KR20100077959A - Controlled release pharmaceutical formulation for oral administration of anxiolytic drug - Google Patents

Abstract

The present invention relates to pharmaceutical preparations for oral administration of controlled release antidepressants, which include, as pharmacologically active ingredients, sulpiron hydrochloride; And a lipophilic substance selected from the group consisting of glyceryl behenate and hydrogenated cottonseed oil and a hydrophilic polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose and carboxymethylcellulose sodium. Pharmaceutical formulations for oral administration of controlled release antidepressants comprising one or both are provided.

The pharmaceutical preparation of the present invention is a pharmaceutical preparation for oral administration of an antidepressant comprising buspyrone hydrochloride as a pharmacologically active ingredient, which not only achieves both initial fast release and sustained release after several hours, but also according to the rapid release of the drug. The likelihood of adverse events in patients can be significantly reduced. Thus, by providing constant drug delivery, it is possible to effectively prevent the occurrence of side effects due to rapid drug release, reduce the frequency of administration and increase the effect of the drug.

Description

Controlled release pharmaceutical formulation for oral administration of anxiolytic drug

The present invention relates to a pharmaceutical formulation for oral administration of controlled release antidepressants, and more particularly to a pharmaceutical formulation for controlled oral administration controlled release rate of antidepressant comprising buspyrone hydrochloride as a pharmacologically active ingredient. .

Buspyrone hydrochloride (C21H31N5O2.HCl) is a white crystalline, water-soluble compound having a molecular weight of 422.0. Chemically, buspyrone hydrochloride is 8- [4- [4- (2-pyrimidinyl) -1-piperazinyl) -1-piperazinyl] butyl] -8-aza-spiro [4.5] decane- 7,9-dione monohydrochloride. Buspyrone is an antidepressant other than benzodiazepines. As an antidepressant, it has the same effect as benzodiazepines, but buspyrone does not cause the sedation or motor disorders found in benzodiazepines. Chemically, buspyrone is an azaspirodecandione derivative (Formula 1). Its hydrochloride form has a molecular weight of 422 and is highly water soluble. Buspyrone is a dibasic heterocyclic compound and has a pK _{a1 of} 4.12 and a pK _a2 of 7.32.

[Formula 1]

Although the mechanism of action of buspyron has not been established, it is known to act on the dopamine pathway of the central nervous system (CNS) and to increase the striatal concentrations of the dopamine metabolites homovanilanic acid and dihydroxyphenylacetic acid. Buspyron is also known to bind to serotonin (5-hydroxytryptamine; 5-HT) receptors in calf hippocampus. Because 5-HT receptors in calves are similar to those in humans, Buspyron will probably bind to 5-HT receptors in humans. The drug binds with high affinity for 5-HT1, in particular 5-HT1A, and this type of activity is believed to be an important part of its mechanism of action. Berlin et al. (1995) suggest that the psychostimulatory effects of buspyron can be caused by its active metabolite 1-pyrimidinylpiperazine (1-PP), a2-adrenoceptor antagonists, whose plasma concentrations are substantially therapeutic. The dosage was reported to be higher than buspyrone.

Buspyron is well absorbed after oral administration, but substantial first pass metabolism reduces oral bioavailability. In a two-way crossover test, eight healthy volunteers were given 1 mg of [14C] buspyron by 10 minutes intravenous infusion or 200mg of [14C] buspyron by oral solution. Blood samples were collected for 24 hours and total radioactivity and buspyron concentrations (using radioimmunoassays) were measured in plasma, urine and feces. The maximum plasma concentration (Cmax) of buspirone after oral administration was about 2.5 mg / L, and the time taken to reach this concentration was less than 1 hour (0.8 hours). The absolute bioavailability of buspyrone is about 4%.

Buspyron is metabolized extensively without changing the dose to less than 1%. Studies on urine metabolites have shown that the metabolism of buspyron occurs through hydroxylation at the spiro and pyrimidine rings and N-dialkylation of the butyl-substituted side chains. Studies also suggest that 1-PP is a major metabolite in plasma and may have similar pharmacological activity as buspyrone. Based on indirect evidence from drug interaction studies, cytochrome P450 (CYP) 3A4 may be involved in the metabolism of buspyron.

On the other hand, there are several reasons why such dosage forms are attractive over the past 30 years, as the cost and problem of marketing new drug entities with the accompanying recognition of the therapeutic benefits of controlled drug delivery have increased. It is generally recognized that a large number of therapeutically effective compounds already exist for many disease states. However, the effectiveness of these drugs is often limited to the inevitable side effects of administering these compounds in clinical trials. The purpose of the delayed delivery system is to reduce the frequency of administration and increase the effectiveness of the drug by localizing the site of action, reducing the required dose or providing constant drug delivery.

The effect of such drugs in sustained delivery systems is to reduce the frequency of administration, improve patient compliance, prevent adverse effects, and maintain the therapeutic blood or tissue levels of the drug for a delayed period of time. Reducing the dosing schedule leads to improved patient compliance as well as ease of drug administration. Systems designed for delayed release can also be in the form of a formulation, with each dose continuing to be released at regular intervals. The pharmacological effect is maintained as long as the amount of drug is within the therapeutic range. Problems arise when the peak concentration is above or below this range. In particular in the case of drugs with a narrow therapeutic window, however, when designing a sustained delivery system, a drug with a narrow therapeutic window may be used to maintain blood or tissue levels of the drug for a delayed period of time, thereby maintaining Reduce the size When designing sustained delivery systems to reduce dosage, these drugs require or provide constant drug delivery by increasing the effect of the drug by localization of the action. After administration of the drug into the stomach with good and rapid absorption, these drugs show high blood concentrations, but as these drugs are designed as delayed-release systems, the systemic adverse effects that occur at high blood levels can be reduced and a strong therapeutic effect The range of safe treatments for drugs with is widened, and the systemic and local adverse effects on patient sensitivity to adverse effects are reduced.

Delayed-release tablets can be prepared by using water insoluble substances, natural or synthetic macromolecules, waxes, fatty acids and alcohols in wet granulation to limit drug solubility. Greater attention has been focused on developing sustained drug delivery systems that can regulate pharmacologic activity by controlling the absorption of drugs using pharmacokinetic and pharmacodynamic factors.

On the other hand, the above-mentioned booth pyrons exhibit very high first-pass metabolism, and after oral administration only about 4% of the therapeutic dose remains unchanged (Cay. Pharmacol. Ther., No. 37, 210, Mayol et al. Page, 1985). In the uptake of buspyrone, large variations between individuals were observed to exhibit up to about 10-fold variation in plasma concentrations {Gammans et al. American J. Med., No. 80, Appendix 3B, pages 41-51, 1986. Reference). Two metabolites were identified, of which 5-OH-buspyron showed no pharmacological activity and 1- (2-pyrimidinyl) piperazine, ie 1-PP by itself, had 20 It was found to represent -25%. While the biological half-life of buspyrone itself is very short in the human body (e.g., 2-11 hours), much less active metabolite 1-PP is removed more slowly (Cay. Pharmacol. Ther., Mayol et al., 37, pp. 210, 1985). These pharmacokinetic properties make it somewhat inevitable to take frequent daily doses, which can negatively affect patient compliance. Because buspyrone is rapidly absorbed after oral administration, high plasma peak values appear immediately after drug administration, which may be related to the development of undesirable side effects that may occur temporarily at the beginning of treatment. This can also seriously affect patient compliance in that it interferes with treatment.

Thus, as described above, because Buspyron has complex pharmacokinetics with extensive first-pass metabolism and higher variability, it provides modified Buspyron oral absorption, maintains desired drug blood levels, and minimizes unwanted side effects. There is a need to develop oral delayed release dosage forms of buspyrone.

Accordingly, the present invention provides a pharmaceutical formulation for oral administration of controlled release antidepressant which delays the release rate of antidepressant comprising buspyrone hydrochloride as pharmacologically active ingredient.

According to the present invention, as the pharmacologically active ingredient, busyrone hydrochloride; And a lipophilic substance selected from the group consisting of glyceryl behenate and hydrogenated cottonseed oil and a hydrophilic polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose and carboxymethylcellulose sodium. Pharmaceutical formulations for oral administration of controlled release antidepressants comprising one or both are provided.

The pharmaceutical preparation of the present invention is a pharmaceutical preparation for oral administration of an antidepressant comprising buspyrone hydrochloride as a pharmacologically active ingredient, which not only achieves both initial fast release and sustained release after several hours, but also according to the rapid release of the drug. The likelihood of adverse events in patients can be significantly reduced. Thus, by providing constant drug delivery, it is possible to effectively prevent the occurrence of side effects due to rapid drug release, reduce the frequency of administration and increase the effect of the drug.

Hereinafter, the present invention will be described in detail.

Pharmaceutical formulations for oral administration of controlled release antidepressants of the present invention are characterized by retarding the release rate of the pharmacologically active ingredient, busyrone hydrochloride, including busyrone hydrochloride and lipophilic substances and / or hydrophilic polymers. .

The components of the pharmaceutical formulation for oral administration of the present invention will be described in detail as follows.

Buspyrone hydrochloride used as a pharmacologically active ingredient in the present invention is an antidepressant, but the amount thereof is not limited thereto, but may be used in an amount of 7 to 48% by weight based on the total weight of the pharmaceutical formulation of the present invention. Preferably it may be used in an amount of 10 to 20% by weight.

In the present invention, the lipophilic material is used to control the release rate of the buspyrone hydrochloride, but is not limited thereto, but may be used in an amount of 40 to 77% by weight based on the total weight of the composition. have. When the content of the lipophilic substance is less than 40% by weight, the release rate of the drug may be too fast to be released all upon oral administration, and when the content exceeds 77% by weight, the release rate of the drug may be too slow. Preferably, the lipophilic material is included in an amount of 30-60% by weight based on the total weight of the composition.

The lipophilic material is selected from the group consisting of glyceryl behenate and hydrogenated cottonseed oil. Preferably, the lipophilic material is not limited thereto, but glyceryl behenate is used.

The lipophilic material can be combined with a drug prepared as a solid dispersion by the melting method, and in the form of a delayed release tablet together with additives such as lactose anhydrous, dibasic calcium phosphate dihydrate or microcrystalline cellulose. It is preferred to be prepared with.

The hydrophilic polymer is also used to control the release rate of the buspyrone hydrochloride, but the amount is not limited thereto, but may be used in an amount of 30 to 80% by weight based on the total weight of the composition. When the content of the hydrophilic polymer is less than 30% by weight, the release rate of the drug may be too fast to be released all upon oral administration, and when the content exceeds 80% by weight, the release rate of the drug may be too slow. Preferably, the hydrophilic polymer is included in an amount of 40 to 70% by weight based on the total weight of the composition.

The hydrophilic polymer can be selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose oz and carboxymethylcellulose sodium.

The hydrophilic polymer can be combined with a drug prepared as a solid dispersion by the solvent method, and in the form of a delayed release tablet with additives such as lactose anhydrous, dibasic calcium phosphate dihydrate or microcrystalline cellulose. It is preferred to be prepared.

The pharmaceutical formulations of the present invention may also further comprise pharmaceutically acceptable additives, which may include diluents, binders, disintegrants, lubricants, swelling agents, surfactants, antioxidants, foaming agents, flavoring agents, controlled release agents, Coatings and combinations thereof.

The additives include, but are not limited to, lactose anhydrous, dibasic calcium phosphate dihydrate, microcrystalline cellulose or mixtures thereof.

The amount of the additive is not limited thereto, but is preferably included in an amount of 0.5 to 57% by weight based on the total weight of the composition.

The pharmaceutical formulation of the present invention can be prepared by a general pharmaceutical preparation method. For example, a solid dispersion of the pharmacologically active ingredient Buspiron HCl may be prepared by melting or solvent method, and the solid dispersion may be prepared in tablet form by direct compression with other ingredients. have.

Hereinafter, the present invention will be described in more detail with reference to examples, which are only intended to help understanding the structure and operation of the present invention, but the scope of the present invention is not limited to these examples.

Example

1. Experiment Method

1-1. material

The following materials were used as received without further purification.

Buspyrone hydrochloride (JiangSu NHWA Pharmacetical Group.Co. Ltd., China)

Glyceryl Palmitostearate (Precirol ^® ATO 5, Gattefosse, sas, France)

Glyceryl Behenate (Compritol ^® 888ATO, Gattefosse, sas, France)

Glyceryl Monostearate (GMS, B & M Chemicals Ltd. India)

Hydrogenated cottonseed oil (Sterotex, Abitec Co, WI, U.S.A.)

Hydroxypropylmethylcellulose (HPMC K15M, Shin-Etsu Chemicals Co., Japan)

Hydroxypropylmethylcellulose (HPMC K4M, Shin-Etsu Chemicals Co., Japan)

Carboxymethylcellulose sodium (NaCMC, Sigma-Aldrich Chemie GmbH, Germany)

Hydroxypropylcellulose, low viscosity (Klucel LF, Hercules U.S.A.)

Hydroxypropylcellulose, high viscosity (Klucel LF, Hercules U.S.A.)

Lactose Anhydrous (DMV International Pharma, Holland)

Dibasic calcium phosphate dihydrate (Emcompress, Edward Mendell Co., U.K.)

Microcrystalline cellulose (Comprecel ^® , Mingtai Chemical Co., Ltd., Taiwan)

Magnesium Stearate (Katayama Chemical Co., Japan)

HPLC grade acetonitrile (J. T. Baker Co., U.S.A.)

HPLC grade methanol (J. T. Baker Co., U.S.A.)

The water was purified and filtered by reverse osmosis.

1-2. Formulation of Buspyrone HCl Solid Dispersion

Solid dispersions were prepared by a solvent method and a melting method.

1-2-1. Preparation of Solid Dispersion by Melting Method

Solid dispersions of buspyrone HCl were prepared by melting. Pricyrrole, GMS, Compritol or Sterox have been used as lipophilic polymers for delayed release matrix purification. The weight ratios of buspyron HCl to polymer were varied to 1: 1, 1: 2, 1: 5 and 1:10 (w / w). Appropriate weights of pure buspyron HCl and polymer were weighed and mixed respectively. The physical mixture was heated under stirring for 15 minutes in a heating block maintained at 90 ° C. until all the mixture was completely dissolved and uniformly dispersed. The mixture was cooled slowly to room temperature. The solidified melt was ground and sieved using 35 and 60 mesh. The powder between 35 and 60 mesh was stored in a closed container.

1-2-2. Preparation of Solid Dispersion by Solvent Method

When solid dispersions were prepared by the solvent method, appropriate weights of Buspyron HCl powder and HPMC were weighed and mixed respectively. Buspyron HCl was dissolved with HPMC in a mixture of methylene chloride and methanol in an appropriate amount. The weight ratios of the drug to HPMC were 1: 1, 1: 2, 1: 5 and 1:10 (w / w). The mixture was sonicated, self-stirred for 30 minutes and stored in an oven maintained at 45 ° C. for 24 hours to evaporate the solvent. The solidified melt was ground and sieved using 35 and 60 mesh. The powder between 35 and 60 mesh was stored in a closed container.

1-3. Preparation and Evaluation of Buspyrone HCl Delayed-Release Tablets

1-3-1. Preparation of Buspyrone HCl Delayed-Release Tablets

The components of the other formulations were mixed for 10 minutes using a motor and a plastic pack and then compressed by direct compression using a concave punch size 8 mm diameter tooling. Each tablet formulation was characterized by weight and hardness changes. The average tablet hardness was 60-70 N as measured by a hardness tester (Dr. Sheleuniger Model 6D Tablet Tester, Pharmatron, U.S.A.).

1-3-2. Preparation of Buspyron HCl Delayed-Release Tablets Containing Lipophilic Polymer

The combination of buspyron HCl delayed-release tablets with lipophilic polymers is shown in Table 4. 30 mg of Buspyron HCl was applied per tablet and lipophilic polymers were formulated in the range of 30-300 mg. Diluents were used in the range 28-178 mg per tablet. Magnesium stearate was applied 2 mg per tablet as lubricant.

As lipophilic polymers, Precirol ^® ATO 5, Compritol ^® 888 ATO, GMS and sterotex were applied respectively. Lactose Anhydrous, Empress or Comprisel were used directly as compression diluents and magnesium stearate was used as lubricant. Different weight ratios of solid dispersions and diluents were compressed by direct compression. Delayed-release tablets using solid dispersions were prepared as follows: ① Busyron HCl and lipid were weighed respectively. ② The lipids were heated in mortar at 45-90 ° C. until complete melting. ③ BSP was added to the molten lipid and stirred well at 45-90 ° C. ④ Mortar was removed from the heater and cooled to room temperature. ⑤ The solid mixture was ground and sieved using a 35 or 60 mesh sieve. ⑥ After adding the diluent, mixed homogeneously. ⑦ Magnesium stearate was added, mixed homogeneously, and compressed to prepare a tablet.

TABLE 1

Formulation of Buspyron HCl ER Tablet with Lipophilic Polymer (in mg / tablet)

combination content Buspyron HCl 30 Lipophilic polymer ^a 30-300 Thinner ^b 28-178 Magnesium stearate 2 gun 62-420

^a Precirol ^® ATO 5, Compritol ^® 888 ATO, GMS and Sterotex

^b Lactose Anhydrous, Emcompress, Comprecel

1-3-3. Preparation of Buspyron HCl Delayed-Release Tablets Containing Lipophilic Polymer

The formulation of the buspyron HCl delayed-release tablet with a lipophilic polymer is shown in Table 2. 30 mg of Buspyron HCl was applied per tablet and lipophilic polymers were formulated in the range of 30-300 mg. Diluent was applied in the range of 28-148 mg / tablet and magnesium stearate was applied at 2 mg / tablet as lubricant.

HPMC K15M, HPC and NaCMC were used as lipophilic polymers for delayed-release materials. Lactose Anhydrous, Empress or Comprisel were used directly as compression diluents and magnesium stearate as lubricant. The drug and polymer were dissolved in the solvent and then the solvent was evaporated completely. Dissolve the dry matter and sift to 35 or 60 mesh, then add diluent for homogeneous mixing. Magnesium stearate was applied as lubricant and then compressed. The drug, polymer, and other excipients were mixed homogeneously, then lubricant magnesium stearate was applied and directly compressed.

TABLE 2

Formulation of Buspyron HCl ER Tablet with Lipophilic Polymer (in mg / tablet)

combination content Buspyron HCl 30 Lipophilic polymer ^a 30-300 Thinner ^b 28-148 Magnesium stearate 2 gun 120-390

^a HPMC, HPC, NaCMC

^b Lactose Anhydrous, Emcompress, Comprecel

1-4. Dissolution of Buspyron HCl Delayed-Release Tablets

The dissolution test of the buspyron HCl delayed-release tablet was measured according to USP XXV and dissolution apparatus 2, paddle method at a stirring speed of 1000 rpm using a dissolution tester (Dissolution tester DST-810, Labfine, Korea) at 37 ± 0.5 ° C. . The dissolution medium was 0.01 N HCl medium and the volume of the dissolution medium was 900 mL. In each dissolution test, a weighed amount of sample containing 30 mg of buspiron HCl was placed in 900 mL of dissolution medium. Aliquots (6 mL) were recovered at predetermined time intervals and filtered through a Nylon Acrodisc ^® 0.45 micrometer membrane filter. At each sampling, 6 mL of volume removed was immediately replaced with fresh dissolution medium. Drug concentration in the medium was measured by UV spectrophotometer. Drug concentrations were detected and expressed as percentage of drug released over time (n = 3 each). Prior to filtering the solution, the membrane filter was set to prevent absorption in the membrane filter by passing through 4 mL of dissolution medium. This process was applied to all filtration processes in this test.

Sakr and Andheria (2001a, b) reported a pharmacokinetic study of buspyron delayed-release tablets, which demonstrated an effective drug release profile from delayed-release tablets in vitro. According to this report, the final formulation was selected and the dissolution rate was compared with the reference formulation. Table 3 shows the appropriate specifications for this dissolution test (Sakr and Andheria (2001a, b)). This showed a dissolution profile, 30-50% at 2 hours, 55-75% at 4 hours, 85-100% at 8 hours and complete dissolution at 12 hours, which will be the target profile of the present invention.

[Table 3]

Specification for Dissolution Testing of Buspyron HCl ER Tablets

Time (hr) Release drug (%) 2 30-50 4 55-75 8 85-100 12 > 90

1-5. Quantitative Analysis of Buspiron HCl

1-5-1. UV-spectrophotometry

The amount of buspyron HCl released from the solid dispersion and delayed release tablets in the dissolution test was determined by UV-spectrophotometry (Takka et al., 2003).

1-5-1-1. Instrument

Samples recovered at predetermined times were analyzed using a UV-Vis spectrophotometer (UV mini 1240, Shimadzu, Japan). UV-spectrophotometer conditions were fixed at a wavelength of 238 nm. The cell used was a 1 × 1 cm 2 quartz cell. The blank sample for baseline was the dissolution medium at 0 hours.

1-5-1-2. Calculation of% Released

The percent release of buspyrone HCl from delayed-release tablets in each sample was calculated using the following formula:

[Equation 1]

Where% R is the cumulative percent release of Buspyron HCl, As is the absorbance of the dissolved sample recovered at predetermined time intervals, Ast is the absorbance of the standard solution, and C is the concentration of the standard solution (μg / mL) Where V is the volume of dissolution medium (mL) and D is the initial amount (mg) of Buspyron HCl in the delayed release tablet. The curve of dissolution profile is expressed as cumulative percent release over time (hr).

1-6. statistics

Statistical processing was performed by linear or quadratic regression using the support of a nonlinear regression program, SigmaPlot ver 8.0 (SPSS Inc., Chicago, IL, USA). Statistical significance was accepted as p <0.05 or p <0.10.

2. Results and discussion

2-1. Dissolution Profile of Buspyron HCl from Immediate Release Tablets and Reference Formulations

Dissolution testing was conducted to evaluate immediate release formulations already present on the market, and bibliographic investigations were added to define the dissolution profile of delayed release tablets.

1 shows the release profile of Buspyron HCl from (A) commercially available immediate release tablets and (B) reference formulations in the literature (Sakr and Andheria, 2001a, b). The result was that the release of the drug from the immediate release tablet was rapid and completed within 5 minutes. The percentage of drug released after 5 minutes from the immediate release tablet was greater than 90%. As shown in FIG. 1, the reference formulation of Buspyron ER slowly dissolved for 12 hours. Dissolution amounts were 30-50%, 55-75% and 85-100% at 2, 4 and 8 hours, respectively, and more than 90% were dissolved at 12 hours (Sakr and Andheria, 2001a, b).

2-2. Dissolution Profile of Buspyron HCl Delayed-Release (ER) Tablets with a Lipophilic Polymer

2-2-1. Effect of the Type of Lipophilic Polymer on the Dissolution of Busyron HCl from ER Tablets

Lipophilic polymers such as Precirol, Compritol, GMS and Sterotex are used in tablets to delay the release of the drug. The effect of these on the rate of release of the drug was evaluated to find the appropriate amount of these in the tablet. Formulations applied using Precirol, Compritol, GMS and Sterotex are given in Tables 4 and 5, respectively.

[Table 4]

Formulation of Buspirone HCl Delayed-Release Tablets Prepared with Precirol and Compritol Using Solid Dispersion (melting)

                                                            (Unit: mg / tablet)

Formulation LMP01 LMP02 LMP03 LMP04 LMC01 LMC02 LMC03 LMC04 Buspyron HCl 30 30 30 30 30 30 30 30 Precirol 30 60 150 300 - - - - Compritol - - - - 30 60 150 300 Magnesium stearate 2 2 2 2 2 60 150 300 gun 62 92 182 332 62 92 182 332

TABLE 5

Formulation of Buspyron HCl Delayed-Release Tablets Prepared by GMS and Sterotex Using Solid Dispersion (melting)

                                                            (Unit: mg / tablet)

Formulation LMG01 LMG02 LMG03 LMG04 LMS01 LMS02 LMS03 LMS04 Buspyron HCl 30 30 30 30 30 30 30 30 GMS 30 60 150 300 - - - - Sterotex - - - - 30 60 150 300 Magnesium stearate 2 2 2 2 2 2 2 2 gun 62 92 182 332 62 92 182 332

Each tablet contained 30 mg of buspyron HCl and 30-300 mg of lipophilic polymer, the dissolution test was performed after compression and the final tablet weight was in the range of 62-332 mg.

2-5 show the release profile of buspyron HCl from ER tablets. Precirol (Reitz and Kleinebudde, 2007; Sinchaipanid et al., 2004; Hamdani et al., 2002, 2003) and GMS (Adeyeye and Price, 1991, 1994; Allababidi and Shah, 1998a, b; Lu et al, 2007) It has been widely used in the development of delayed release dosage forms. However, the results in this test showed that the release of drug from tablets made with Precirol or GMS was rapid in all formulations. The percentage of drug released after 5 minutes from a tablet made with Precirol or GMS is at least 80-90%. Therefore, the influence of the lipid matrix on the release of buspyron HCl was not significant.

However, the release profile of the drug from tablets with Compritol or Sterotex was delayed depending on the amount of lipophilic polymer. Compritol is an atomized glyceryl behenate which is commonly applied as a delayed release excipient in many irradiations. Large amounts of Sterotex showed a dramatic delayed release of the drug from the tablet. T _80% (80% release time) of Buspyron HCl from ER tablets made with Compritol increased from 9.2 minutes to 20.6 minutes as the amount of Compritol increased from 30 mg / tablet to 300 mg / tablet (FIG. 6).

As shown in FIG. 6, the amount of Compritol increase in the range of 30-150 mg was performed in a linear relationship for T _80% (p <0.05, r ² = 0.998). Compritol amount in the range 30-300mg for T _80% can be interpreted as _{(T 80%) = 0.079 x} ( amount of Compritol) + 6.597. However, at over 150 mg of Compritol, the rate of increase of T _80% decreased.

T _50% (50% release time) of Buspyron HCl from ER tablets made with Sterotex increased from 9.4 minutes to 25.4 minutes as the amount of Sterotex increased from 30 mg / tablet to 300 mg / tablet (FIG. 7). Figure 7 also shows that a linear increase of T _50% occurs as the amount of Sterotex increases from 60 mg to 300 mg (p <0.05, r ² = 0.999). However, when the amount of Sterotex is less than 60 mg, T _50% is rather Therefore, in view of these experimental results, Compritol or Sterotex could be used for subsequent testing.

2-2-2. Effect of Compritol Amount on the Dissolution of Buspyron HCl from ER Purification

For the purpose of evaluating the effect of Compritol on the dissolution profile, the amount of Compritol was varied in the tablet for delayed release of the drug. The effect on drug release rate was evaluated to find the appropriate amount of these in the tablet. Formulations applied using Compritol and Lactose Anhydrous are given in Table 6. 8 and 9 show the release profile of buspyron HCl from ER tablets. 8 and 9 also show that the formulation is releasing the drug either faster (LMCL01, LMCL02, LMCL05, LMCL06) or slower than the target reference dissolution (LMCL03, LMCL04, LMCL07, LMCL08). Matrix tablets were prepared using a solid dispersion method (melting method) and the amount of lipophilic polymer varied from 30 to 300 mg per tablet. The amount of lactose anhydrous was fixed at 58 mg or 88 mg per tablet. As a result, drug release from tablets made with Compritol 30 mg (LMCL01 and LMCL05) was at least 80% within 1 hour and drug release from tablets made with Compritol 60 mg (LMCL02 and LMCL06) was at least 80% at approximately 3 hours. . However, drug release profiles from tablets prepared using Compritol 150 mg or 300 mg lasted dramatically depending on the amount of Compritol. About 55.6% drug release was obtained for 12 hours from LMCL03 (Compritol 150mg) and only 23.8% drug release was made for 12 hours from LMCL04 (Compritol 300mg). Both formulations contained 58 mg of lactose anhydroose. In contrast, drug release rates were faster than LMCL03 and LMCL04 from formulations containing Lactose Anhydrous 88 mg, LMCL07 (Compritol 150 mg) and LMCL08 (Compritol 300 mg), respectively. Drug release from LMCL07 and LMCL08 was 75.4% and 58.6% for 12 hours, respectively. From these results, we suggest that the rate of release of drug from the matrix tablet can be controlled by controlling the amount of Compritol, and that the amount of lactose anhydroose can affect the rate of drug release from the matrix tablet. do. Thus, the effect of the amount of additive and the type of additive on the rate of drug release was also evaluated.

TABLE 6

Formulation of Boothpyron HCl Delayed-Release Tablets Prepared with Various Amounts of Compritol Using Solid Dispersion (melting)

                                                            (Unit: mg / tablet)

Formulation LMCL01 LMCL02 LMCL03 LMCL04 LMCL05 LMCL06 LMCL07 LMCL08 Buspyron HCl 30 30 30 30 30 30 30 30 Compritol 30 60 150 300 30 60 150 300 Lactose Anhydrous 58 58 58 58 88 88 88 88 Magnesium stearate 2 2 2 2 2 2 2 2 gun 120 150 240 390 150 180 270 420

3-2-3. Effect of Additive Type on Dissolution of Busyron HCl from ER Tablets Prepared with Compritol

The amount of additives and the type of additives in the tablets were varied to delay the release rate of the drug. The effect of these on drug release was evaluated to find the appropriate amount of these in the tablets.

The formulations applied using Compritol and Lactose Anhydrous are shown in Table 7. The amount of lactose anhydroose was varied from 28 to 118 mg / tablet and the amount of Compritol was fixed to 60 mg / tablet. 10 shows the release profile of Buspyron HCl from ER tablets. The percentage of drug released after 4 hours from tablets made with 28, 58 or 118 mg lactose anhydrous was 86.7, 90.0 or 92.8%, respectively. Drug release was faster than baseline in all three combinations. T80% (80% release time) of buspyron HCl from ER tablets prepared with lactose anhydrous decreased from 3.1 to 2.0 hours as the amount of lactose anhydroose increased from 28 to 118 mg / tablet (FIG. 11). ). Therefore, the effect of the amount of lactose anhydroose on the release of buspyrone HCl was not significant and was not significant (p> 0.10).

The amount of Emcompress varied from 28 to 118 mg / tablet and the amount of Compritol was fixed to 60 mg / tablet. 12 shows the release profile of buspyron HCl from ER tablets. The percentage of drug released after 12 hours from tablets made with 28, 58 or 118 mg Emcompress was 70.8, 67.8 or 60.0%, respectively. In the case of Emcompress, all formulations showed dissolution slower than the target dissolution profile. T50% (50% release time) of buspyron HCl from ER tablets prepared with Emcompress increased from 5.1 to 6.9 hours as the amount of Emcompress increased from 28 to 118 mg / tablet (FIG. 13). A slight increase in T50% was not significant (p> 0.10). Therefore, the effect of the amount of Emcompress on the release of buspyrone HCl was not significant.

The formulations applied using Compritol and Comprecel are shown in Table 7. Comprecel is often regarded as one of the best excipients for direct compression. Comprecel incorporated into the formulation has been shown to increase the dissolution rate and compression rate of tablets prepared by high shear granulation. The amount of Comprecel was changed from 28 to 118 mg / tablet and the amount of Compritol was fixed at 60 mg / tablet. 14 shows the release profile of buspyron HCl from ER tablets. The percentage of drug released after 4 hours from tablets made with 28, 58 or 118 mg Comprecel was 66.4, 70.5 or 87.4%, respectively. As shown in FIG. 14, LMCC01 and LMCC02 showed nearly ideal drug release for the target profile. From ER tablets made with Comprecel, T80% (80% drug release time) of Buspyron HCl decreased from 5.4 to 3.5 hours as the amount of Comprecel increased from 28 to 118 mg / tablet (FIG. 15). As shown in FIG. 15, the increase in the amount of Comprecel in the range of 30-120 mg is linearly related to T80% (p <0.10, r ² = 0.980). The correlation between Comprecel amount and T80% in the 30-120 mg range can be expressed as (T80%) = -0.022 x (Comprecel amount) + 6.155. Therefore, the effect of the amount of Comprecel on the release of buspyrone HCl was significant.

TABLE 7

Formulation of Buspirone HCl Delayed-Release Tablets Prepared with Compritol and Various Additives by Solid Dispersion (melting)

                                                            (Unit: mg / tablet)

Formulation LMCL09 LMCL02 LMCL10 LMCE01 LMCE02 LMCE03 LMCC01 LMCC02 LMCC03 Buspyron HCl 30 30 30 30 30 30 30 30 30 Compritol 60 60 60 60 60 60 60 60 60 Lactose Anhydrous 28 58 118 - - - - - Emcompress - - - 28 58 118 - - - Comprecel - - - - - - 28 58 118 Magnesium stearate 2 2 2 2 2 2 2 2 2 gun 120 150 120 120 150 210 120 120 120

3-2-4. Effect of the amount of Sterotex on the dissolution of buspyrone HCl from ER purification

The amount of Sterotex was changed in the tablet to slow the rate of drug release. In addition, the amount of additives and the type of additives in the tablets were varied to delay the release rate of the drug. The effect of these on drug release was evaluated to find the appropriate amount of these in the tablets.

The formulations applied using Sterotex and Lactose Anhydrous are shown in Table 8. 16 shows the release profile of buspyron HCl from ER tablets. Matrix tablets were prepared using a solid dispersion method (melting method) and the amount of Sterotex varied from 30 to 300 mg per tablet. The amount of lactose anhydrous was fixed at 58 mg / tablet. As a result, the drug release from tablets made with 30 mg Sterotex (LMSL01) and 60 mg Sterotex (LMSL02) was more than 80% in 1 and 2 hours, respectively. However, the release profile of the drug from tablets prepared using 150 mg or 300 mg Sterotex was dramatically sustained depending on the amount of Sterotex. Drug release from LMSL03 (150 mg Sterotex) and LMSL04 (300 mg Sterotex) was 66.8% and 15.5%, respectively. As shown in FIG. 16, the dissolution profile of the test formulation was faster (LMSL01, LMSL02) or slower than the reference target profile (LMSL03, LSMSL04). These results suggest that the amount of Sterotex can be controlled to control the rate of drug release from the matrix tablets. Therefore, in order to control the rate of drug release, the effect of the amount of the additive and the type of the additive on the rate of drug release was further evaluated.

The amount of lactose anhydrous was varied from 58 to 178 mg / tablet and the amount of Sterotex was fixed at 150 mg / tablet (Table 9). 17 shows the release profile of buspyron HCl from ER tablets. The percentage of drug released after 12 hours from tablets made with 58, 118 or 178 mg lactose anhydrous was 68.7, 76.4 or 84.2%, respectively. All three combinations showed slower drug dissolution than the target criteria. T50% (50% release time) of buspyron HCl from ER tablets prepared with lactose anhydrous decreased from 6.1 to 4.2 hours as the amount of lactose anhydroose increased from 58 to 178 mg / tablet (FIG. 18). ). Increasing the amount of lactose anhydrous in the 58-178 mg range resulted in a linear increase of T50% (p <0.10, r ² = 0.989). The correlation of T80% with Lactose Anhydros in the 58-178 mg range can be expressed as (T50%) = -0.016 x (amount of Lactose Anhydrous) + 6.976. Thus, the effect of the amount of lactose anhydrous on the release of buspyrone HCl was significant.

[Table 8]

Formulation of Buspirone HCl Delayed-Release Tablets Prepared with Various Volumes of Sterotex Using Solid Dispersion (melting)

                                                            (Unit: mg / tablet)

Formulation LMSL01 LMSL02 LMSL03 LMSL04 Buspyron HCl 30 30 30 30 Sterotex 30 60 150 300 Lactose Anhydrous 58 58 58 58 Magnesium stearate 2 2 2 2 gun 120 150 240 390

The formulations applied using Sterotex and Emcompress are shown in Table 9. The amount of Emcompress was varied from 58 to 178 mg / tablet and the amount of Sterotex was fixed at 150 mg / tablet. The percentage of drug released after 12 hours from tablets prepared at 28, 58 or 118 mg was 19.6, 25.1 or 29.4%, respectively. Application of Sterotex and Emcompress led to a significant reduction in drug release. T20% (20% release time) of buspyron HCl from ER tablets made with Emcompress decreased from 12.7 to 5.5 hours as the amount of Emcompress increased from 28 to 118 mg / tablet (FIG. 20). Although Emcompress reduced the overall drug release kinetics, the effect of the amount of Emcompress on the release of buspyrone HCl was not significant (p> 0.10).

TABLE 9

Formulation of Buspirone HCl Delayed-Release Tablets Prepared with Sterotex and Various Additives Using Solid Dispersion Method

                                                            (Unit: mg / tablet)

Formulation LMSL05 LMSL06 LMSL07 LMSE01 LMSE02 LMSE03 LMSC01 LMSC02 LMSC03 Buspyron HCl 30 30 30 30 30 30 30 30 30 Sterotex 150 150 150 150 150 150 150 150 150 Lactose Anhydrous 58 118 178 - - - - - Emcompress - - - 58 118 178 - - - Comprecel - - - - - - 58 118 178 Magnesium stearate 2 2 2 2 2 2 2 2 2 gun 240 300 360 240 300 360 240 300 360

The formulations applied using Sterotex and Comprecel are shown in Table 9. The amount of Comprecel was changed from 58 to 178 mg / tablet and the amount of Sterotex was fixed at 150 mg / tablet. 21 shows the release profile of buspyron HCl from ER tablets. The percentage of drug released after 12 hours from tablets made with 28, 58 or 118 mg Comprecel was 73.3, 79.6 or 83.9%, respectively. All three of these combinations released the drug slower than the reference profile. T50% (50% release time) of buspyron HCl from ER tablets made with Comprecel decreased from 7.4 to 3.9 hours as the amount of Comprecel increased from 28 to 118 mg / tablet. Increasing amounts of Comprecel tended to decrease T50%, but were not statistically significant (p> 0.10). Therefore, the effect of the amount of Comprecel on the release of buspyron HCl was not significant.

2-3. Dissolution Profile of Buspyron HCl ER Tablets Using Hydrophilic Polymer

2-3-1. Effect of HPMC on the Dissolution of Buspyron HCl from ER Purification

HPMC is a pH-dependent material and the rate of drug release from the HPMC matrix formulation is generally independent of process variables such as compression pressure, drug particle size and incorporation of lubricants. Thus, HPMC is widely used to prepare delayed release dosage forms such as promethazine and acetaminophen.

In this test, HPMC K15M and HPMC K4M were used as hydrophilic polymers to prepare ER tablets. In order to confirm the influence of the manufacturing method on the dissolution rate of the ER tablets, ER tablets containing HPMC K15M were prepared by two different methods, the direct compression method and the solid dispersion method (solvent method). The applied formulations of Buspyron HCl ER tablets made with HPMC K15M and HPMC K4M are shown in Table 10.

The amount of HPMC K15M was used in the range of 60-300 mg / tablet for the direct compression method and the amount of HPMC K15M or HPMC K4M was applied in the range of 30-300 mg / tablet for the solid dispersion method. The effect of HPMC on the release profile of buspyron is shown in Figures 23-25.

TABLE 10

Formulation of Buspirone HCl Delayed-Release Tablets Prepared with Various Quantities of HPMC K15M or HPMC K4M Using Direct Compression or Solid Dispersion (Solvent)

                                                            (Unit: mg / tablet)

Formulation HMHMD01 ^a HMHMD02 ^a HMHMD03 ^a HMHMD04 ^a HMHMML01 ^b HMHML02 ^b HMHML03 ^b HMH4L01 ^b HMH4L02 ^b HMH4L03 ^b Buspyron HCl 30 30 30 30 30 30 30 30 30 30 HPMC K15M 30 60 150 300 60 150 300 - - - HPMC K4M - - - - - - - 60 150 300 Lactose Anhydrous 58 58 58 58 58 58 58 58 58 58 Magnesium stearate 2 2 2 2 2 2 2 2 2 2 gun 120 150 240 390 150 240 390 150 240 390

adirect compression

b Solid dispersion method (solvent method)

With increasing amount of HPMC K15M, the release of buspyron HCl decreased in the formulations prepared by direct compression method (FIG. 23). The high content of the expandable polymer leads to higher gel formation, thus delaying drug release. However, the release of buspyrone HCl from ER tablets made with HPMC K15M was still fast compared to the desired dissolution profile, especially at the initial stage for all formulations. The percentages of drug released after 2 hours from the formulation of HMHMD01, HMHMD02, HMHMD03 and HMHMD04 were 65.6, 50.3, 44.9 and 30.4%, respectively. Despite the high content of HPMC K15M in tablets, as in the case of the combination of HMHMD04, it did not reduce the rate of release of the drug at an early stage.

HPMC is a useful hydrophilic polymer that can be used for the manufacture of oral controlled release drug systems. However, HPMC relies on water absorption to produce gel swelling and matrix relaxation, which in turn promotes drug dissolution and diffusion from the matrix. This explains why buspyron HCl was released rapidly through the gel layer of HPMC. In the initial dissolution step, a gel barrier controlling release was not yet formed, which resulted in rapid dissolution of the drug from the tablet surface.

The formulations applied using HPMC K15M as the solid dispersion method (solvent method) are shown in Table 10. The percentage of drug released after 12 hours from HMHML01, HMHML02 and HMHML03 was 58.5, 73.7 or 45.4%, respectively. The formulations applied using HPMC K4M as the solid dispersion method (solvent method) are shown in Table 10. The percentage of drug released after 12 hours from HMH4L01, HMH4L02 and HMH4L03 was 64.5, 73.3 or 36.2%, respectively. As in the case of combinations containing HPMC K15M and HPMC K4M, they reduced the release rate of the drug at an early stage. Thus, it is useful for preparing matrix tablets made using a solid dispersion method containing HPMC K15M and HPMC K4M. Moreover, the effect of HPMC K15M and HPMC K4M on the release of buspyron HCl was significant.

2-3-2. Effect of Additive Type on Dissolution of Busyron HCl from ER Purification with HPMC K4M

The amount of additive and the type of additive in the tablet containing HPMC K4M were varied to delay the release rate of buspyrone. The effect of these on the rate of drug release was evaluated to find the appropriate amount of these in the tablets.

The formulations applied using HPMC K4M and Lactose Anhydrous are shown in Table 11. The amount of lactose anhydrous varied from 28 to 148 mg / tablet and the amount of HPMC K4M was fixed to 150 mg / tablet. 26 shows the release profile of buspyron HCl from ER tablets. The percentage of drug released after 12 hours from tablets made with 28, 58 or 148 mg lactose anhydrous was 71.7, 74.7 or 70.7%, respectively. Drug release was slower than the baseline dissolution profile in all three formulations. T50% (50% release time) of buspyron HCl from ER tablets prepared with lactose anhydrous did not vary from 3.1 to 4.0 hours depending on the amount of lactose anhydroose (FIG. 27). Therefore, the effect of the amount of lactose anhydroose on the release of buspyrone HCl was not significant (p> 0.10).

The formulations applied using HPMC K4M and Emcompress are shown in Table 11. The amount of Emcompress varied from 28 to 148 mg / tablet and the amount of HPMC K4M was fixed to 150 mg / tablet. 28 shows the release profile of buspyron HCl from ER tablets. The percentage of drug released after 12 hours from tablets made with 28, 58, 118 or 148 mg Emcompress was 58.8, 56.2, or 51.7%, respectively. All four of these combinations showed slower drug release than the target solubility. T50% (50% release time) of buspyron HCl from ER tablets made with Emcompress increased to 6.7 to 9.9 hours as the amount of Emcompress increased from 28 to 148 mg / tablet (FIG. 29). As shown in FIG. 29, the increase in amount of Emcompress within the range of Emcompress 28-148 mg resulted in a linear increase of T50% (p <0.05, r ² = 0.988). Therefore, the correlation between Emcompress and T50% in this range can be expressed as (T50%) = -0.027 x (amount of Emcompress) + 5.826. Therefore, the effect of the amount of Emcompress on the release of buspyrone HCl was significant.

The formulations applied using HPMC K4M and Comprecel are shown in Table 11. The amount of Comprecel was changed to 28-148 mg / tablet and the amount of HPMC K4M was fixed at 150 mg / tablet. 30 shows the release profile of buspyron HCl from ER tablets. The percentage of drug released after 12 hours from tablets made with 28, 58, 118 or 148 mg of Comprecel was 62.3, 59.2, 59.2 or 59.0%, respectively. All four combinations tested showed slower drug release than the reference target profile. T50% (50% release time) of Buspyron HCl from ER tablets prepared with Comprecel increased from 5.0 to 7.1 hours as the amount of Emcompress increased from 28 to 148 mg / tablet (FIG. 31). As shown in FIG. 31, the amount of Comprecel increase in the range of 28-148 mg resulted in a linear increase of T50% (p <0.10, r ² = 0.901). The correlation between the amount of comprecel and T50% can be expressed as (T50%) = 0.016 x (amount of comprecel) + 4.846. Therefore, the effect of the amount of Comprecel on the release of buspyrone HCl was significant.

TABLE 11

Formulation of Buspyron HCl Delayed-Release Tablets Prepared with HPMC K4M and Various Additives Using Solid Dispersion (Solvent)

                                                            (Unit: mg / tablet)

Formulation HMH4L04 HMH4L05 HMH4L06 HMH4E01 HMH4E02 HMH4E03 HMH4E04 HMH4C01 HMH4C02 HMH4C03 HMH4C04 Buspyron HCl 30 30 30 30 30 30 30 30 30 30 30 HPMC K4M 150 150 150 150 150 150 150 150 150 150 150 Lactose Anhydrous 28 58 148 - - - - - - - - Emcompress - - - 28 58 118 148 - - - - Comprecel - - - - - - - 28 58 118 148 Magnesium stearate 2 2 2 2 2 2 2 2 2 2 2 gun 210 240 330 210 240 300 330 210 240 300 330

2-3-3. Effect of HPC on the Dissolution of Buspyron HCl from ER Purification

The amount of HPC in the tablets was varied to slow the rate of release of the drug. HPC LF and HPC HF were used for hydrophilic polymers. The effect of HPC on drug release rate was evaluated to find the appropriate amount of these in the tablets.

The formulations applied using HPC LF and Lactose Anhydrous are shown in Table 12. 32 shows the release profile of buspyron HCl from ER tablets. The amount of HPL LF varied from 30-300 mg per tablet. The amount of lactose anhydrous was fixed at 58 mg / tablet. Drug release from HMHLL01 (HPC LF 30 mg) was 66.1% and did not actually change after 1 hour. Drug release from HMHLL02 (HPC LF 60 mg) and HMHLL03 (HPC LF 150 mg) also did not change after 3 hours. However, drug release profiles from HMHLL04 (HPC LF 300 mg) gradually increased over 7 hours. The amount of drug release from HMHLL04 was 62.0% for 7 hours.

The formulations applied using HPC HF and lactose anhydrous are shown in Table 12. 33 shows the release profile of buspyron HCl from ER tablets. The amount of HPC HF varied from 30-300 mg per tablet. Drug release profiles from tablets with HPC HF were delayed depending on the amount of HPC HF. In particular, large amounts of HPC HF showed dramatic drug release delay effects from tablets. T50% (50% release time) of buspyron HCl from ER tablets prepared with HPC HF increased from 0.6 to 8.6 hours as the amount of HPC HF increased from 30 to 300 mg / tablet (FIG. 34).

TABLE 12

Formulation of Buspirone HCl Delayed-Release Tablets Prepared with Various Amounts of HPC LF or HPC HF Using Direct Compression or Solid Dispersion (Solvent)

                                                            (Unit: mg / tablet)

Formulation HMHLL01 HMHLL02 HMHLL03 HMHLL04 HMHHL01 HMHHL02 HMHHL03 HMHHL04 Buspyron HCl 30 30 30 30 30 30 30 30 HPC LF 30 60 150 300 - - - - HPC HF - - - - 30 60 150 300 Lactose Anhydrous 58 58 58 58 58 58 58 58 Magnesium stearate 2 2 2 2 2 2 2 2 gun 120 150 240 390 120 150 240 390

As shown in FIG. 34, an increase in the amount of HPC HF in the 30-300 mg range was linearly correlated with T50% (p <0.10, r ² = 0.901). This correlation between the amount of HPC HF and T50% can be expressed as (T50%) = 0.028 x (amount of HPC HF)-0.121. Therefore, the effect of the amount of HPC HF on the release of buspyrone HCl was significant.

2-3-4. Effect of Additive Type on the Dissolution of Buspyron HCl from ER Purification with HPC HF

The formulations applied using HPC HF and lactose anhydrous are shown in Table 13. The amount of lactose anhydrous was changed to 28-148 mg / tablet and the amount of HPC HF was fixed at 150 mg / tablet. 35 shows the release profile of buspyron HCl from ER tablets. After 6 hours the rate of dissolution slightly decreased, but HMHHL showed a dissolution profile similar to the target reference formulation. T80% (80% release time) of buspyrone HCl from ER tablets prepared with lactose anhydrous increased to 5.3-11.4 hours as the amount of lactose anhydroose increased to 28-58 mg / tablet, but lactose The amount of anhydrous decreased to 11.4-5.1 hours as it increased to 58-148 mg / tablet (FIG. 36).

As shown in FIG. 36, the amount of lactose anhydrous increase in the 28-148 mg range was secondary to T80% (p <0.05, r ² = 0.997). The relationship between HPC HF amount and T50% in this range can be explained as (T80%) = -0.002 x (amount of lactose anhydrous) ² +0.379 x (amount of lactose anhydroose)-3.488. Thus, the delayed effect of lactose anhydrous on the release of buspyrone HCl was maximized at 58-118 mg / tablet concentration in the formulation containing HPC HF.

The formulations applied using HPC HF and Emcompress are shown in Table 13. The amount of Emcompress was changed to 28-148 mg / tablet and the amount of HPC HF was fixed at 150 mg / tablet. 37 shows the release profile of buspyron HCl from ER tablets. All four formulations showed similar dissolution profiles for up to 4 hours, but then lower drug release resulting in about 80% solubility at 12 hours. T80% (80% release time) of buspyron HCl from ER tablets made with Emcompress increased to 7.7-10.1 hours as the amount of Emcompress increased to 28-118 mg / tablet, but the amount of Emcompress increased to 118-148 mg / tablet. As it increased, it decreased to 10.1-8.8 hours. The increase in the amount of Emcompress in the 28-148 mg range was secondary to T80%, similar to lactose anhydrous (p <0.10, r ² = 0.9992). The correlation between HPC HF and T50% can be described as (T80%) = -0.0006 x (amount of Emcompress) ² + 0.116 x (amount of Emcompress) + 5.017. Thus, the sustained release effect of Emcompress on buspyrone HCl was maximized at 58-118 mg / tablet concentration in the formulation containing HPC HF.

The formulations applied using HPC HF and Comprecel are shown in Table 13. The amount of Comprecel was changed to 28-148 mg / tablet and the amount of HPC HF was fixed at 150 mg / tablet. 39 shows the release profile of buspyron HCl from ER tablets. All four formulations showed lower dissolution rates compared to Emcompress. This appeared to have a secondary relationship as in the case of lactose anhydrous or Emcompress, but there was no statistically significant difference between the amount of Comprecel and T50% (p> 0.10) (FIG. 40). Thus, the T50% (50% release time) of Buspyron HCl from ER tablets made with Comprecel did not depend on the amount of Comprecel, and the effect of the amount of Comprecel on the release of Boothpyron HCl was not significant.

TABLE 13

Formulation of Buspirone HCl Delayed-Release Tablets Prepared with HPC HF and Various Additives Using Direct Compression

                                                            (Unit: mg / tablet)

Formulation HMHHL05 HMHHL06 HMHHL07 HMHHL08 HMHHE01 HMHHE02 HMHHE03 HMHHE04 HMHHC01 HMHHC02 HMHHC03 HMHHC04 Buspyron HCl 30 30 30 30 30 30 30 30 30 30 30 30 HPC HF 150 150 150 150 150 150 150 150 150 150 150 150 Lactose Anhydrous 28 58 118 148 - - - - - - - - Emcompress - - - - 28 58 118 148 - - - - Comprecel - - - - - - - - 28 58 118 148 Magnesium stearate 2 2 2 2 2 2 2 2 2 2 2 2 gun 210 240 300 330 210 240 300 330 210 240 300 330

2-3-5. Effect of NaCMC on the Diffusion of Buspyron HCl from ER Purification

The amount of NaCMC in the tablets was varied to delay the rate of drug release. In addition, the amount of additives and the type of additives in the tablets were varied to delay the rate of drug release. Their impact on drug release rates was evaluated to find their proper amount in tablets.

The formulations applied using NaCMC and lactose anhydrous are shown in Table 14. 41 shows the release profile of buspyron HCl from ER tablets. The amount of NaCMC was varied to 30-300 mg / tablet. The amount of lactose anhydrous was fixed at 58 mg / tablet. As shown in FIG. 41, these formulations showed faster (HMCML01, HMCML02) or slower (HMCML03, HMCML04) dissolution than the standard dissolution. The dissolution rate was less than 90% in 12 hours. T50% (50% release time) of buspyrone HCl from ER tablets prepared with NaCMC increased to 1.3-5.1 hours as the amount of NaCMC increased to 30-300 mg / tablet (FIG. 42). As shown in Figure 42, the increase in NaCMC in the range 30-300 mg linearly increased T50% ((p <0.05, r ² = 0.986). In this range the relationship between NaCMC and T50% was (T50% ) = 0.014 x (amount of NaCMC) + 0.970. Thus, in order to control the rate of drug release, the effect of the amount of additive and the type of additive on the rate of drug release was further evaluated.

[Table 14]

Formulation of Buspirone HCl Delayed-Release Tablets Prepared with Various Amounts of NaCMC Using Direct Compression

                                                            (Unit: mg / tablet)

Formulation HMCML01 HMCML02 HMCML03 HMCML04 Buspyron HCl 30 30 30 30
NaCMC 30 60 150 300 Lactose Anhydrous 58 58 58 58
Magnesium stearate 2 2 2 2
gun 120 150 240 390

The amount of additives such as lactose anhydrous, Emcompress and Comprecel was changed to 28-148 mg / tablet and the amount of NaCMC was fixed at 150 mg / tablet (Table 15). 43-45 show the release profile of buspyron HCl from ER tablets. The formulations HMCML05 to HMCML07 and HMCMC01 to HMCMC04 released the drug similar to the target profile by 4 hours, and then tended to show gradually lower dissolution. Combinations HMCME01 to HMCME04 showed a dissolution profile similar to the baseline target drug by 6 hours and then gradually decreased (FIG. 44).

TABLE 15

Formulation of Buspirone HCl Delayed-Release Tablets Prepared with NaCMC and Various Additives Using Direct Compression

                                                            (Unit: mg / tablet)

Formulation HMCML05 HMCML06 HMCML07 HMCML08 HMCME01 HMCME02 HMCME03 HMCME04 HMCMC01 HMCMC02 HMCMC03 HMCMC04 Buspyron HCl 30 30 30 30 30 30 30 30 30 30 30 30 NaCMC 150 150 150 150 150 150 150 150 150 150 150 150 Lactose Anhydrous 28 58 118 148 - - - - - - - - Emcompress - - - - 28 58 118 148 - - - - Comprecel - - - - - - - - 28 58 118 148 Magnesium stearate 2 2 2 2 2 2 2 2 2 2 2 2 gun 210 240 300 330 210 240 300 330 210 240 300 330

3. Conclusion

From the above results, lipophilic substances such as glyceryl behenate (Compritol 888 ATO) or hardened cottonseed oil (Sterotex) prepared together with the drug in the solid dispersion by the melting method are lactose anhydrous, dibasic calcium phosphate di It has been found that the release profile of buspyrone HCl can be effectively controlled in the form of delayed release tablets with other additives such as hydrate (Emcompress) or microcrystalline cellulose (Comprecel). Hydrophilic polymers, such as hydroxypropylmethylcellulose (HPMC K4M), hydroxypropylcellulose (HPC) or carboxymethylcellulose sodium (NaCMC), are prepared with lactose anhydrous, dibasic calcium phosphate dihydrate (Emcompress) or undetermined. Release Profile of Buspyron HCl with Additives Such as Vaginal Cellulose It was found that can be adjusted. In particular, it was found that glyceryl behenate (Compritol 888 ATO) is a lipophilic compound that can most effectively control the release profile of Busyron HCl.

FIG. 1 shows the release profile of Buspyron HCl from (A) commercially available immediate release tablets (mean ± S.D., N = 3) and (B) reference formulations in literature (Sakr and Andheria, 2001a, b).

Figure 2 shows the effect of Precirol concentration on the dissolution profile of the busupyron HCl delayed-release tablet (mean ± S.D., n = 3) (•; LMP01, ■; LMP02, ▲; LMP03, ▼; LMP04).

Figure 3 shows the effect of Compritol concentration on the dissolution profile of the busupyron HCl delayed release tablets (mean ± S.D., n = 3) (•; LMC01, ■; LMC02, ▲; LMC03, ▼; LMC04).

4 shows the effect of GMS concentration on the dissolution profile of the busupyron HCl delayed release tablet (mean ± S.D., N = 3) (•; LMG01, ■; LMG02, ▲; LMG03, ▼; LMG04).

FIG. 5 shows the effect of Sterotex concentration on the dissolution profile of the busupyron HCl delayed release tablets (mean ± S.D., N = 3) (•; LMS01, ■; LMS02, ▲; LMS03, ▼; LMS04).

Figure 6 shows the effect of the amount of Compritol on T _80% of buspyrone HCl.

Figure 7 shows the effect of the amount of Sterotex on T _50% of buspyrone HCl.

FIG. 8 shows the effect of Compritol concentration on the dissolution profile of the busupyron HCl delayed-release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile in the literature reference formulation) (•; LMCL01, ■; LMCL02, ▲; LMCL03, ▼; LMCL04).

FIG. 9 shows the effect of Compritol concentration on the dissolution profile of the busupyron HCl delayed release tablets (mean ± SD, n = 3, dashed line indicates target dissolution profile of reference formulation in literature) (•; LMCL05, ■; LMCL06 , ▲; LMCL07, ▼; LMCL08).

FIG. 10 shows the effect of lactose anhydrous concentration on the dissolution profile of the busupyron HCl delayed release tablet (mean ± SD, n = 3, dashed line represents the target dissolution profile of the reference formulation in the literature) (LMCL09 , ■; LMCL02, ▲; LMCL10).

11 shows the effect of the amount of lactose anhydrous on T _80% of buspirone HCl.

FIG. 12 shows the effect of Emcompress concentration on the dissolution profile of the busupyron HCl delayed release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (•; LMCE01, ■; LMCE02 , ▲; LMCE03).

FIG. 13 shows the effect of the amount of Emcompress on T _50% of Buspyron HCl.

FIG. 14 shows the effect of Comprecel concentration on the dissolution profile of the busupyron HCl delayed-release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (•; LMCC01, ■; LMCC02 , ▲; LMCC03).

15 shows the effect of the amount of Comprecel on T _80% of Buspyron HCl.

FIG. 16 shows the effect of Sterotex concentration on the dissolution profile of the busupyron HCl delayed-release tablet (mean ± SD, n = 3, dashed line indicates target dissolution profile in literature reference formulation) (•; LMSL01, ■; LMSL02, ▲; LMSL03, ▼; LMSL04).

FIG. 17 shows the effect of lactose anhydroose concentration on the dissolution profile of the busupyron HCl delayed release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (LMSL05 , ■; LMSL06, ▲; LMSL07).

18 shows the effect of the amount of lactose anhydrous on T _50% of buspirone HCl.

FIG. 19 shows the effect of Emcompress concentration on the dissolution profile of the busupyron HCl delayed release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (•; LMSE01, ■; LMSE02 , ▲; LMSE03).

20 shows the effect of the amount of Emcompress on T _20% of Buspyron HCl.

FIG. 21 shows the effect of Comprecel concentration on the dissolution profile of the busupyron HCl delayed release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (•; LMSC01, ■; LMSC02 , ▲; LMSC03).

22 shows the effect of the amount of Comprecel on T _50% of buspyrone HCl.

FIG. 23 shows the effect of HPMC K15M concentration on the dissolution profile of the busupyron HCl delayed-release tablet (mean ± SD, n = 3, dashed line indicates target dissolution profile of the reference formulation in the literature) (HMHMD01, ■; HMHMD02, ▲; HMHMD03, ▼; HMHMD04).

FIG. 24 shows the effect of HPMC K15M concentration on the dissolution profile of the busupyron HCl delayed release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (HMHML01, ■ ; HMHML02, ▲; HMHML03).

FIG. 25 shows the effect of HPMC K15M concentration on the dissolution profile of the busupyron HCl delayed release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (HMH4L01, ■; HMH4L02, ▲; HMH4L03).

FIG. 26 shows the effect of lactose anhydrous concentration on the dissolution profile of the busupyron HCl delayed release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (HMH4L04) , ■; HMH4L05, ▲; HMH4L06).

27 shows the effect of the amount of lactose anhydrous on T _50% of buspyrone HCl.

FIG. 28 shows the effect of Emcompress concentration on the dissolution profile of the busupyron HCl delayed-release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (HMH4E01, H; , ▲; HMH4E03, ▼; HMH4E04).

29 shows the effect of the amount of Emcompress on T _50% of buspirone HCl.

FIG. 30 shows the effect of Comprecel concentration on the dissolution profile of the busupyron HCl delayed-release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (• HMH4C01, , ▲; HMH4C03, ▼; HMH4C04).

31 shows the effect of the amount of Comprecel on T _50% of Buspyron HCl.

FIG. 32 shows the effect of HPC LF concentration on the dissolution profile of the busupyron HCl delayed release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (HMHLL01, ■; HMHLL02, ▲; HMHLL03, ▼; HMHLL04).

FIG. 33 shows the effect of HPC HF concentration on the dissolution profile of the busupyron HCl delayed release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (HMHHL01, ■; HMHHL02, ▲; HMHHL03, ▼; HMHHL04).

34 shows the effect of the amount of HPC HF on T _50% of buspyrone HCl.

FIG. 35 shows the effect of lactose anhydroz concentration on the dissolution profile of the busupyron HCl delayed-release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (HMHHL05 , ■; HMHHL06, ▲; HMHHL07, ▼; HMHHL08).

36 shows the effect of the amount of lactose anhydroz on T _80% of buspyrone HCl.

FIG. 37 shows the effect of Emcompress concentration on the dissolution profile of the busupyron HCl delayed release tablet (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature) (HMHHE01, HMHHE02) , ▲; HMHHE03, ▼; HMHHE04).

38 shows the effect of the amount of Emcompress on T _80% of buspyrone HCl.

FIG. 39 shows the effect of Comprecel concentration on the dissolution profile of the busupyron HCl delayed-release tablet using the direct compression method (mean ± SD, n = 3, dashed line represents the target dissolution profile of the reference formulation in the literature); HMHHC01, ■; HMHHC02, ▲; HMHHC03, ▼; HMHHC04).

40 shows the effect of the amount of Comprecel on T _50% of Buspyron HCl.

FIG. 41 shows the effect of NaCMC concentration on the dissolution profile of the busupyron HCl delayed-release tablet using the direct compression method (mean ± SD, n = 3, dashed line represents the target dissolution profile of the reference formulation in the literature); HMCML01, ■; HMCML02, ▲; HMCML03, ▼; HMCML04).

42 shows the effect of the amount of NaCMC on T _50% of buspyrone HCl.

FIG. 43 shows the effect of lactose anhydrous concentration on the dissolution profile of the busupyron HCl delayed-release tablet using the direct compression method (mean ± SD, n = 3, dashed line shows the target dissolution profile in the literature reference formulation). (●; HMCML05, ■; HMCML06, ▲; HMCML07, ▼; HMCML08).

FIG. 44 shows the effect of Emcompress concentration on the dissolution profile of the busupyron HCl delayed release tablet using the direct compression method (mean ± SD, n = 3, dashed line indicates the target dissolution profile of the reference formulation in the literature); HMCME01, ■; HMCME02, ▲; HMCME03, ▼; HMCME04).

FIG. 45 shows the effect of Comprecel concentration on the dissolution profile of the busupyron HCl delayed-release tablet using the direct compression method (mean ± SD, n = 3, dashed line represents the target dissolution profile of the reference formulation in the literature); HMCMC01, ■; HMCMC02, ▲; HMCMC03, ▼; HMCMC04).

Claims (9)

Buspirone hydrochloride as a pharmacologically active ingredient; And A lipophilic substance selected from the group consisting of glyceryl behenate and hydrogenated cottonseed oil and a hydrophilic polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose and carboxymethylcellulose sodium Species or both Pharmaceutical formulations for oral administration of controlled release antidepressant comprising a. 2. The pharmaceutical formulation for oral administration of controlled release antidepressant according to claim 1, characterized in that the buspyron hydrochloride is contained in an amount of 7 to 48% by weight based on the total weight of the composition. The pharmaceutical formulation for oral administration of controlled release antidepressant according to claim 1, wherein the lipophilic substance is included in an amount of 40 to 77% by weight based on the total weight of the composition. The pharmaceutical formulation for oral administration of controlled release antidepressant according to claim 1, wherein the lipophilic substance is glyceryl behenate. 2. The pharmaceutical formulation for oral administration of controlled release antidepressant according to claim 1, wherein the hydrophilic polymer is included in an amount of 30 to 80% by weight based on the total weight of the composition. 2. A pharmaceutical formulation for oral administration of controlled release antidepressant according to claim 1, further comprising a pharmaceutically acceptable additive. 7. The method of claim 6, wherein the additive is selected from the group consisting of diluents, binders, disintegrants, lubricants, swelling agents, surfactants, antioxidants, foaming agents, flavoring agents, controlled release agents, coating agents, and combinations thereof. A pharmaceutical formulation for oral administration of an antidepressant with controlled release. 8. The pharmaceutical formulation for oral administration of controlled release antidepressant according to claim 7, wherein the additive is lactose anhydrous, dibasic calcium phosphate dihydrate, microcrystalline cellulose or a mixture thereof. 8. The pharmaceutical formulation for oral administration of controlled release antidepressant according to claim 7, wherein the additive is contained in an amount of 0.5 to 57% by weight based on the total weight of the composition.

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