CN100551373C - Buspirone Hydrochloride Sustained/Controlled Release Pellets - Google Patents

Abstract

The invention discloses buspirone hydrochloride slow/controlled release pellets and capsules capable of treating anxiety and a preparation method thereof. The buspirone hydrochloride sustained/controlled-release pellets of the present invention contain a buspirone hydrochloride drug pellet core and are covered with an isolation layer outside the pellet core. The buspirone hydrochloride drug ball core can be composed of a blank ball core and a drug layer containing buspirone hydrochloride sprayed on the outer layer of the blank ball core, and the ball core is covered with an isolation layer and a slow-release coating layer. The core of buspirone hydrochloride drug pellets can also be formed by mixing buspirone hydrochloride with auxiliary materials, and can also be wrapped with an isolation layer and a slow-release layer outside the core. The buspirone hydrochloride sustained/controlled release pellets of the present invention are packed into hollow capsules according to required specifications to obtain the buspirone hydrochloride sustained/controlled release capsules.

Description

Buspirone Hydrochloride Sustained/Controlled Release Pellets

technical field

The invention relates to the field of drug slow/controlled release preparations, in particular to buspirone hydrochloride slow/controlled release pellets and capsules that can treat anxiety.

Background technique

At present, anti-anxiety and antidepressant drugs are rising rapidly. In 2000, the global sales of antidepressant drugs were about 11 billion US dollars. In China, selective serotonin reuptake inhibitors have gradually occupied an absolute share of the anxiolytic and antidepressant drug market. In 2000, the market share of selective serotonin reuptake inhibitors reached 85%.

According to the analysis of Dongyi Xinda Pharmaceutical Market Research Center, the overall scale of China's antidepressant drug market is still quite small, with sales of about 1.5 billion yuan in 2000, accounting for a very low proportion of the total pharmaceutical market. Considering that mental illnesses are on the rise and China is about to enter an aging society, the market potential of anti-anxiety and anti-depressant drugs will be quite large.

Buspirone Hydrochloride (Buspirone Hydrochloride, referred to as BH) is a new type of non-benzodiazepine anxiolytic drug, its chemical name is: 8-[4-[4-(2-pyrimidinyl)-1-piperazine Base]butyl]-8-azaspiro[4,5]decane-7,9-dione hydrochloride, the chemical formula is C ₂₁ H ₃₁ N ₅ O ₂ ·HCl, the molecular weight is 421.97, and the structural formula is as follows:

Buspirone hydrochloride can be used to treat generalized anxiety disorder, does not produce drug resistance, has no risk of abuse, and has no obvious sedative effect while anxiolytic. It has also been reported to be used to treat symptoms of withdrawal anxiety in drug users. The oral tablet of BH has been included in the United States Pharmacopoeia. The oral BH tablet is absorbed quickly and completely, and the drug effect is certain, and no dependence has been found so far.

Buspirone hydrochloride is absorbed quickly and completely after oral administration, reaching the peak plasma concentration in 0.5 to 1 hour. Buspirone has a strong first-pass effect, and only about 4% of the therapeutic dose enters the systemic circulation as the prototype after oral administration (Mayol et.al, Clin.Pharmacol.Ther., 37, 210, 1985). Obvious inter-individual differences were observed in the absorption of buspirone, and the variation range of the highest plasma concentration was nearly 10 times different (Gammans et.al, American J.Med., 80, Suppl.38, 41-51, 1986). Two metabolites of buspirone were identified in the human body, 5-hydroxybuspirone with no pharmacological activity and 1-(2-pyrimidinyl)-piperazine with buspirone activity, namely 1-PP , and its activity is about 20-25% of that of buspirone. The half-life of buspirone in humans is very short, ranging from 2 to 11 hours, and the active metabolite 1-PP is eliminated slowly (Mayol et.al, Clin.Pharmacol.Ther., 37, 210, 1985).

The physicochemical properties, pharmacokinetics, and pharmacological properties of a drug usually determine how the drug is used in clinical therapy. In order to maintain the plasma drug concentration and pharmacological effects of drugs with a short biological half-life, the dosing interval is very short, which will greatly destroy the patient's compliance and cause the blood drug concentration between administrations to fail to reach the effective value. The ideal form of oral administration is a preparation that can be taken once a day and can maintain the therapeutic drug level in the body within 24 hours without causing adverse reactions.

The pharmacokinetic properties of buspirone necessitate frequent daily dosing of its regular tablet, negatively impacting patient compliance. Since buspirone is rapidly absorbed after oral administration, a high blood drug peak will appear soon after taking ordinary tablets, which will be accompanied by the occurrence of adverse events, especially after the first administration of treatment.

Oral sustained-release or controlled-release preparations can prolong the release time of the drug, slow down the drug absorption rate, and make up for the shortcoming of the short biological half-life of the drug. Compared with ordinary tablets, the development of buspirone hydrochloride slow/controlled release preparations will have the following advantages: ordinary tablets are taken 2 to 3 times a day, and slow/controlled release preparations generally only need to be taken once a day, which can greatly improve Patient compliance; slow/controlled release preparations can control the drug release rate, release the drug slowly and steadily, and reduce the peak-valley phenomenon; the therapeutic window of buspirone hydrochloride is narrow, and it is easy to produce toxicity when the blood concentration is low. Sustained/controlled release preparations can reduce adverse reactions caused by peak blood drug concentrations. The maintenance treatment time of buspirone hydrochloride generally takes 1 month to 1 year, and the benefits of convenient medication for a long period of time are very significant.

The extensive or complex metabolism of drugs makes the design of oral sustained/controlled release formulations very difficult, especially when the biological activity of the drug is wholly or partly derived from metabolites, such as the case of buspirone. It has been reported in the literature that the difference in systemic availability due to metabolism during absorption is greater in sustained/controlled release formulations than in immediate release formulations. Therefore, it has been reported that drugs with strong first-pass clearance are not suitable for oral sustained/controlled release administration. (J.R.Robinson and V.H.L.Lee, Controlled Drug Delivery. Fundamentals and Applications, Marcel Dekker Inc., USA, 1987, ISBN0-8247-7588-0)

There is an obvious first-pass effect of buspirone, and there are significant differences in pharmacokinetics among individuals, which makes the development of slow/controlled release formulations of buspirone quite difficult. This may be because there are few slow/controlled release formulations of buspirone Due to the reasons reported in the study, there is currently no sustained/controlled release formulation of buspirone used in clinical treatment.

European patent application EP 0313535 A1 discloses oral sustained/controlled release preparations of buspirone and salts thereof, including tablets and capsules. The sustained/controlled release preparation of buspirone is prepared by matrix tablets and coated pellets or microcapsules, and the involved sustained release materials include polyethylene, cellulose, fat, wax and the like. European patent application EP 1266656 A discloses the anion-exchange polymer compound of buspirone, mainly relates to the anion-exchange polymer compound sustained-release tablet of buspirone with acrylic resin as the skeleton material, and what the technology adopts is the skeleton tablet mechanism. U.S. Patent US 5431922 discloses the administration method of buspirone, relates to the oral administration method of buspirone or its pharmaceutically acceptable salt with controlled release/sustained release preparation, including matrix tablet, coated pellet wait. The coating materials mentioned therein include povidone, ethyl cellulose, sodium carboxymethyl cellulose, hypromellose and the like.

Contents of the invention

The buspirone hydrochloride slow/controlled release pellets of the present invention are different from the buspirone hydrochloride slow/controlled release preparations in the prior art, and are prepared by a method different from the prior art. The buspirone hydrochloride sustained/controlled release pellets of the present invention contain the buspirone hydrochloride drug ball core, and the ball core is covered with an isolation layer, and finally coated with a slow release layer, so that the slow release effect is good. And different micropills prepared according to the present invention can be mixed and filled into hollow capsules to further adjust the law of drug release to meet different clinical needs.

The buspirone hydrochloride sustained-release/controlled-release pellets of the present invention contain a drug pellet core of buspirone hydrochloride and an isolation layer wrapped outside the drug pellet core. We found in the experimental research that the sustained/controlled release effect can be achieved or better achieved only when there is an isolation layer outside the drug pellet core.

The buspirone hydrochloride slow/controlled release pellets of the present invention mainly include two kinds of buspirone hydrochloride slow/controlled release pellets.

The first kind of buspirone hydrochloride slow/controlled release pellets of the present invention, the core of buspirone hydrochloride drug pellet is made up of a blank pellet core and a drug layer containing buspirone hydrochloride sprayed on the outer layer of the blank pellet core , and the isolation layer is covered with a slow-release coating layer. The first buspirone hydrochloride sustained/controlled release pellets of the present invention contain a blank pellet core, a drug layer, an isolation layer and a sustained release coating layer. Wherein the isolation layer plays the role of protecting and isolating the drug pellet core and the slow-release coating layer, which can make the healing effect of the slow-release coating layer film better. In our experimental research, we found that when there is no isolation layer, no matter how thick the sustained-release coating layer is, the prepared preparations do not have slow/controlled release characteristics and cannot achieve the purpose of sustained release, so the isolation layer is necessary.

The drug blank pellet core includes a skeleton material, a binder and a lubricant. The framework material of the blank core can be selected from microcrystalline cellulose, sucrose, methacrylic acid polymer or ethyl cellulose, preferably microcrystalline cellulose or sucrose, wherein the content of the framework material accounts for 10% to 10% of the total weight of the blank core. 90%, preferably 60% to 80%; the binder in the blank core is hypromellose or powdered sugar, preferably powdered sugar, and its content accounts for 1% to 15% of the total weight of the blank core, preferably 3% to 8%. Lubricants are magnesium stearate or sodium lauryl sulfate.

The drug layer contains buspirone hydrochloride, hypromellose and polyethylene glycol, a hydrophilic film-forming material. Among them, the specification of hypromellose is preferably 3-50 mPa.s; the specification of polyethylene glycol can be 1000, 1500, 2000, 3000, 4000 or 6000, preferably PEG4000. The concentration of hypromellose is in the range of 2%-15%, and the concentration of PEG4000 is in the range of 0.2-2.0%. The weight ratio of buspirone hydrochloride and blank ball core can be at 1: 5～50, more preferably range is 1: 10～15; The weight ratio of buspirone hydrochloride and hypromellose and polyethylene glycol can be In 15～5:1 and 10～50:1. Preferably, talc is also contained in the drug layer.

The isolation layer is composed of hypromellose, polyethylene glycol and talcum powder. Among them, the specification of hypromellose is preferably 3-50 mPa.s; the specification of polyethylene glycol can be 1000, 1500, 2000, 3000, 4000 or 6000, preferably PEG4000. The concentration of hypromellose is in the range of 2%-15%, and the concentration of PEG4000 is in the range of 0.2-2.0%.

固体物含量为25％，内除乙基纤维素外还加有增塑剂及抗粘着剂等。盐酸丁螺环酮与乙基纤维素水分散体的固体物的重量比可以在1∶0.5～5，这一比例直接影响盐酸丁螺环酮的释放速度。The sustained-release coating layer contains an ethylcellulose film coating material or an acrylic resin film coating material. For water-soluble drugs such as buspirone hydrochloride, ethylcellulose film coating materials are preferred. It is more preferred to use a commercially available ethyl cellulose aqueous dispersion

The solid content is 25%, and in addition to ethyl cellulose, plasticizers and anti-adhesive agents are added. The weight ratio of the buspirone hydrochloride to the solid matter of the ethyl cellulose aqueous dispersion can be 1:0.5-5, and this ratio directly affects the release rate of the buspirone hydrochloride.

The second kind of buspirone hydrochloride slow/controlled release pellets of the present invention, the slow/controlled release pellets contain the drug ball core formed by mixing buspirone hydrochloride and auxiliary materials and have an isolation layer on the outside of the ball core, and finally Covered with a slow-release coating. The buspirone hydrochloride pharmaceutical pill core contains the active drug buspirone hydrochloride and suitable auxiliary materials. The suitable adjuvant in the drug pellet core is selected from the adjuvant suitable for preparing buspirone hydrochloride slow/controlled release pellets disclosed in the prior art US 5431922. The isolation layer and the sustained-release coating layer in the second buspirone hydrochloride slow/controlled release pellets of the present invention are the same as the isolation layer and sustained-release coating layer in the first buspirone hydrochloride slow/controlled release pellets of the present invention. The release layer is the same.

The sustained/controlled release capsule of buspirone hydrochloride of the present invention is obtained by filling the sustained/controlled release pellets of buspirone hydrochloride of the present invention into hollow capsules. For the first kind of slow/controlled release pellets, the slow/controlled release capsules of buspirone hydrochloride of the present invention can be packed into hollow capsules by a kind of slow release pellets of film thickness, and can also be obtained by the pellets of different film thicknesses according to It is mixed in a certain proportion and filled into hollow capsules to obtain better sustained-release effect. The sustained/controlled-release capsules of buspirone hydrochloride of the present invention are preferably filled with sustained-release pellets composed of a blank core, a drug layer, an isolation layer and a sustained-release coating layer.

The slow/controlled-release pellets of the first buspirone hydrochloride of the present invention are formed by coating buspirone hydrochloride on a blank pellet core to form a drug pellet core, and then wrapping the drug pellet core with a A protective isolation layer is provided, and a slow-release coat layer is also wrapped outside the isolation layer to obtain slow/controlled release pellets of buspirone hydrochloride.

The coating of the above drug layer, isolation layer and sustained-release coating layer can be implemented through a fluidized bed, or through other equipment such as a high-efficiency coating pan.

When using fluidized bed coating to prepare sustained-release pellets, the range of process parameters used is: air inlet temperature is 40°C-80°C, material temperature is 30°C-60°C, air volume is 75-150m ³ /h, and spray pressure is 1-80°C. 4×10 ⁵ Pa.

The preparation method of the second kind of sustained-release pellets in the present invention is to first make slow/controlled release pellets (pills) of buspirone hydrochloride according to the method disclosed in the prior art US 5,431,922. The preparation method of the pellets (pills) can be powder layering method, suspension drug method or wet pelleting method, etc., and the equipment used can be centrifugal pot coating granulator, fluidized bed, extrusion spheronization, etc. machine, etc., to make slow-release pellets, and then wrap the isolation layer and/or slow-release layer, and then pack into capsules according to the required preparation specifications.

The preparation of buspirone hydrochloride sustained/controlled release capsules of the present invention is by filling the slow/controlled release spherical drug pellets of the present invention containing 5 mg to 30 mg of buspirone hydrochloride and having a diameter of 0.5 to 10 mm into hollow capsules. Capsule preparation.

The in vitro biorelease measurement of the buspirone hydrochloride slow/controlled release capsules prepared in specific examples of the present invention shows that the buspirone hydrochloride slow/controlled release capsules of the present invention have good slow/controlled release characteristics.

The buspirone hydrochloride slow/control-release capsule prepared by specific embodiments of the present invention has carried out the mensuration of the pharmacokinetics in the beagle dog body, its result is the same as the pharmacokinetics in the beagle dog body of the buspirone hydrochloride common tablet. Significant differences in properties prove that the buspirone hydrochloride slow/controlled release capsules of the present invention have good slow/controlled release properties in vivo.

"Slow/controlled release" in this patent application refers to sustained release or controlled release.

Description of drawings

Fig. 1 release curve of sustained-release capsules of 3 batches of buspirone hydrochloride prepared according to specific embodiments of the present invention.

Fig. 2 six Beagle dogs single-dose oral sustained-release capsules and ordinary tablet mean drug-time curves.

Detailed ways

The present invention is further described below through specific examples, which do not constitute a limitation to the present invention.

Example 1

Buspirone Hydrochloride 60g

Blank ball core 500g

Hypromellose (6mPa.s) 20g

Polyethylene glycol 4000 (PEG4000) 4g

Talc powder 3g

Aqueous dispersion of ethyl cellulose 200g

Appropriate amount of water

The specific coating process is as follows:

1) Weigh 700/900 500g of blank pellet core, put it in the fluidized bed, set the equipment parameters, control the inlet air temperature at 61°C, the material temperature at 50°C, the air volume at 120m ³ /h, and the spray pressure at 2×10 ⁵ Pa , use coating solution 1 ^* to coat the blank pellet core.

2) After coating the drug layer, take 10% HPMC+0.5% PEG4000 100ml to coat the isolation layer.

3) After coating, take 2 ^* of the coating solution to coat the slow-release coating layer.

4) Fill the empty capsules according to the specifications (eg, 15 mg or 30 mg per capsule).

^* Coating solution 1: Weigh 10g of HPMC, add 100ml of water, mix well, add 3.5g of PEG4000, stir magnetically, add 3g of talcum powder, add 60g of buspirone, and mix well.

Coating solution 2: 200g of EC aqueous dispersion (Surelease), add 200ml of water, and mix well.

Example 2

Buspirone Hydrochloride 60g

Blank ball core 500g

Hypromellose (6mPa.s) 20g

Polyethylene glycol 4000 (PEG4000) 4g

Talc powder 3g

Aqueous dispersion of ethyl cellulose 200g

Appropriate amount of water

1) Weigh 700/900 500g of blank pellet core, put it in the fluidized bed, set the equipment parameters, control the inlet air temperature at 61°C, the material temperature at 50°C, the air volume at 120m ³ /h, and the spray pressure at 2×10 ⁵ Pa , use coating solution 1 ^* to coat the blank pellet core.

2) After coating the drug layer, take 10% HPMC+0.5% PEG4000 100ml to coat the isolation layer.

3) After coating, take 2 ^* of the coating solution to coat the slow-release coating layer.

4) After wrapping the slow-release coat, cure at a suitable temperature for 24 hours.

5) Fill the empty capsules according to the specifications (eg, 15 mg or 30 mg per capsule).

^* Coating solution 1: Weigh 10g of HPMC, add 100ml of water, mix well, add 3.5g of PEG4000, stir magnetically, add 3g of talcum powder, add 60g of buspirone, and mix well.

Coating solution 2: 200 g of acrylic resin aqueous dispersion (Eudragit), add 300 ml of water, and mix well.

Example 3

Buspirone Hydrochloride 60g

Blank ball core 500g

Hypromellose (6mPa.s) 20g

Polyethylene glycol 4000 (PEG4000) 4g

Talc powder 3g

Aqueous dispersion of ethyl cellulose 374g

Appropriate amount of water

The specific coating process is as follows:

1) Weigh 700/900 500g of blank pellet core, put it in the fluidized bed, set the equipment parameters, control the inlet air temperature at 61°C, the material temperature at 50°C, the air volume at 120m ³ /h, and the spray pressure at 2×10 ⁵ Pa , use coating solution 1 ^* to coat the blank pellet core.

2) After coating the drug layer, take 10% HPMC+0.5% PEG4000 100ml to coat the isolation layer.

3) After coating, use the coating liquid 2*Surelease to coat the slow-release coating layer.

4) Fill the prepared sustained-release pellets into capsules containing 15 mg of buspirone hydrochloride, and measure the release curve according to the method described below.

^* Coating solution 1: Weigh 10g of HPMC, add 100ml of water, mix well, add 3.5g of PEG4000, stir magnetically, add 3g of talcum powder, add 60g of buspirone, and mix well.

Coating solution 2: EC water dispersion (Surelease) 374g, add water 500ml, mix well.

Example 4

Buspirone Hydrochloride 60g

Blank ball core 500g

Hypromellose (6mPa.s) 20g

Polyethylene glycol 4000 (PEG4000) 4g

Talc powder 3g

Aqueous dispersion of ethyl cellulose 374g

Appropriate amount of water

The specific coating process is as follows:

1) Weigh 700/900 500g of blank pellet core, put it in the fluidized bed, set the equipment parameters, control the inlet air temperature at 61°C, the material temperature at 50°C, the air volume at 120m ³ /h, and the spray pressure at 2×10 ⁵ Pa , use coating solution 1 ^* to coat the blank pellet core.

2) After coating the drug layer, take 10% HPMC+0.5% PEG4000 100ml to coat the isolation layer.

3) After coating, the slow-release coating layer is coated with slow-release coating solution 2 ^* and coating solution 3 ^* respectively.

4) The pellet coated with drug layer and isolation layer is marked as pellet I, the pellet coated with slow-release coating solution 2 is then labeled as pellet II, and the pellet coated with sustained-release coating solution 3 is then labeled as pellet III. The micropills with different coating dosages were mixed in proportion (1:5:4), and each capsule contained 15 mg of buspirone hydrochloride to be filled into capsules. According to this recipe process, three batches of pilot scale scale-up were carried out, and the batch numbers of the prepared capsules were 041201, 041202 and 041203, respectively. Release profiles were determined as described below.

^* Coating solution 1: Weigh 10g of HPMC, add 100ml of water, mix well, add 3.5g of PEG4000, stir magnetically, add 3g of talcum powder, add 60g of buspirone, and mix well.

Coating solution 2: EC aqueous dispersion (Surelease) 374g, add water 300ml, mix well.

Coating solution 3: 200g of EC aqueous dispersion (Surelease), add 200ml of water, and mix well.

Example 5

Buspirone Hydrochloride 15g

Microcrystalline Cellulose 135g

Povidone K30 5g

Hypromellose (6mPa.s) 3g

Polyethylene glycol 4000 (PEG4000) 1g

Talc powder 1g

Aqueous dispersion of ethyl cellulose 40g

Appropriate amount of water

Get the prescribed amount of buspirone hydrochloride and microcrystalline cellulose, put them in a centrifugal granulator, set appropriate instrument parameters, add povidone K30 aqueous solution, and make a pill core containing medicine. Take it out, put it in the fluidized bed, set the equipment parameters, control the inlet air temperature at 55°C, material temperature at 40°C, air volume at 120m ³ /h, spray pressure at 2×10 ⁵ Pa, use 8%HPMC+0.8%PEG4000 50ml, and coat the core of the pill with an isolation layer. Dilute with 40g of coating solution and 30ml of water, and then coat with slow-release coating.

Determination of release rate:

The release rate is an important indicator of sustained/controlled release preparations, and a method for measuring the release rate of buspirone hydrochloride sustained-release capsules was established during the development process. According to the release measurement method (Chinese Pharmacopoeia 2005 edition two appendix XD first method), with 0.2% sodium lauryl sulfate aqueous solution as the release medium, the rotating speed is 100 revolutions per minute, according to the law, after 1 hour, 4 hours And 8 hours, respectively get solution 5ml, filter, and replenish the same temperature, the release medium of same volume simultaneously, measure absorbance at the wavelength place of 235nm according to ultraviolet-visible spectrophotometry (two appendices IVA of Chinese Pharmacopoeia version in 2005), another Take an appropriate amount of buspirone hydrochloride reference substance, accurately weigh it, add release medium to dissolve and quantitatively dilute to make a solution containing 15 μg per 1 ml, and measure in the same way. Calculate and get.

The release curves of the three batches of scaled-up capsules are shown in Figure 1.

Figure 1 release curve shows that the buspirone hydrochloride slow/controlled release capsules prepared by specific examples of the present invention have good slow/controlled release characteristics.

Determination of the pharmacokinetics of buspirone hydrochloride in vivo:

The single and multiple oral pharmacokinetics of the sample in Example 4 were investigated in dogs, and compared with common tablets. A double-period, two-drug randomized crossover trial design was adopted to offset the impact of the experimental period on the test results, and the single-dosing and multiple-dosing trials were combined. Six Beagle dogs were randomly divided into two groups, with 3 dogs in each group. The first group takes the test preparation (T) first, then the reference preparation (R); the second group takes the reference preparation (R) first, then the test preparation (T), see Table 1. The interval between two cycles is 7 days (purification period).

Single dose :

The test animals were fasted for 12 hours before administration, and at 6:10 in the morning of the first day, 1 buspirone hydrochloride sustained-release capsule (15 mg/capsule) or 3 buspirone hydrochloride ordinary tablets (5 mg/tablet) were orally administered in a single dose. . Open the dog's mouth by hand, hold the capsule or tablet with long tweezers and place it at the mouth of the throat, wash it with 10ml of water, then quickly close the dog's mouth and hold it tightly with both hands to make the dog's head look up. Observe that the drug is administered successfully after swallowing. If the capsule or tablet is not swallowed and is bitten and spit out, the dog cannot be used temporarily and must be fed for 2 weeks before being used for the test. Water can be given 2 hours after taking the medicine, and food can be fed 4 hours after taking the medicine.

Multiple doses :

After a single administration on the first day for Beagle dogs, following the second day, take one buspirone hydrochloride sustained-release capsule (15 mg/capsule) orally at 6:30 every morning for 7 consecutive days or at 6:30 the first day. Oral administration of 1 tablet of buspirone hydrochloride ordinary tablet (5 mg/tablet) at one time, oral administration of 1 tablet of buspirone hydrochloride ordinary tablet (5 mg/tablet) at 14:30, and oral administration of buspirone hydrochloride ordinary tablet (5 mg/tablet) at 22:30 for the third time Cycloketone common tablet (5mg/tablet) 1 tablet, administered continuously for 7 days. On the 4th, 5th, 6th, and 7th day, blood samples were collected to determine the trough concentration before the administration in the morning.

Last dose :

Beagle dogs were administered continuously for 7 days after the plasma concentration reached a steady state, and at 6:10 in the morning of the 8th day, a single dose of buspirone hydrochloride sustained-release capsules (15 mg/grain) or buspirone hydrochloride ordinary tablets ( 5mg/tablet) 1 tablet.

Blood sample collection :

Beagle dogs were given 1ml of blood from the leg vein at 0.33, 0.67, 1, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours after the single administration on the first day and the last administration on the eighth day. The exact time of blood draw was recorded each time. The collected blood samples were placed in the refrigerator for 2 hours, centrifuged at 3500r/min for 15 minutes, and the plasma was separated, and 0.2ml of the plasma was transferred to a 10ml test tube (the same sample should be kept as a backup), and the test number, the random number of the Beagle dog and the time of blood collection were marked. Blood samples were stored in the freezer for processing and analysis.

Instrument and analysis conditions :

A LC/MS/MS system was used. TSQ Quantum liquid chromatography-mass spectrometry (LC/MS/MS) from Finnigan Company in the United States, consisting of Finnigan Surveyor LC pump, Surveyor AS autosampler, electrospray ionization ionization source (ESI) and three-stage tandem mass spectrometer . The control software is Xcalibur1.4, and the mass spectrometry data analysis uses Lcquan2.0 data processing system.

HPLC conditions: the chromatographic column is a ZORBAX SB-C18 column (2.1mm×100mm, 3.5μm), Agilent Company of the United States; the mobile phase is methanol-water-formic acid (40:60:0.1); the flow rate is 0.2ml min-1; The sample volume is 10 μl; the column temperature is room temperature.

Tandem mass spectrometry conditions: LC interface adopts pneumatic-assisted electrospray ionization ionization source (ESI), source voltage (IS) 4.8KV; heating capillary temperature (TEM) 300°C; sheath gas N ₂ , flow rate 29 (ARB); auxiliary gas N ₂ , flow rate 4 (ARB); collision gas (CAD) Ar, pressure 1.5 (ARB); source collision-induced dissociation (Source CID) energy is 12 (ARB), secondary collision energy is 34 (ARB) Cycloketone) and 16 (ARB) (internal standard, tramadol); positive ion mode detection; mass spectrometry scanning mode is selected reaction monitoring (SRM), respectively determine buspirone hydrochloride and internal standard (tramadol) positive ion m/z 386.2→121.97 and m/z 264.3→58.0; the scan time is 0.5S.

Processing and determination of plasma samples :

Precisely measure 200 μl of plasma sample, put it in a 10ml stoppered test tube, add 50 μl of internal standard aqueous solution (tramadol hydrochloride 10ng·ml ^-1 ) and mix well, then add 50 μl of saturated sodium bicarbonate solution → vortex for 20 seconds → add ring Vortex 2ml of hexane on a micro-mixer for 2min (extract once) → centrifuge (3500r/min) for 15min to separate layers, take out the upper layer of cyclohexane into another test tube, put it in a water bath at 37°C, and dry it with nitrogen flow. Before the measurement, use 100 μl of mobile phase to fix the solution, vortex to mix for 3 minutes, centrifuge at high speed (10000r/min) for 10 minutes, take 10 μl of supernatant and inject for detection. The measured blood drug concentration results are shown in the table below:

Table 1 Beagle dog single-dose oral buspirone hydrochloride sustained-release capsules (15mg) plasma concentration

Table 2 Beagle dog single dose oral buspirone hydrochloride common tablet (15mg) plasma concentration

Table 3 Paired t-test for main kinetic parameters of single-dose oral sustained-release capsules and ordinary tablets

^* Significantly different (P<0.01)

The mean drug-time curves of single-dose oral sustained-release capsules and ordinary tablets for Beagle dogs are shown in Figure 2.

As can be seen from the above data, the buspirone hydrochloride slow/controlled release capsules prepared by specific embodiments of the present invention have carried out the measurement of the pharmacokinetics in the beagle dog body, and the buspirone hydrochloride common tablet of the beagle dog There are significant differences in the pharmacokinetic properties in vivo, indicating that the buspirone hydrochloride slow/controlled release capsules of the present invention have good slow/controlled release properties in vivo.

Claims (10)

1. a slow/controlled release pellet of buspirone hydrochloride is characterized in that the pellet contains buspirone hydrochloride medicine ball core, is wrapped in the isolation layer outside the buspirone hydrochloride medicine ball core, and wraps Sustained release layer on top of the barrier layer. 2. The slow/controlled release pellets of claim 1, wherein the barrier layer is composed of hypromellose, polyethylene glycol and talcum powder. 3. The slow/controlled release pellets according to claim 2, wherein the hypromellose in the isolation layer has a specification of 3 mPa.s to 10 mPa.s, and the polyethylene glycol has a specification of PEG1000 to 4000. 4. The slow/controlled release pellets described in any one of claims 1 to 3, wherein the buspirone hydrochloride medicine ball core is made of a blank ball core and the buspirone hydrochloride containing buspirone hydrochloride sprayed on the blank ball core outer layer Drug layer composition. 5. The slow/controlled release pellet of claim 4, wherein the buspirone hydrochloride drug layer contains buspirone hydrochloride and hydrophilic film-forming materials hypromellose and polyethylene glycol. 6. The sustained/controlled release pellets according to claim 4 or 5, wherein the sustained release coating layer is selected from ethyl cellulose film coating material or acrylic resin film coating material. 7. The sustained/controlled release pellets according to claim 6, wherein the sustained release coating layer is an ethyl cellulose film coating material

8. The sustained/controlled release pellets according to any one of claims 1 to 3, wherein the buspirone hydrochloride drug pellet core is formed by mixing buspirone hydrochloride with suitable auxiliary materials and then making pellets. 9. A slow/controlled release capsule of buspirone hydrochloride, comprising a slow/controlled release pellet or several slow/controlled release pellets with different film thicknesses according to any one of claims 1 to 8 Mix evenly and pack into hollow capsules to obtain. 10. the preparation method of the described slow/controlled release pellet of claim 4, buspirone hydrochloride is wrapped on the blank ball core in the mode of coating to form medicine ball core, then wraps one deck in medicine ball core and plays a protective role The isolation layer is also coated with a slow-release coating layer outside the isolation layer to obtain the slow/controlled release pellets of buspirone hydrochloride, and the coating of the drug layer, the isolation layer and the slow-release coating layer can be implemented by a fluidized bed, It can also be implemented by high-efficiency coating pans.

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