma concentration versus time curve of the active ingredient of the formulation of example 2.
Example 3
According to a similar method to that described in example 1, tablets of the following composition were prepared.
TABLE 3
mg/tablet
% tablet
| Active component (a) | 345.38 | 43.2 |
| MilkSugar NF | 49.31 | 6.2 |
| Microcrystalline cellulose NF | 49.31 | 6.2 |
| Citric acid sodium salt | 100.00 | 12.5 |
| METHOCEL®K100LV Premium CR(b) | 200.00 | 25.0 |
| METHOCEL®K4M Premium CR(c) | 40.00 | 5.0 |
| Pure water (d) | Proper amount of | - |
| Magnesium stearate NF | 16.00 | 2.0 |
(a) The active component is 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine hemifumarate
(b)METHOCEL®K100LV Premium CR is a hydroxypropyl methylcellulose having a viscosity of 80-120cps, a methoxyl content of 19-24% by weight, and a hydroxypropoxyl content of 7-12% by weight, available from The Dow Chemical Company, Michigan, USA. The product meets the criteria of HPMC 2208 USP. Note the specific METHOCEL used in this example®The hydroxypropoxyl content of K100LV Premium CR must be less than 9.0 percent by weight.
(c)METHOCEL®K4M Premium CR is a hydroxypropyl methylcellulose having a viscosity of 3500-. The product meets the criteria of HPMC 2208 USP.
(d) Added but not retained.
Example 4
According to a similar method to that described in example 1, tablets of the following composition were prepared.
TABLE 4
mg/tablet
% tablet
| Active component (a) | 345.38 | 43.2 |
| Lactose NF | 89.31 | 11.1 |
| Microcrystalline cellulose NF | 89.31 | 11.1 |
| Citric acid sodium salt | 100.00 | 12.5 |
| METHOCEL®K100LV PremiumCR(b) | 120.00 | 15.0 |
| METHOCEL®E4M Premium CR(c) | 40.00 | 5.0 |
| Pure water (d) | Proper amount of | - |
| Magnesium stearate NF | 16.00 | 2.0 |
(a) The active component is 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine hemifumarate.
(b)METHOCEL®K100LV Premium CR is a hydroxypropyl methylcellulose having a viscosity of 80-120cps, a methoxyl content of 19-24% by weight, and a hydroxypropoxyl content of 7-12% by weight, available from The Dow Chemical Company, Michigan, USA. The product meets the criteria of HPMC 2208 USP. Note the specific METHOCEL used in this example®The hydroxypropoxyl content of K100LV Premium CR must be less than 9.0 percent by weightAmount).
(c)METHOCEL®E4M Premium CR is a hydroxypropyl methylcellulose having a viscosity of 3500-. This product met the criteria for HPMC 2910 USP.
(d) Added but not retained.
Example 5
According to a similar method to that described in example 1, tablets of the following composition were prepared.
TABLE 5
mg/tablet
% tablet
| Active component (a) | 345.38 | 43.2 |
| Lactose NF | 69.31 | 8.7 |
| Microcrystalline cellulose NF | 69.31 | 8.7 |
| Citric acid sodium salt | 100.00 | 12.5 |
| METHOCEL®K100LV PremiumCR(b) | 200.00 | 25.0 |
| Pure water (d) | Proper amount of | - |
| Magnesium stearate NF | 16.00 | 2.0 |
(a) The active component is 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine hemifumarate
(b)METHOCEL®K100LV Premium CR is a hydroxypropyl methylcellulose having a viscosity of 80-120cps, a methoxyl content of 19-24% by weight, and a hydroxypropoxyl content of 7-12% by weight, available from The Dow Chemical Company, Michigan, USA. The product meets the criteria of HPMC 2208 USP. Note that METHOCEL used in this example®The hydroxypropoxyl content of K100LV Premium CR must be less than 9.0 percent by weight.
(c) Added but not retained.
Example 6
According to the same method as described in example 1, tablets of the following composition were prepared.
TABLE 6
mg/tablet
% tablet
| Active groupMinute (a) | 345.38 | 43.2 |
| Povidone USP (b) | 40.00 | 5.0 |
| Microcrystalline cellulose NF | 38.62 | 4.8 |
| Citric acid sodium salt | 200.00 | 25.0 |
| METHOCEL®E50LV Premium(c) | 80.00 | 10.0 |
| METHOCEL®E4M Premium CR(d) | 80.00 | 10.0 |
| Pure water (e) | Proper amount of | - |
| Magnesium stearate NF | 16.00 | 2.0 |
(a) The active component is 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine hemifumarate.
(b) The agent is a polyvinylpyrrolidone polymer having a K value of 29-32 available from ISPTECOLOGIES Inc. Wayne, New Jersey, USA under the trademark PLASDONE®K-29/32. The product meets the criteria of povidone USP.
(c)METHOCEL®E50LV Premium is a hydroxypropyl methylcellulose having a viscosity of 40-60cps, a methoxyl content of 28-30% by weight, and a hydroxypropoxyl content of 7-12% by weight, available from The Dow Chemical companyy, Michigan, USA. This product met the criteria for HPMC 2910 USP. Note the specific METHOCEL used in this example®The hydroxypropoxy content of E50LV Premium must be less than 9.0% by weight.
(d)METHOCEL®E4M Premium CR is a hydroxypropyl methylcellulose having a viscosity of 3500-. This product met the criteria for HPMC 2910 USP.
(e) Added but not retained.
Example 7
According to a similar method to that described in example 1, tablets of the following composition were prepared.
TABLE 7
mg/tablet
% tablet
| Active component (a) | 345.38 | 43.2 |
| Povidone USP (b) | 40.00 | 5.0 |
| Microcrystalline cellulose NF | 38.62 | 4.8 |
| Citric acid sodium salt | 200.00 | 25.0 |
| METHOCEL®E50LV Premium(c) | 80.00 | 10.0 |
| METHOCEL®E4M Premium CR(d) | 80.00 | 10.0 |
| Pure water (e) | Proper amount of | - |
| Magnesium stearate NF | 16.0 | 2.0 |
(a) The active component is 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine hemifumarate
(b) The reagent is a polyvinylpyrrolidone polymer having a K value of 90, available from ISPTtechnologies Inc. Wayne, New Jersey, USA under the trademark PLASDONE®K-90. The product meets the criteria of povidone USP.
(c)METHOCEL®E50LV Premium is a hydroxypropyl methylcellulose having a viscosity of 40-60cps, a methoxyl content of 28-30% by weight, and a hydroxypropoxyl content of 7-12% by weight, available from The Dow Chemical Company, Michigan, USA. This product met the criteria for HPMC 2910 USP. Note the specific METHOCEL used in this example®The hydroxypropoxy content of E50LV Premium must be less than 9.0% by weight.
(d)METHOCEL®E4M Premium CR with a viscosity of 3500-2% by weight of hydroxypropyl methylcellulose, available from The Dow Chemical Company, Michigan, USA. This product met the criteria for HPMC 2910 USP.
(e) Added but not retained.
According to a similar process to that described in example 1, tablets of the following composition were prepared:
TABLE 8
Example 8 example 9 example 10
mg/tablet%
| Active component (a) | 345.38 | 43.2 | 345.38 | 43.2 | 345.38 | 43.2 |
| Lactose NF | 109.31 | 13.7 | 69.31 | 8.7 | 49.31 | 6.2 |
| Microcrystalline cellulose NF | 109.31 | 13.7 | 69.31 | 8.7 | 49.31 | 6.2 |
| Citric acid sodium salt | 100.00 | 12.5 | 100.00 | 12.5 | 100.00 | 12.5 |
| METHOCEL®E100LV | 120.00 | 15.0 | 200.00 | 25.0 | 200.00 | 25.00 |
| Premium CR(b) | ||||||
| METHOCEL®E4MPremium CR(c) | - | - | - | - | 40.00 | 5.0 |
| Pure water (d) | Proper amount of | - | Proper amount of | - | Proper amount of | - |
| Magnesium stearate NF | 16.00 | 2.0 | 16.00 | 2.0 | 16.00 | 2.0 |
(a) The active component is 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine hemifumarate
(b)METHOCEL®K100LV Premium CR is a hydroxypropyl methylcellulose having a viscosity of 80-120cps, a methoxyl content of 19-24% by weight, and a hydroxypropoxyl content of 7-12% by weight, available from The Dow Chemical Company, Michigan, USA. The product meets the criteria of HPMC 2208 USP. Note the specific METHOCEL used in this example®K100LV Premium CR has a viscosity of 90cps, a methoxy content of 22.7% by weight and a hydroxypropoxy content of 8.5% by weight.
(c)METHOCEL®K4M Premium CR is a hydroxypropyl methylcellulose having a viscosity of 3500-. The product meets the criteria of HPMC 2208 USP. Note the specific METHOCEL used in this example®K4M Premium CR had a viscosity of 4105cps, a methoxy content of 22.3% by weight and a hydroxypropoxy content of 9.7% by weight.
(d) Added but not retained.
Figure 1 shows the release dissolution profiles of the formulations of examples 8, 9 and 10.
Example 11
According to a similar process to that described in example 1, tablets of the following composition were prepared:
mg/tablet
% tablet
| Active component (a) | 345.38 | 43.2 |
| Povidone USP (b) | 80.00 | 10.00 |
| Sodium citrate USP | 100.00 | 12.5 |
| Microcrystalline cellulose NF | 138.62 | 17.3 |
| METHOCEL®E4M Premium CR(c) | 120.00 | 15.0 |
| Pure water (d) | Proper amount of | - |
| Magnesium stearate NF | 16.0 | 2.0 |
(a) The active component is 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine hemifumarate.
(b) The reagent isPolyvinylpyrrolidone polymer having a K value of 90, available from ISPTECtechnologies Inc., Wayne, New Jersey, USA under the trademark PLASDONE®K-90. The product meets the criteria of povidone USP.
(c)METHOCEL®E4M Premium CR is a hydroxypropyl methylcellulose having a viscosity of 3500-. This product met the criteria for HPMC 2910 USP. Note the specific METHOCEL used in this example®E4M Premium CR had a viscosity of 4364cps, a methoxy content of 28.5% by weight and a hydroxypropoxy content of 7.8% by weight.
(d) Added but not retained.
Example 12
| Tablet core | mg/tablet |
| Active component (a) | 115.13 |
| Povidone USP (b) | 8.33 |
| Dicalcium phosphate dihydrate USP | 10.00 |
| Microcrystalline cellulose NF | 32.88 |
| Sodium starch glycolate NF | 8.33 |
| Lactose NF | 22.33 |
| Magnesium stearate NF | 3.00 |
| Pure water (c) | Proper amount of |
| Coating film | mg/tablet |
| Hydroxypropylmethylcellulose 2910 USP (d) | 5.00 |
| Polyethylene glycol 400NF | 1.00 |
| Iron oxide yellow NF | 0.15 |
| Titanium dioxide USP | 1.85 |
(a) The active component is 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine hemifumarate.
(b) The agent is a polyvinylpyrrolidone polymer having a K value of 29-32 available from ISPTECOLOGIES Inc., Wayne, New Jersey, USA under the trademark PLASDONE®K-29/32. The product meets the criteria of povidone USP.
(c) Added but not retained.
(d) The hydroxypropyl methylcellulose used in this example was PHARMACOAT®606 available from Shin-Etsu, Ltd., Japan, having a viscosity of 4.5-8.0cps and a methoxy group content of 28-30 wt%) And a hydroxypropoxy group content of 7 to 12% by weight.
The immediate release composition described above was prepared according to the following method: the active ingredient, povidone, dicalcium phosphate dihydrate and a portion of microcrystalline cellulose and sodium starch glycolate are mixed on a mixer-granulator (e.g., littleford mgt) for about 5 minutes. Purified water was added with mixing until a suitable mass was obtained. The wet granulation is passed through a conical mill equipped with a suitable screen (e.g., 6.35mm) and then dried in a fluid bed dryer (inlet temperature set at about 65 ℃) to a loss on drying of less than 2.5% (w/w). The dried granules are then passed through a suitable mill equipped with a suitable screen (e.g., #20 mesh screen, hammer mill). The granules are mixed with lactose and the remainder of the microcrystalline cellulose and sodium starch glycolate in a mixer (e.g., a V-blender) for about 5 minutes. Magnesium stearate is passed through a suitable mill fitted with a suitable screen (e.g. a 40 mesh screen) and then added to the dried particulate material and mixed for about 3 minutes. The blended mixture is then compressed into tablets using conventional rotary tableting equipment. The tablets were then film coated with an aqueous suspension of the film coating ingredients (i.e., hydroxypropyl methylcellulose, polyethylene glycol 400, yellow iron oxide, and titanium dioxide) using conventional drum coating equipment at an inlet temperature of about 80 ℃.
Claims (15)
1. A sustained release formulation comprising a gelling agent and 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo- [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
2. The sustained release formulation according to claim 1, wherein the gelling agent is hydroxypropylmethylcellulose.
3. The sustained release formulation of claim 2 comprising about 5 to 50% by weight of a hydroxypropyl methylcellulose selected from the group consisting of: (a) hydroxypropyl methylcellulose having a viscosity of about 40-60cps, a methoxy content of about 28-30% by weight, and a hydroxypropoxy content of about 7% to less than 9% by weight, (b) hydroxypropyl methylcellulose having a viscosity of about 3500-5600cps, a methoxy content of about 28-30% by weight, and a hydroxypropoxy content of about 7-12% by weight, (c) hydroxypropyl methylcellulose having a viscosity of about 80-120cps, a methoxy content of about 19-24% by weight, and a hydroxypropoxy content of about 7-less than 9% by weight, and (d) hydroxypropylmethylcellulose having a viscosity of about 3500-; with the proviso that if the preparation contains hydroxypropylmethylcellulose according to item (d) above, the total amount of hydroxypropylmethylcellulose present in the preparation must be higher than 25.8% by weight.
4. The sustained release formulation of claim 3 comprising about 5-40% by weight of hydroxypropyl methylcellulose selected from the group consisting of (a) - (d) or mixtures thereof.
5. The sustained release formulation of claim 4 comprising about 8-35% by weight of hydroxypropyl methylcellulose selected from the group consisting of (a) - (d) or mixtures thereof.
6. The formulation of claim 5 comprising about 10-30% by weight of hydroxypropyl methylcellulose selected from groups (a) - (d) or mixtures thereof.
7. The formulation of claim 6 comprising about 15-30% by weight of hydroxypropyl methylcellulose selected from groups (a) - (d) or mixtures thereof.
8. The formulation of any one of claims 1-7, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of microcrystalline cellulose, lactose, magnesium stearate, sodium citrate, and povidone.
9. The formulation of claim 8, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of (a) about 4-20% by weight microcrystalline cellulose, (b) about 5-20% by weight lactose, (c) about 1-3% by weight magnesium stearate, (d) about 10-30% by weight sodium citrate, and (e) about 1-15% by weight povidone.
10. The formulation of claim 1, wherein 11- [4- [2- (2-hydroxyethoxy) -ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1, 4] thiazepine is in the form of a hemifumarate.
11. The formulation of any one of claims 1-7, wherein one of the one or more pharmaceutically acceptable excipients is a pH adjusting agent.
12. The formulation of claim 11, wherein the pH adjusting agent is sodium citrate.
13. A method for treating psychosis or hyperactivity in a warm-blooded animal, comprising administering to the warm-blooded animal an effective amount of a formulation according to any one of claims 1-12.
14. A process for preparing a formulation according to any one of claims 1 or 2, which process comprises mixing 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] -dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof, a gelling agent and other excipients.
15. A method of preparing a formulation according to any one of claims 1 or 2, the method comprising:
(a) mixing 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] -dibenzo [ b, f ] [1, 4] thiazepine or a pharmaceutically acceptable salt thereof, a gelling agent, 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 are
(f) Compressing the blended mixture into tablets.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9611328.7 | 1996-05-31 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK05100397.4A Addition HK1068260A (en) | 1996-05-31 | 2005-01-14 | Pharmaceutical compositions |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK05100397.4A Division HK1068260A (en) | 1996-05-31 | 2005-01-14 | Pharmaceutical compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1109063A true HK1109063A (en) | 2008-05-30 |
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