WO2018223895A1 - Long-acting sustained-release preparation of drug against parkinson's disease and preparation method thereof - Google Patents

Abstract

A long-acting sustained-release preparation of a drug for treating Parkinson's disease and a preparation method thereof. The long-acting sustained-release preparation is microspheres comprising rasagiline or a pharmaceutically acceptable salt thereof and a biodegradable and biocompatible high molecular weight polymer. The microspheres comprise microspheres with an average particle size of 0.5-5 mm and microspheres with an average particle size of 20-150 mm.

Description

Long-acting sustained-release preparation for anti-Parkinson's disease medicine and preparation method thereof Technical field

The invention belongs to the field of pharmacy, and particularly relates to a long-acting sustained-release preparation for anti-Parkinson's disease medicine and a preparation method thereof.

Background technique

Rasagiline is a second-generation monoamine oxidase inhibitor that blocks the breakdown of the neurotransmitter dopamine, compared to first-generation monoamine oxidase inhibitors, including selegiline, sigrin, imipenem, and Jinsi. The inhibitory effect is stronger, and it also has an effect on the patients whose long-term application of dopa preparations has a deteriorating effect. In addition, the metabolite of rasagiline is an inactive non-amphetamine substance with small side effects and, more importantly, the drug has a certain symptom relief effect, and there is more evidence that these drugs have certain nerves. The role of protection.

Rasagiline currently has only oral tablets in the clinic. Although oral tablets are convenient to take, patients with Parkinson's disease often develop with nerve damage and memory loss, which leads to missed medication and the inability to regularly take drugs, leading to further deterioration of the disease. In addition, late Parkinson's patients often have difficulty swallowing and are not suitable for taking drugs. In addition, oral administration may have significant fluctuations in blood concentration, aggravating side effects, and appearing at the end of the agent and switching.

Patent CN 103494766 discloses a rasagiline oral disintegration composition, which solves the problem of difficulty in swallowing a drug, but cannot solve the problem of drug leakage and frequent medication.

Patent CN 1762495 discloses a preparation process of a long-acting sustained-release preparation for treating Parkinson's disease, using an organic solvent to dissolve a drug and a biodegradable medicinal polymer auxiliary, and injecting an organic solvent phase into a pharmaceutically acceptable water-soluble polymer. The continuous aqueous phase forms microspheres, then volatilizes the organic solvent, and filters to obtain a sustained release microsphere, that is, an O/W process; or dissolves the drug and the biodegradable medicinal polymer auxiliary with an organic solvent, and then spray-drying Obtaining microspheres; or dissolving the drug and biodegradable medicinal polymer excipients in an organic solution with an organic solvent, spraying them into an organic non-solvent or water, and extracting them to form microspheres, ie, O/O Process or O/W process. With the O/W process, since the drug is water-soluble, there is no protective measure and it is directly exposed to the external aqueous phase to lower the encapsulation efficiency, and therefore, it is difficult to obtain microspheres having a high content and a high encapsulation efficiency. The use of the O/O process requires the use of a large amount of organic solvent, and requires the removal of all organic solvents used, and the process is complicated. The first use of spray drying requires high temperature to cause degradation of raw materials, and the organic solvent spray drying requires explosion protection and has certain risks.

Patent CN 105769771 discloses a preparation method of an exenatide sustained-release microsphere composition, which first dissolves a drug substance using a strong polar solvent, then dissolves the polymer with a weakly polar solvent, and then adds a strong polar solvent. A suspension or a homogeneous solution is formed in the weakly polar solvent, and then added to the quencher to obtain fine particles. The quenching agent is selected from the group consisting of silicone oil, liquid paraffin, mineral oil, requires a large amount of organic solvent, and needs to remove all the organic solvents used, and the process is complicated.

The article "Controlled release of rasagiline mesylate promotes neuroprotection in a rotenone-induced advanced model of Parkinson's disease" by M. Fernández et al. discloses the use of 50/50 PLGA as a sustained release material using O/W and W/O/W. Process for preparing rasagiline sustained release microspheres. However, the microspheres prepared by the method have a short release period of only two weeks, and the drug loading amount is low. Under the same dose, the total amount of the injected drug is too large, which is unfavorable for patient compliance.

Patent CN 103338752 discloses a risperidone sustained release microsphere composition which discloses the use of two polymers of different viscosities to prepare microspheres for controlled release purposes, eliminating delayed release periods. However, the use of two polymers without viscosity at the same time dissolved in an organic solvent and then the preparation of microspheres, on the one hand will increase the complexity of the prescription, different viscosity polymers may bring prescription compatibility problems, on the other hand, the method is applied in this The invention also causes problems with product release. Patent CN 104010629 discloses a triptorelin microsphere pharmaceutical composition which modulates release by adding glucose or mannitol to the microspheres to increase the initial release of the drug, thereby allowing the drug to function as quickly as possible. However, the method of adding a release regulator also increases the complexity of the prescription on the one hand, and may bring about the problem of prescription compatibility. On the other hand, the application of the method in the present invention also causes a problem of product release.

Summary of the invention

OBJECT OF THE INVENTION: To solve the problems in the prior art, the present invention provides a rasagiline long-acting sustained-release composition and a preparation method thereof. The invention improves the compliance of the rasagiline drug which is currently only administered orally in the clinical form, and improves the short release period and low drug loading of the sustained release microsphere preparation pharmaceutical composition disclosed in the prior literature, and No delayed release period.

The present inventors attempted to prepare rasagiline as a sustained-release microsphere with a longer release period according to the presently disclosed technical data, and replace the 50/65/35-100/0 PLGA with the technical means commonly used by those skilled in the art. A PLGA of 50 found that the release period of the microspheres could be prolonged, but it was found that the microspheres showed a delayed release period.

In this field, common techniques for solving the delayed release period of microspheres are the use of polymers of different viscosity types, as well as the addition of release modifiers, but each of these methods increases the complexity of the prescription and may lead to a prescription phase. The problem of capacitiveness, the other is that the application in the present invention causes a problem of product release.

In addition, the inventors have found that within the conventional particle size range of microspheres, as the particle size of the microspheres decreases, the microsphere release cycle and the delayed release period do become shorter, but the changes are not significant. However, the inventors have creatively discovered that the preparation of microspheres into the nanometer to submicron level has resulted in significant changes in the release behavior of the microspheres. The first is that there is no delayed release period and no burst release, and the second is that the release cycle is significantly shortened. . Moreover, the inventors have miraculously discovered that the release period of nano-to-submicron-sized microspheres is close to the delayed release period of ordinary particle size microspheres, even in some embodiments.

Therefore, the inventors thought that mixing two kinds of microspheres of different particle diameters can not only obtain a product with a long release period, but also has no delayed release period.

Further, the inventors have experimentally found that a product having a high drug loading amount and an encapsulation ratio cannot be obtained by using a conventionally known technique. However, according to the technique disclosed in the present invention, microspheres having a high drug loading amount and a high encapsulation ratio can be obtained.

Specifically, in order to achieve the technical object of the present invention, the technical solution of the present invention is:

A long-acting sustained-release preparation for treating a Parkinson's disease drug, the long-acting sustained-release preparation being a microsphere comprising rasagiline or a pharmaceutically acceptable salt thereof and biodegradable biocompatibility A polymer comprising microspheres having an average particle diameter of 0.5 to 5 μm and microspheres having an average particle diameter of 20 to 150 μm.

The microspheres having an average particle diameter of 0.5 to 5 μm account for 10 to 50% by weight of the long-acting sustained-release preparation, and the microspheres having an average particle diameter of 20 to 150 μm account for 50 to 90% by weight.

Further preferably, the microspheres having an average particle diameter of 0.5 to 5 μm account for 20 to 40% by weight of the long-acting sustained-release preparation, and the microspheres having an average particle diameter of 20 to 150 μm account for 60 to 80% by weight.

Preferably, a long-acting sustained-release preparation for treating a Parkinson's disease drug, the long-acting sustained-release preparation being a microsphere comprising rasagiline or a pharmaceutically acceptable salt thereof and a biodegradable organism As the compatible polymer, the microspheres preferably include microspheres having an average particle diameter of 0.5 to 3 μm and microspheres having an average particle diameter of 40 to 100 μm.

The microspheres having an average particle diameter of 0.5 to 3 μm account for 10 to 50% by weight of the long-acting sustained-release preparation, and the microspheres having an average particle diameter of 40 to 100 μm account for 50 to 90% by weight.

Further preferably, the microspheres having an average particle diameter of 0.5 to 3 μm account for 20 to 40% by weight of the long-acting sustained-release preparation, and the microspheres having an average particle diameter of 40 to 100 μm account for 60 to 80% by weight.

Preferably, rasagiline or a pharmaceutically acceptable salt thereof is from 10 to 50% by weight of the long-acting sustained release preparation.

A low-level drug may increase the total drug weight, and a high drug-loading amount may lower the encapsulation efficiency. Further preferably, rasagiline or a pharmaceutically acceptable salt thereof accounts for 20-40% by weight of the long-acting sustained-release preparation. .

In a preferred embodiment, the biodegradable biocompatible polymer is poly(lactide-glycolide).

Further preferably, in the poly(lactide-glycolide), the molar ratio of lactide to glycolide is from 65:35 to 100:0.

In clinical applications, the longer the drug release time, the better, but it may be administered too much at a time, which is not conducive to patient compliance, so in some cases, the poly(lactide-glycolide) The preferred molar ratio of lactide to glycolide is from 70:30 to 95:5.

In clinical applications, the longer the drug release time, the better, but it may be administered too much at a time, which is not conducive to patient compliance, so in some cases, the poly(lactide-glycolide) More preferably, the molar ratio of lactide to glycolide is from 75:25 to 85:15.

In a preferred embodiment, the poly(lactide-glycolide) has a viscosity in the range of from 0.2 to 0.8 dl/g.

Further preferably, the poly(lactide-glycolide) has a viscosity in the range of from 0.3 to 0.6 dl/g.

In a preferred embodiment, the poly(lactide-glycolide) has a molecular weight ranging from 21 kDa to 89 kDa.

In a preferred embodiment, the terminal group of the poly(lactide-glycolide) is an ester group or a carboxyl group.

Further preferably, the terminal group of the poly(lactide-glycolide) is a carboxyl group.

The release period of the long-acting sustained-release preparation of the present invention is 4 to 12 weeks.

The invention further provides a preparation method of a long-acting sustained-release preparation for treating a Parkinson's disease medicine, comprising the following steps:

a) dissolving the biodegradable biocompatible polymer in the first type of organic solvent to obtain a uniform solution A;

b) rasagiline or a pharmaceutically acceptable salt thereof is dissolved in a second type of organic solvent which is miscible with the first type of organic solvent to obtain a homogeneous solution B;

c) the uniform solution B obtained in step b) is added to the homogeneous solution A obtained in step a) to obtain a uniform emulsion C;

d) adding the uniform emulsion C obtained in the step c) to the continuous aqueous phase prepared by using the pharmaceutically acceptable water-soluble polymer to form microspheres; preferably, the pharmaceutically acceptable water-soluble polymer is polyvinyl alcohol; the polyvinyl alcohol solution The concentration is from 0.5 to 4%; the continuous aqueous phase temperature is from 2 to 15 ° C, preferably 4 ° C.

e) removing the organic solvent in the step d) microspheres, filtering, washing;

f) The microspheres obtained in step e) are freeze-dried to obtain sustained-release microspheres.

Preferably, the first type of organic solvent is selected from any one of dichloromethane, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide or dimethylacetamide. The second type of organic solvent is selected from any one of ethanol, acetic acid, hydrochloric acid, dimethyl sulfoxide, dimethylformamide or dimethylacetamide.

Further preferably, the first type of organic solvent is selected from any one of dichloromethane, ethyl acetate, and tetrahydrofuran. The second type of organic solvent is selected from any one of ethanol, acetic acid, dimethyl sulfoxide, dimethylformamide or dimethylacetamide.

Still more preferably, the first type of organic solvent is selected from the group consisting of dichloromethane. The second type of organic solvent is selected from any one of ethanol and acetic acid.

The solution obtained in step b) is added to step a) by sonication, vortexing, homogenization or stirring.

The uniform emulsion C obtained in the step c) is added to the continuous aqueous phase prepared by using the pharmaceutically acceptable water-soluble polymer by ultrasonication, vortexing, homogenization, high pressure homogenization or stirring.

The ultrasonic power is 200-400w, the vortex rotation speed is 2000-4000rpm, the homogenization speed is 4000-20000rpm, the high pressure homogenization is 600-1500bar, and the stirring speed is 1000-3000rpm.

Preferably, the ratio of the first type of organic solvent to the second type of organic solvent is from 2:1 to 20:1.

Further preferably, the ratio of the first type of organic solvent to the second type of organic solvent is from 2:1 to 10:1.

Advantageous Effects: Compared with the prior art, the pharmaceutical composition in the form of microspheres proposed by the present invention has the property of long-term release of drugs, and can release rasagiline in more than one month. The present invention is characterized in that fluctuations in the concentration of rasagiline in plasma can be significantly reduced by using a suitable combination of two microparticles of different particle sizes in the pharmaceutical composition of the present invention without a significant delayed release period. Another feature of the present invention is that in the case of a high drug loading amount, there is no drug burst phenomenon.

DRAWINGS

Figure 1 shows the release characteristics of the sustained release microspheres obtained in Example 1, Example 1-2, Example 1-4 and Example 1-6. It can be seen from the figure that within the ordinary particle size range, that is, 20- In the particle size range of 150 μm, although the release behavior of microspheres in different particle size ranges is different, it is not obvious;

2 is a mixture of Example 1 sustained release microspheres (labeled as Example 1), Example 2 sustained release microspheres (labeled as Example 2), two parts of Example 1 and one example of Example 2 (labeled as an example) 1+2) in vitro release profile;

Figure 3 is a mixture of Example 3 sustained release microspheres (labeled as Example 3), Example 4 sustained release microspheres (labeled as Example 4), three parts of Example 1 and one example of Example 4 (labeled as examples) In vitro release profile of 3+4);

Figure 4 is a mixture of Example 5 sustained release microspheres (labeled as Example 5), Example 6 sustained release microspheres (labeled as Example 6), three of Example 5 and one of Example 6 (labeled as an example) In vitro release profile of 5+6);

Figure 5 is a mixture of Example 7 sustained release microspheres (labeled as Example 7), Example 8 sustained release microspheres (labeled as Example 8), two parts of Example 7 and one example of Example 8 (labeled as examples) In vitro release profile of 7+8).

Figure 6 is a mixture of Example 9 sustained release microspheres (labeled as Example 9), Example 10 sustained release microspheres (labeled as Example 10), five parts of Example 9 and a portion of Example 10 (labeled as examples) In vitro release profile of 9+10).

Figure 7 is a mixture of Example 11 sustained release microspheres (labeled as Example 11), Example 12 sustained release microspheres (labeled as Example 12), triplicate Example 11 and two Examples of Example 12 (labeled as examples) In vitro release profile of 11+12).

detailed description

The technical solution of the present invention will be described in detail below, but the scope of protection of the present invention is not limited to the embodiment.

Example 1. Preparation of sustained release microspheres.

8.00 g of PLGA (lactide / glycolide = 65 / 35, the same below, are lactide / glycolide, 0.65dl / g, 71kDa, ester end groups) dissolved in 80.00g of dichloromethane, Uniform solution A; 2.00 g of rasagiline dissolved in 10.00 g of ethanol to obtain a homogeneous solution B; solution A was added to solution B under vortex conditions at 3000 rpm to obtain a uniform emulsion C. The homogeneous solution C was added to a 1.0% aqueous solution of polyvinyl alcohol at 4 ° C, and the microspheres were prepared by stirring using a mechanical stirrer at 2000 rpm. Then, the organic solvent was evaporated by heating to 40 ° C, and then the microspheres were filtered, and the microspheres were washed 7 times with water for injection, and then freeze-dried to obtain sustained-release microspheres.

Example 2. Preparation of sustained release microspheres.

8.00 g of PLGA (65/35, 0.65 dl/g, 71 kDa, ester end group) was dissolved in 80.00 g of dichloromethane to obtain a homogeneous solution A; 2.00 g of rasagiline was dissolved in 10.00 g of ethanol to obtain a homogeneous solution. B; under ultrasonic conditions, power 300w, solution A was added to solution B to obtain a uniform emulsion C. The homogeneous solution C was added to a 1.0% polyvinyl alcohol continuous aqueous phase at 4 ° C, and the microspheres were prepared by high pressure homogenization under a pressure of 900 bar. Then, the organic solvent was evaporated by heating to 40 ° C, and then the microspheres were filtered to remove the continuous aqueous phase, and the microspheres were washed 7 times with water for injection, and then freeze-dried to obtain sustained-release microspheres.

Example 3. Preparation of sustained release microspheres.

7.00 g of PLGA (75/25, 0.5 dl/g, 57 kDa, carboxyl end group) was dissolved in 70.00 g of ethyl acetate to obtain a homogeneous solution A; 3.00 g of rasagiline was dissolved in 15.00 g of acetic acid to obtain a homogeneous solution B. Solution A was added to solution B under vortex conditions of 3000 rpm to obtain a uniform emulsion C. The homogeneous solution C was added to a continuous aqueous phase of 0.5% polyvinyl alcohol at 4 ° C, and the microspheres were homogenized using a homogenizer at 4000 rpm. Then, the organic solvent was evaporated by heating to 40 ° C, and then the microspheres were filtered, and the microspheres were washed 7 times with water for injection, and then freeze-dried to obtain sustained-release microspheres.

Example 4. Preparation of sustained release microspheres.

7.00 g of PLGA (75/25, 0.5 dl/g, 57 kDa, carboxyl end group) was dissolved in 70.00 g of ethyl acetate to obtain a homogeneous solution A; 3.00 g of rasagiline was dissolved in 15.00 g of acetic acid to obtain a homogeneous solution B. Solution A was added to solution B under vortex conditions at 4000 rpm to obtain a uniform emulsion C. The homogeneous solution C was added to a continuous aqueous phase of 0.5% polyvinyl alcohol at 4 ° C, and the microspheres were prepared by high pressure homogenization under a pressure of 1000 bar. Then, the organic solvent was evaporated by heating to 40 ° C, and then the microspheres were filtered, and the microspheres were washed 7 times with water for injection, and then freeze-dried to obtain sustained-release microspheres.

Example 5. Preparation of sustained release microspheres.

6.00 g of PLGA (85/15, 0.4 dl/g, 46 kDa, carboxyl end group) was dissolved in 60.00 g of dichloromethane to obtain a homogeneous solution A; 4.00 g of rasagiline was dissolved in 20.00 g of ethanol to obtain a homogeneous solution B. Under ultrasonic conditions, power 300w, solution A was added to solution B to obtain a uniform emulsion C. The homogeneous solution C was added to a continuous aqueous phase of 0.5% polyvinyl alcohol at 4 ° C, and microspheres were prepared using mechanical stirring at 1000 rpm. Then, the organic solvent was evaporated by heating to 40 ° C, and then the microspheres were filtered, and the microspheres were washed 7 times with water for injection, and then freeze-dried to obtain sustained-release microspheres.

Example 6. Preparation of sustained release microspheres.

600g PLGA (85/15, 0.45dl/g, 51kDa, carboxyl end group) was dissolved in 60.00g of dichloromethane to obtain a uniform solution A; 4.00g of rasagiline was dissolved in 20.00g of ethanol to obtain a uniform solution B; Solution A was added to solution B under vortex conditions of 4000 rpm to obtain a uniform emulsion C. The homogeneous solution C was added to a continuous aqueous phase of 1.5% polyvinyl alcohol at 4 ° C, and the microspheres were prepared by high pressure homogenization under a pressure of 1000 bar. Then, the organic solvent was evaporated by heating to 40 ° C, and then the microspheres were filtered, and the microspheres were washed 7 times with water for injection, and then freeze-dried to obtain sustained-release microspheres.

Example 7. Preparation of sustained release microspheres.

5.00 g of PLGA (100/0, 0.65 dl/g, 73 kDa, ester end group) was dissolved in 50.00 g of tetrahydrofuran to obtain a homogeneous solution A; 5.00 g of rasagiline was dissolved in 25.00 g of dimethyl sulfoxide. Uniform solution B; under ultrasonic conditions, power 400w, solution A was added to solution B to obtain a uniform emulsion C. The homogeneous solution C was added to a continuous aqueous phase of 0.5% polyvinyl alcohol at 4 ° C, and microspheres were prepared using mechanical stirring at 1000 rpm. Then, the organic solvent was evaporated by heating to 40 ° C, and then the microspheres were filtered, and the microspheres were washed 7 times with water for injection, and then freeze-dried to obtain sustained-release microspheres.

Example 8. Preparation of sustained release microspheres.

5.00 g of PLGA (100/0, 0.45 dl/g, 53 kDa, carboxyl end group) was dissolved in 50.00 g of tetrahydrofuran to obtain a homogeneous solution A; 5.00 g of rasagiline was dissolved in 25.00 g of dimethyl sulfoxide to obtain uniformity. Solution B; Solution A was added to Solution B under vortex conditions at 4000 rpm to obtain a homogeneous emulsion C. The homogeneous solution C was added to a continuous aqueous phase of 1.5% polyvinyl alcohol at 4 ° C, and the microspheres were prepared by high pressure homogenization under a pressure of 1000 bar. Then, the organic solvent was evaporated by heating to 40 ° C, and then the microspheres were filtered, and the microspheres were washed 7 times with water for injection, and then freeze-dried to obtain sustained-release microspheres.

Example 9. Preparation of sustained release microspheres.

6.00 g of PLGA (75/25, 0.6 dl/g, 69 kDa, ester end group) was dissolved in 100.00 g of dimethyl sulfoxide to obtain a homogeneous solution A; 4.00 g of rasagiline was dissolved in 10.00 g of dimethyl group. Formamide was obtained as a homogeneous solution B; solution A was added to solution B under mechanical stirring at 2000 rpm to obtain a uniform emulsion C. The homogeneous solution C was added to a continuous aqueous phase of 3.0% polyvinyl alcohol at 10 ° C, and microspheres were prepared using mechanical stirring at 1500 rpm. Then, the organic solvent was evaporated by heating to 40 ° C, and then the microspheres were filtered, and the microspheres were washed 7 times with water for injection, and then freeze-dried to obtain sustained-release microspheres.

Example 10. Preparation of sustained release microspheres.

6.00 g of PLGA (65/35, 0.5 dl/g, 58 kDa, carboxyl end group) was dissolved in 150.00 g of dimethylformamide to obtain a homogeneous solution A; 4.00 g of rasagiline was dissolved in 8.00 g of acetic acid to obtain uniformity. Solution B; Solution A was added to Solution B under homogeneous conditions of 4000 rpm to obtain a homogeneous emulsion C. The homogeneous solution C was added to a continuous aqueous phase of 3.0% polyvinyl alcohol at 10 ° C, and microspheres were prepared under high-speed homogenization conditions of 10,000 rpm. Then, the organic solvent was evaporated by heating to 40 ° C, and then the microspheres were filtered, and the microspheres were washed 7 times with water for injection, and then freeze-dried to obtain sustained-release microspheres.

Example 11. Preparation of sustained release microspheres.

6.50g PLGA (85/15, 0.75dl/g, 81kDa, carboxyl end group) was dissolved in 150.00g of dichloromethane to obtain a homogeneous solution A; 3.50g of rasagiline was dissolved in 10.00g of acetic acid to obtain a uniform solution B; Solution A was added to solution B under vortex conditions of 2000 rpm to obtain a homogeneous emulsion C. The homogeneous solution C was added to a continuous aqueous phase of 4.0% polyvinyl alcohol at 15 ° C, and microspheres were prepared using high pressure homogenization of 600 bar. Then, the organic solvent was evaporated by heating to 40 ° C, and then the microspheres were filtered, and the microspheres were washed 7 times with water for injection, and then freeze-dried to obtain sustained-release microspheres.

Example 12. Preparation of sustained release microspheres.

6.50 g of PLGA (100/0, 0.3 dl/g, 27 kDa, ester end group) was dissolved in 50.00 g of dichloromethane to obtain a homogeneous solution A; 3.50 g of rasagiline was dissolved in 10.00 g of acetic acid to obtain a homogeneous solution B. Solution A was added to solution B under mechanical agitation at 2000 rpm to obtain a uniform emulsion C. The homogeneous solution C was added to a continuous aqueous phase of 4.0% polyvinyl alcohol at 15 ° C, and microspheres were prepared using high pressure homogenization of 1500 bar. Then, the organic solvent was evaporated by heating to 40 ° C, and then the microspheres were filtered, and the microspheres were washed 7 times with water for injection, and then freeze-dried to obtain sustained-release microspheres.

Example 13. Determination of microsphere process recovery.

The sustained-release microspheres obtained after lyophilization in Examples 1-12 were weighed and weighed, and then the process recovery was calculated. The results are shown in Table 1. Among them, the process recovery rate = microsphere weight / feed amount *100% after lyophilization

Table 1

project	Process recovery rate /%
Example 1	87.5
Example 2	86.7
Example 3	89.3
Example 4	83.2
Example 5	90.5
Example 6	84.2
Example 7	89.5
Example 8	83.9
Example 9	90.3
Example 10	87.6
Example 11	91.5
Example 12	87.7

Example 14. Determination of particle size distribution of sustained release microspheres.

The particle size distribution of the microspheres was measured by a laser particle size tester. The pump speed is 40%, the measurement time is 90s, the waiting time is 30s, the PIDS is set to "on", and the number of measurements is 1. For the determination, take appropriate amount of slow-release microspheres, add 5-10 drops of 1% surfactant solution, then add 1ml of water and mix. The instrument was turned on, and the sample was loaded into the sample cell until the opacity was 8-12%. The measurement results were recorded, and the measurements were performed three times in parallel, and the average value was obtained. The results are shown in Table 2. Wherein D10 represents that the number of microspheres smaller than the particle diameter accounts for 10% of the total amount, D50 represents the intermediate particle diameter, that is, the microspheres smaller than the particle diameter account for 50% of the total amount, and D90 represents the number of microspheres smaller than the particle diameter. 90% of the total.

Table 2

project	D10/μm	D50/μm	D90/μm
Example 1	38.64	70.21	113.88
Example 2	0.51	0.90	2.17
Example 3	29.53	74.07	118.68
Example 4	0.58	1.10	1.96
Example 5	35.34	81.05	138.05
Example 6	0.61	2.75	4.36
Example 7	27.46	60.57	112.89
Example 8	0.67	2.53	3.84
Example 9	23.17	40.31	60.08
Example 10	0.49	0.62	1.08
Example 11	65.89	108.4	145.79
Example 12	3.58	4.15	4.87

Example 15. Determination of rasagiline content.

The slow-release microspheres were accurately weighed, and the acetonitrile-dispersed microspheres were added, and then the mobile phase of the triethylamine-glacial acetic acid buffer solution-acetonitrile (52:48) having a pH of 6.5 was dissolved and quantified to about 100 μg/ml. Product. The same method was used to prepare a reference substance. The results were determined by HPLC, and the results are shown in Table 3. The content is the percentage of the drug amount to the weight of the microspheres. Content = drug amount / microsphere amount * 100

table 3

project	content/%
Example 1	17.5

Example 2	16.9
Example 3	28.7
Example 4	26.8
Example 5	37.4
Example 6	35.9
Example 7	45.6
Example 8	42.3
Example 9	38.7
Example 10	37.9
Example 11	34.7
Example 12	33.9

Example 16. Sustained release microsphere release characteristics.

Screening of sustained-release microspheres: Partially-released microspheres were lyophilized in Example 1 and sieved with 100, 115, 150, 175, 230, 325, and 500 mesh screens to obtain different meshes of microspheres. For the examples 1-1 to 1-6, as shown in Table 4. It is used to investigate the difference in release behavior of microspheres with different particle sizes in the range of ordinary particle size, that is, in the range of 20-150 μm. The following table means: For example, Example 1-1 shows a 100-115 mesh microsphere obtained by sieving part of Example 1.

Table 4

project	Number of mesh
Example 1-1	100-115
Example 1-2	115-150
Examples 1-3	150-175
Examples 1-4	175-230
Examples 1-5	230-325
Example 1-6	325-500

The sustained-release microspheres prepared in Examples 1 to 12 and the microspheres sieved into different particle diameters in Example 1, that is, Example 1-2, Example 1-4, and Example 1-6, were released in vitro.

Test method: Microspheres (30 mg) were accurately weighed, and 100 ml of PBS having a pH of 7.4 was added as a release medium, and a release experiment was carried out in a 37 ° C water bath shaker. The shaker was rotated at 100 rpm. At a fixed time, the sample was taken out and allowed to stand, and then the supernatant was passed through a 0.45 μm microporous membrane while fresh release medium was added and the content was determined by HPLC. Each batch of microspheres was run in triplicate. The release data is shown in Table 5, Table 6, and Figures 1 to 7 below.

According to the results of the release of Examples 1-1, 1-4 and 1-6, in the range of the ordinary particle size, that is, in the range of 20-150 μm, although the release behavior of the microspheres in different particle size ranges is different, But it is not obvious.

According to the release behaviors of Example 1, Example 3, Example 5, Example 7, Example 9, and Example 11, it can be seen that the microsphere release period is longer in the range of the ordinary particle size, that is, between 20 and 150 μm. A delayed release period occurs; by the release data of Example 2, Example 4, Example 6, Example 8, Example 10, and Example 12, it is known that the nanometer to submicron particle size range, that is, 0.5-5 micrometers During the period, the release period of the microspheres was short, but there was no delayed release period and no burst release.

By mixing the nano-submicron particle size microspheres with the ordinary particle size microspheres in a certain ratio, as in the case of the release period of the first embodiment, the release period is 30 days, and the release period of the embodiment 2 is 10 days. No delayed release period. Then, Example 1 can be used in combination with Example 2. The microspheres of Example 2 were responsible for the prophase release of the combination drug, and the microspheres of Example 1 were responsible for the later release. If the drug dosage required for the entire release cycle is 3 parts, then Example 1 provides two copies and Example 2 provides one portion. Specifically, if the drug dosage required for the entire release cycle is 30 mg, then Example 1 needs to provide 20 mg of the drug, that is, 72.73 mg of microspheres (microsphere weight = required drug amount/content); Example 2 requires 10 mg of drug, ie 37.17 Mg microspheres; such as three parts of Example 3 mixed with one part of Example 4 (release cycle of about 5.7 weeks), three parts of Example 5 mixed with one part of Example 6 (release cycle of about 8.6 weeks), two implementations Example 7 was mixed with one part of Example 8 (release cycle of about 12 weeks), five parts of Example 9 were mixed with one part of Example 8 (release cycle of about 6 weeks), and three parts of Example 11 were mixed with two parts of Example 12 ( The release period is about 7 weeks), and then an in vitro release test is performed, that is, a pharmaceutical composition having a release period of 4 to 12 weeks and no burst release and delayed release period can be obtained. The premise of mixing is that the release period of the nano-submicron microspheres can just overlap with the delayed release period of the ordinary particle size microspheres. Examples 2/4/6/8/10/12 correspond to the nano-to-submicron particle size microspheres of Example 1/3/5/7/9/11, respectively, which can achieve a longer release period and No purpose for a delayed release period.

table 5

Table 6

In summary, this study found that within the conventional particle size range of the microspheres, as the particle size of the microspheres decreases, the microsphere release cycle and the delayed release period do become shorter, but the changes are not obvious. In addition, the creative discovery found that the microspheres were prepared to a submicron level, and the microsphere release behavior changed significantly. The first was no delayed release period and no burst release, and the second was that the release cycle was significantly shortened. At the same time, it was unexpectedly found that the release period of the submicron-sized microspheres of the present invention is the same as that of the ordinary particle size microspheres. By mixing two microspheres of different particle sizes, not only a product with a long release period but also a delayed release period is obtained. The microspheres with high drug loading and high encapsulation efficiency can be obtained by using the technical scheme, and the rasagiline in plasma can be significantly reduced by using a suitable combination of two microspheres of different particle sizes in the pharmaceutical composition of the invention. Fluctuations in concentration without significant delayed release. At the same time, in the case of high drug loading, the present invention has no sudden release of the drug.

Claims (11)

1. A long-acting sustained-release preparation for treating a Parkinson's disease drug, characterized in that the long-acting sustained-release preparation is a microsphere comprising rasagiline or a pharmaceutically acceptable salt thereof and biodegradable A biocompatible high molecular polymer comprising microspheres having an average particle diameter of 0.5 to 5 μm and microspheres having an average particle diameter of 20 to 150 μm.
2. The long-acting sustained-release preparation according to claim 1, wherein the microspheres having an average particle diameter of 0.5 to 5 μm account for 10 to 50% by weight of the long-acting sustained-release preparation, and the average particle diameter is 20 to 150 μm. The ball accounts for 50-90% by weight.
3. The long-acting sustained-release preparation according to claim 1, wherein rasagiline or a pharmaceutically acceptable salt thereof accounts for 10 to 50% by weight of the long-acting sustained-release preparation.
4. The long-acting sustained release preparation according to claim 1, wherein the biodegradable biocompatible high molecular polymer is poly(lactide-glycolide).
5. The long-acting sustained-release preparation according to claim 4, wherein a molar ratio of lactide to glycolide in the poly(lactide-glycolide) is from 65:35 to 100:0.
6. The long-acting sustained-release preparation according to claim 4, wherein the poly(lactide-glycolide) has a viscosity in the range of 0.2 to 0.8 dl/g.
7. The long-acting sustained-release preparation according to claim 4, wherein the poly(lactide-glycolide) has a molecular weight ranging from 21 kDa to 89 kDa.
8. The long-acting sustained-release preparation according to claim 1, wherein the long-acting sustained-release preparation has a release period of 4 to 12 weeks.
9. A preparation method of a long-acting sustained-release preparation for treating a Parkinson's disease medicine, comprising the following steps:

   a) dissolving the biodegradable biocompatible polymer in the first type of organic solvent to obtain a uniform solution A;

   b) rasagiline or a pharmaceutically acceptable salt thereof is dissolved in a second type of organic solvent which is miscible with the first type of organic solvent to obtain a homogeneous solution B;

   c) the uniform solution B obtained in step b) is added to the homogeneous solution A obtained in step a) to obtain a uniform emulsion C;

   d) adding the uniform emulsion C obtained in the step c) to a continuous aqueous phase solution prepared by using a pharmaceutically acceptable water-soluble polymer to form microspheres;

   e) removing the organic solvent in the step d) microspheres, filtering, washing;

   f) The microspheres obtained in step e) are freeze-dried to obtain sustained-release microspheres.
10. The preparation method according to claim 8, wherein the first type of organic solvent is selected from the group consisting of dichloromethane, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide or dimethylacetamide. Any one; the second type of organic solvent is selected from any one of ethanol, acetic acid, hydrochloric acid, dimethyl sulfoxide, dimethylformamide or dimethylacetamide.
11. The preparation method according to any one of claims 9 to 10, wherein the ratio of the first type of organic solvent to the second type of organic solvent is from 2:1 to 20:1.

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