CN107049985B - Long-acting sustained-release preparation of anti-Parkinson disease drug and preparation method thereof - Google Patents
Long-acting sustained-release preparation of anti-Parkinson disease drug and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a long-acting sustained-release preparation of a medicine for treating Parkinson's disease and a preparation method thereof, wherein the long-acting sustained-release preparation is microspheres, the microspheres comprise rasagiline or pharmaceutically acceptable salt thereof and a biodegradable biocompatible high polymer, and the microspheres comprise microspheres with the average particle size of 0.5-5 mu m and microspheres with the average particle size of 20-150 mu m. By using a suitable combination of 2 microspheres of different particle sizes in the pharmaceutical composition of the invention, fluctuations in the concentration of rasagiline in plasma can be significantly reduced without an appreciable delayed release period. Meanwhile, the invention has no drug burst release phenomenon under the condition of high drug loading.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a long-acting sustained-release preparation of an anti-Parkinson disease drug and a preparation method thereof.
Background
Rasagiline is a second generation monoamine oxidase inhibitor, can block the decomposition of neurotransmitter dopamine, has stronger inhibition effect compared with a first generation monoamine oxidase inhibitor comprising selegiline, seginine, pyridoxine, cispine and the like, and also has the effect of improving patients with declined drug effect after long-term application of dopa preparations. 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 relieving effect, and more evidences prove that the drug has a certain neuroprotective effect.
Rasagiline currently has only oral tablets clinically. Although the oral tablet is convenient to take, the Parkinson patients often have nerve injury along with the development of the disease, and the memory is reduced, so that the patients can not take the medicine regularly, and the disease condition is further worsened. Furthermore, patients in the late stage of Parkinson often have difficulty swallowing and are not suitable for taking medicines. In addition, oral administration can cause significant blood concentration fluctuation, aggravate side effects, and cause dose end and switch phenomena.
Patent CN 103494766 discloses a rasagiline orally disintegrating composition, which solves the problem of difficulty in swallowing drugs, but fails to solve the problems of missed medication, frequent medication, etc.
Patent CN 1762495 discloses a preparation process of a long-acting sustained-release preparation for treating Parkinson's disease, which comprises dissolving a medicament and a biodegradable medical polymer auxiliary material by using an organic solvent, injecting the organic solvent phase into a continuous water phase prepared from a water-soluble polymer for medication to form microspheres, volatilizing the organic solvent, and filtering to obtain sustained-release microspheres, namely an O/W process; or dissolving the medicine and the biodegradable medical polymer auxiliary material by using an organic solvent, and then preparing the microspheres by adopting a spray drying method; or dissolving the medicine and biodegradable medicinal polymer adjuvant with organic solvent to obtain organic solution, spraying the organic solution onto an organic non-solvent or water, and extracting to obtain microsphere, i.e. O/O process or O/W process. With the O/W process, it is difficult to obtain microspheres with high content and high encapsulation efficiency because the drug is water-soluble active, without any protective measures, and exposed directly to the external aqueous phase, which reduces the encapsulation efficiency. The O/O process requires a large amount of organic solvent and the removal of all the organic solvent, which is complicated. The first is that the raw and auxiliary materials are degraded by high temperature in the spray drying process, and the spray drying process of the organic solvent needs explosion prevention and has certain danger.
Patent CN 105769771 discloses a method for preparing exenatide sustained release microsphere composition, which comprises dissolving the raw material drug with a strong polar solvent, dissolving the polymer with a weak polar solvent, adding the strong polar solvent into the weak polar solvent to form a suspension or a homogeneous solution, and adding the suspension or the homogeneous solution into a quencher to obtain microparticles. Wherein the quenching agent is selected from silicone oil, liquid paraffin and mineral oil, a large amount of organic solvent is required, all the used organic solvent is required to be removed, and the process is complex.
M. Fern-ndez et al, Controlled release of rasagiline mesylprolodens in a rotenone-induced advanced model of Parkinson's disease, discloses a method for preparing rasagiline sustained release microspheres using 50/50PLGA as sustained release material and O/W and W/O/W processes. However, the release period of the microspheres prepared by the method is short, only two weeks exist, the drug loading rate of the drug is low, and the total amount of the injected drug is large under the same dosage, which is not beneficial to the compliance of patients.
Patent CN 103338752 discloses a risperidone sustained release microsphere composition, which discloses the use of two polymers with different viscosities to prepare microspheres, thereby achieving the purpose of adjusting release and eliminating the delayed release period. However, the use of two polymers of different viscosities dissolved in an organic solvent at the same time to prepare microspheres increases formulation complexity, and the polymers of different viscosities may cause formulation compatibility problems, and the use of this method in the present invention may also cause product burst problems. Patent CN 104010629 discloses a triptorelin microsphere pharmaceutical composition, which is prepared by adding glucose or mannitol into microspheres to regulate release and improve the initial release amount of the drug, so that the drug can take effect as soon as possible. However, the use of the method of adding a release modifier also increases the complexity of the prescription and may cause compatibility problems with the prescription, and the use of the method in the present invention may cause burst release of the product.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the problems in the prior art, the invention provides a rasagiline long-acting slow-release composition and a preparation method thereof. The invention improves the compliance of the existing rasagiline medicine which is only administrated in an oral form clinically, overcomes the defects of short release period and low drug loading rate of the slow release microsphere preparation pharmaceutical composition disclosed by the existing literature, and has no delayed release period.
The inventors tried to prepare rasagiline as sustained release microspheres with longer release period according to the presently disclosed technical data, and used 65/35-100/0 PLGA instead of 50/50PLGA according to the commonly used technical means of those skilled in the art, and found that the release period of the microspheres could be prolonged, but found that the microspheres exhibited a delayed release period.
In the field, common technologies for solving the delayed release period of the microspheres include methods of using polymers with different viscosity models in a mixed manner, adding a release regulator and the like, but one of the methods increases the complexity of the prescription and possibly brings a problem of prescription compatibility, and the other method causes a problem of burst release of the product when the method is applied to the invention.
In addition, the inventor finds that in the conventional particle size range of the microspheres, the release period and the delayed release period of the microspheres are actually shortened along with the reduction of the particle size of the microspheres, but the change is not obvious. However, the inventor creatively discovers that when the microspheres are prepared into the nanometer to submicron grade, the release behavior of the microspheres is obviously changed, firstly, the release period is not delayed and not burst, and secondly, the release period is obviously shortened. And the inventors have surprisingly found that the release period of the nano to submicron sized microspheres is close to, and in some embodiments the same as, the delayed release period of the normal particle size microspheres.
Therefore, the inventor thinks that the combination of two microspheres with different particle sizes can not only obtain products with longer release period, but also have no delayed release period.
In addition, the inventor experimentally finds that products with high drug loading and encapsulation efficiency cannot be obtained by using the currently known technology. However, according to the technology disclosed by the invention, microspheres with high drug loading and high encapsulation efficiency can be obtained.
Specifically, to achieve the technical purpose of the present invention, the technical solution of the present invention is:
a long-acting sustained-release preparation of a drug for treating Parkinson's disease, which is a microsphere, the microsphere comprises rasagiline or a pharmaceutically acceptable salt thereof and a biodegradable biocompatible polymer, and the microsphere comprises a microsphere with the average particle size of 0.5-5 μm and a microsphere with the average particle size of 20-150 μm.
The microspheres with the average particle size of 0.5-5 mu m account for 10-50wt% of the long-acting sustained-release preparation, and the microspheres with the average particle size of 20-150 mu m account for 50-90 wt%.
Further preferably, the microspheres with the average particle size of 0.5-5 μm account for 20-40 wt% of the long-acting sustained release preparation, and the microspheres with the average particle size of 20-150 μm account for 60-80 wt%.
Preferably, the long-acting sustained-release preparation of the drug for treating the Parkinson disease is microspheres, the microspheres comprise rasagiline or pharmaceutically acceptable salt thereof and biodegradable biocompatible high molecules, and the microspheres preferably comprise microspheres with the average particle size of 0.5-3 μm and microspheres with the average particle size of 40-100 μm.
The microspheres with the average particle size of 0.5-3 mu m account for 10-50wt% of the long-acting sustained-release preparation, and the microspheres with the average particle size of 40-100 mu m account for 50-90 wt%.
Further preferably, the microspheres with the average particle size of 0.5-3 μm account for 20-40 wt% of the long-acting sustained release preparation, and the microspheres with the average particle size of 40-100 μm account for 60-80 wt%.
Preferably, rasagiline or a pharmaceutically acceptable salt thereof comprises 10-50wt% of the long acting sustained release formulation.
A low drug loading would increase the total administered weight and a high drug loading would decrease the encapsulation efficiency, further preferably rasagiline or a pharmaceutically acceptable salt thereof comprises 20-40 wt% of the long acting sustained release formulation.
In a preferred embodiment, the biodegradable, biocompatible polymer is poly (lactide-co-glycolide).
Further preferably, in the poly (lactide-glycolide), the molar ratio of lactide to glycolide is 65: 35-100: 0.
In clinical applications, the longer the drug release time, the better, but the longer the drug release time, the more likely one-time administration is not favorable for patient compliance, so in some cases, the preferred molar ratio of lactide to glycolide in the poly (lactide-glycolide) is 70: 30-95: 5.
In clinical applications, the longer the drug release time, the better, but the longer the drug release time, the more likely it is that one time administration is too much, which is not favorable for patient compliance, so in some cases, the more preferable molar ratio of lactide to glycolide in the poly (lactide-glycolide) is 75: 25 to 85: 15.
In a preferred embodiment, the poly (lactide-co-glycolide) has a viscosity in the range of 0.2 to 0.8 dl/g.
Further preferably, the poly (lactide-co-glycolide) has a viscosity in the range of 0.3 to 0.6 dl/g.
In a preferred embodiment, the poly (lactide-glycolide) has a molecular weight in the range of 21kDa to 89 kDa.
In a preferred embodiment, the terminal group of the poly (lactide-co-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 is 4-12 weeks.
The invention further provides a preparation method of the long-acting sustained-release preparation of the drug for treating the Parkinson disease, which comprises the following steps:
a) dissolving biodegradable biocompatible polymer in a first organic solvent to obtain a uniform solution A;
b) dissolving rasagiline or a pharmaceutically acceptable salt thereof in a second organic solvent which is mutually soluble with the first organic solvent to obtain a uniform solution B;
c) adding the uniform solution B obtained in the step B) into the uniform solution A obtained in the step a) to obtain a uniform emulsion C;
d) adding the uniform emulsion C obtained in step C) into a continuous aqueous phase prepared from a medicinal water-soluble polymer to form microspheres; preferably, the water-soluble polymer for medicine is polyvinyl alcohol; the concentration of the polyvinyl alcohol solution is 0.5-4%; the temperature of the continuous aqueous phase is 2-15 ℃, preferably 4 ℃.
e) Removing the organic solvent in the microspheres in the step d), filtering and washing;
f) freezing and drying the microspheres obtained in the step e) to obtain the slow 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, dimethyl formamide or dimethyl acetamide.
Further preferably, the first 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, dimethyl formamide or dimethyl acetamide.
Even more preferably, the first type of organic solvent is selected from dichloromethane. The second type of organic solvent is selected from any one of ethanol and acetic acid.
Adding the solution obtained in the step b) into the step a) by adopting an ultrasonic, vortex, homogenizing or stirring mode.
Adding the uniform emulsion C obtained in the step C) into a continuous water phase prepared from the medicinal water-soluble polymer by adopting an ultrasonic, vortex, homogenizing, high-pressure homogenizing or stirring mode.
Wherein the ultrasonic power is 200-400w, the vortex rotation speed is 2000-4000rpm, the homogenizing speed is 4000-20000rpm, and the high-pressure homogenizing is 600-1500 bar; the stirring speed was 1000-3000 rpm.
Preferably, the ratio of the first type of organic solvent to the second type of organic solvent is from 2:1 to 20: 1.
It is further preferred that the ratio of the first type of organic solvent to the second type of organic solvent is from 2:1 to 10: 1.
Has the advantages that: compared with the prior art, the pharmaceutical composition in the form of microspheres provided by the invention has the property of long-term drug release, and can release rasagiline in more than one month. The invention is characterized in that by using a suitable combination of 2 microspheres of different particle sizes in the pharmaceutical composition of the invention, fluctuations in the concentration of rasagiline in plasma can be significantly reduced without a significant delay in the release period. The invention is also characterized in that under the condition of high drug loading, the drug burst release phenomenon does not occur.
Drawings
FIG. 1 is a graph showing the release characteristics of the sustained-release microspheres obtained in examples 1, 1 to 2, 1 to 4 and 1 to 6, and it can be seen from the graph that in the ordinary particle size range, i.e., in the particle size range of 20 to 150 μm, although the release behavior of the microspheres in different particle size ranges is different, it is not obvious;
FIG. 2 is an in vitro release profile of the sustained release microspheres of example 1 (labeled example 1), of example 2 (labeled example 2), of two mixtures of example 1 and one mixture of example 2 (labeled example 1+ 2);
FIG. 3 is an in vitro release profile of the sustained release microspheres of example 3 (labeled example 3), the sustained release microspheres of example 4 (labeled example 4), three mixtures of example 1 and one mixture of example 4 (labeled example 3+ 4);
FIG. 4 is an in vitro release profile of the sustained release microspheres of example 5 (labeled example 5), the sustained release microspheres of example 6 (labeled example 6), three mixtures of example 5 and one mixture of example 6 (labeled example 5+ 6);
figure 5 is an in vitro release profile of the sustained release microspheres of example 7 (labeled example 7), the sustained release microspheres of example 8 (labeled example 8), two mixtures of example 7 and one mixture of example 8 (labeled example 7+ 8).
FIG. 6 is an in vitro release profile of the sustained release microspheres of example 9 (designated example 9), the sustained release microspheres of example 10 (designated example 10), five mixtures of example 9 and one mixture of example 10 (designated example 9+ 10).
FIG. 7 is an in vitro release profile of the sustained release microspheres of example 11 (designated example 11), the sustained release microspheres of example 12 (designated example 12), three mixtures of example 11 and two mixtures of example 12 (designated example 11+ 12).
Detailed Description
The technical solution of the present invention is described in detail below, but the scope of the present invention is not limited to the embodiments.
Example 1. sustained release microsphere preparation.
Dissolving 8.00g of PLGA (lactide/glycolide 65/35, hereinafter both lactide/glycolide, 0.65dl/g, 71kDa, ester group end group) in 80.00g of dichloromethane to obtain a uniform solution A; dissolving 2.00g of rasagiline in 10.00g of ethanol to obtain a uniform solution B; solution A was added to solution B under vortex conditions of 3000rpm to give homogeneous emulsion C. The homogeneous solution C was added to a 1.0% aqueous solution of polyvinyl alcohol at 4 ℃ and stirred using a mechanical stirrer at 2000rpm to prepare microspheres. And then heating to 40 ℃ to volatilize the organic solvent, then filtering the microspheres, washing the microspheres 7 times by using water for injection, and then freeze-drying to obtain the sustained-release microspheres.
Example 2. preparation of sustained release microspheres.
8.00g of PLGA (65/35, 0.65dl/g, 71kDa, ester end group) was dissolved in 80.00g of dichloromethane to give a homogeneous solution A; dissolving 2.00g of rasagiline in 10.00g of ethanol to obtain a uniform solution B; under the ultrasonic condition, the power is 300w, and the solution A is added into the solution B to obtain uniform emulsion C. Adding the uniform solution C into 1.0% polyvinyl alcohol continuous water phase at 4 ℃, and homogenizing under high pressure of 900bar to prepare the microspheres. Then heating to 40 ℃ to volatilize the organic solvent, then filtering the microspheres to remove the continuous water phase, washing the microspheres for 7 times by using water for injection, and then freeze-drying to obtain the sustained-release microspheres.
Example 3. preparation of sustained release microspheres.
Dissolving 7.00g PLGA (75/25, 0.5dl/g, 57kDa, carboxyl end group) in 70.00g ethyl acetate to obtain a uniform solution A; dissolving 3.00g of rasagiline in 15.00g of acetic acid to obtain a uniform solution B; solution A was added to solution B under vortex conditions of 3000rpm to give homogeneous emulsion C. The homogeneous solution C was added to a 0.5% polyvinyl alcohol continuous aqueous phase at 4 ℃ and homogenized using a homogenizer at 4000rpm to prepare microspheres. And then heating to 40 ℃ to volatilize the organic solvent, then filtering the microspheres, washing the microspheres 7 times by using water for injection, and then freeze-drying to obtain the sustained-release microspheres.
Example 4. preparation of sustained release microspheres.
Dissolving 7.00g PLGA (75/25, 0.5dl/g, 57kDa, carboxyl end group) in 70.00g ethyl acetate to obtain a uniform solution A; dissolving 3.00g of rasagiline in 15.00g of acetic acid to obtain a uniform solution B; solution A was added to solution B under a vortex at 4000rpm to give a homogeneous emulsion C. Adding the uniform solution C into 0.5 percent polyvinyl alcohol continuous water phase at 4 ℃, and homogenizing under high pressure of 1000bar to prepare the microspheres. And then heating to 40 ℃ to volatilize the organic solvent, then filtering the microspheres, washing the microspheres 7 times by using water for injection, and then freeze-drying to obtain the sustained-release microspheres.
Example 5 preparation of sustained release microspheres.
6.00g PLGA (85/15, 0.4dl/g, 46kDa, carboxyl end group) was dissolved in 60.00g dichloromethane to give a homogeneous solution A; dissolving 4.00g of rasagiline in 20.00g of ethanol to obtain a uniform solution B; under the ultrasonic condition, the power is 300w, and the solution A is added into the solution B to obtain uniform emulsion C. The homogeneous solution C was added to a 0.5% continuous aqueous phase of polyvinyl alcohol at 4 ℃ and the microspheres were prepared using mechanical stirring at 1000 rpm. And then heating to 40 ℃ to volatilize the organic solvent, then filtering the microspheres, washing the microspheres 7 times by using water for injection, and then freeze-drying to obtain the 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 dichloromethane to give a homogeneous solution A; dissolving 4.00g of rasagiline in 20.00g of ethanol to obtain a uniform solution B; solution A was added to solution B under a vortex at 4000rpm to give a homogeneous emulsion C. Adding the uniform solution C into 1.5 percent polyvinyl alcohol continuous water phase at 4 ℃, and homogenizing under high pressure of 1000bar to prepare the microspheres. And then heating to 40 ℃ to volatilize the organic solvent, then filtering the microspheres, washing the microspheres 7 times by using water for injection, and then freeze-drying to obtain the sustained-release microspheres.
Example 7 preparation of sustained release microspheres.
Dissolving 5.00g PLGA (100/0, 0.65dl/g, 73kDa, ester group end group) in 50.00g tetrahydrofuran to obtain a uniform solution A; dissolving 5.00g of rasagiline in 25.00g of dimethyl sulfoxide to obtain a uniform solution B; under the ultrasonic condition, the power is 400w, and the solution A is added into the solution B to obtain uniform emulsion C. The homogeneous solution C was added to a 0.5% continuous aqueous phase of polyvinyl alcohol at 4 ℃ and the microspheres were prepared using mechanical stirring at 1000 rpm. And then heating to 40 ℃ to volatilize the organic solvent, then filtering the microspheres, washing the microspheres 7 times by using water for injection, and then freeze-drying to obtain the sustained-release microspheres.
Example 8 preparation of sustained release microspheres.
5.00g PLGA (100/0, 0.45dl/g, 53kDa, carboxyl end group) was dissolved in 50.00g tetrahydrofuran to give a homogeneous solution A; dissolving 5.00g of rasagiline in 25.00g of dimethyl sulfoxide to obtain a uniform solution B; solution A was added to solution B under a vortex at 4000rpm to give a homogeneous emulsion C. Adding the uniform solution C into 1.5 percent polyvinyl alcohol continuous water phase at 4 ℃, and homogenizing under high pressure of 1000bar to prepare the microspheres. And then heating to 40 ℃ to volatilize the organic solvent, then filtering the microspheres, washing the microspheres 7 times by using water for injection, and then freeze-drying to obtain the sustained-release microspheres.
Example 9 preparation of sustained release microspheres.
6.00g PLGA (75/25, 0.6dl/g, 69kDa, ester end group) was dissolved in 100.00g dimethyl sulfoxide to obtain a homogeneous solution A; dissolving 4.00g of rasagiline in 10.00g of dimethylformamide to obtain a uniform solution B; solution A was added to solution B with mechanical stirring at 2000rpm to give homogeneous emulsion C. The homogeneous solution C was added to a 3.0% continuous aqueous phase of polyvinyl alcohol at 10 ℃ and the microspheres were prepared using 1500rpm mechanical agitation. And then heating to 40 ℃ to volatilize the organic solvent, then filtering the microspheres, washing the microspheres 7 times by using water for injection, and then freeze-drying to obtain the sustained-release microspheres.
Example 10 preparation of sustained release microspheres.
6.00g of PLGA (65/35, 0.5dl/g, 58kDa, carboxyl end group) was dissolved in 150.00g of dimethylformamide to give a homogeneous solution A; dissolving 4.00g of rasagiline in 8.00g of acetic acid to obtain a uniform solution B; under the homogeneous condition of 4000rpm, the solution A is added into the solution B to obtain a uniform emulsion C. Adding the uniform solution C into a 3.0% polyvinyl alcohol continuous water phase at 10 ℃, and preparing microspheres under the high-speed homogenization condition of 10000 rpm. And then heating to 40 ℃ to volatilize the organic solvent, then filtering the microspheres, washing the microspheres 7 times by using water for injection, and then freeze-drying to obtain the sustained-release microspheres.
Example 11 preparation of sustained release microspheres.
6.50g of PLGA (85/15, 0.75dl/g, 81kDa, carboxyl end groups) was dissolved in 150.00g of dichloromethane to give a homogeneous solution A; dissolving 3.50g of rasagiline in 10.00g of acetic acid to obtain a uniform solution B; solution A was added to solution B under vortex conditions of 2000rpm to give homogeneous emulsion C. Adding the uniform solution C into a 4.0% polyvinyl alcohol continuous water phase at 15 ℃, and homogenizing under high pressure of 600bar to prepare microspheres. And then heating to 40 ℃ to volatilize the organic solvent, then filtering the microspheres, washing the microspheres 7 times by using water for injection, and then freeze-drying to obtain the sustained-release microspheres.
Example 12 preparation of sustained release microspheres.
6.50g of PLGA (100/0, 0.3dl/g, 27kDa, ester end group) was dissolved in 50.00g of dichloromethane to give a homogeneous solution A; dissolving 3.50g of rasagiline in 10.00g of acetic acid to obtain a uniform solution B; solution A was added to solution B with mechanical stirring at 2000rpm to give homogeneous emulsion C. Adding the uniform solution C into a 4.0% polyvinyl alcohol continuous water phase at 15 ℃, and homogenizing under high pressure of 1500bar to prepare microspheres. And then heating to 40 ℃ to volatilize the organic solvent, then filtering the microspheres, washing the microspheres 7 times by using water for injection, and then freeze-drying to obtain the sustained-release microspheres.
Example 13 determination of microsphere Process recovery.
The sustained-release microspheres obtained after lyophilization in examples 1 to 12 were respectively weighed, and the process recovery rates were calculated, with the results shown in table 1. Wherein, the process recovery rate is 100 percent of the weight of the microspheres after freeze-drying/feeding amount
TABLE 1
| Item | 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 released microspheres is determined by a laser particle size tester. Pump speed 40%, measurement time 90s, wait time 30s, PIDS set to "on", and number of measurements 1. During the determination, a proper amount of the sustained-release microspheres are taken, 5-10 drops of 1% surfactant solution are added, then 1ml of water is added, and the mixture is uniformly mixed. The instrument was opened and sample was added to the cell until the opacity was 8-12%, the results were recorded and 3 replicates were taken and the results are shown in table 2. Where D10 represents the number of microspheres smaller than this particle size at 10% of the total, D50 represents the median particle size, i.e. the number of microspheres smaller than this particle size at 50% of the total, and D90 represents the number of microspheres smaller than this particle size at 90% of the total.
TABLE 2
| Item | 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 rasagiline content determination.
Precisely weighing the sustained-release microspheres, adding acetonitrile to disperse the microspheres, adding a triethylamine-glacial acetic acid buffer solution with a pH value of 6.5-acetonitrile (52: 48) mobile phase for dissolving, and quantifying to about 100 mu g/ml of a test sample. Preparing a reference substance by the same method. The results of HPLC measurements are shown in Table 3. The content is the percentage content of the drug in the weight of the microsphere. Content is drug amount/microsphere amount 100
TABLE 3
Example 16. sustained release microsphere release characteristics.
Screening the slow-release microspheres: a part of the sustained-release microspheres obtained in the freeze-dried process of example 1 is sieved by using 100, 115, 150, 175, 230, 325 and 500-mesh sieves respectively to obtain microspheres with different mesh numbers, which are marked as example 1-1 to example 1-6, and are shown in Table 4. Used for observing the difference of the release behaviors of microspheres with different particle sizes in a common particle size range, namely a range of 20-150 mu m. The following meanings: for example, example 1-1 shows 100-115 mesh microspheres obtained after sieving a portion of example 1.
TABLE 4
| Item | Number of meshes |
| Examples 1 to 1 | 100-115 |
| Examples 1 to 2 | 115-150 |
| Examples 1 to 3 | 150-175 |
| Examples 1 to 4 | 175-230 |
| Examples 1 to 5 | 230-325 |
| Examples 1 to 6 | 325-500 |
The sustained release microspheres prepared in examples 1 to 12 and the microspheres sieved to different particle sizes from example 1, namely, examples 1-2, examples 1-4 and examples 1-6 were taken for in vitro release.
The test method comprises the following steps: microspheres (30mg) were precisely weighed, 100ml of PBS pH 7.4 was added as release medium, and the release experiments were performed in a 37 ℃ water bath shaker. The shaker rotates at 100rpm and the sample is removed and allowed to stand for a fixed period of time, and the supernatant is then taken and passed through a 0.45 μm microfiltration membrane while being supplemented with fresh release medium and the content is determined by HPLC. Each batch of microspheres was run in triplicate. The release data are shown in table 5, table 6, and fig. 1 to 7 below.
As is clear from the results of examples 1-1, 1-4 and 1-6, the release behavior of microspheres in the range of ordinary particle size, i.e., in the range of particle size of 20-150 μm, is not obvious, although it is different.
As can be seen from the release behaviors of example 1, example 3, example 5, example 7, example 9 and example 11, the release period of the microspheres is longer in the ordinary particle size range, namely, between 20 and 150 μm, but a delayed release period occurs; from the release data of examples 2, 4, 6, 8, 10 and 12, it can be seen that the release period of the microspheres is short, but there is no delayed release period and no burst release in the range of nanometer to submicron particle size, i.e. 0.5-5 microns.
By mixing the nano-to submicron-sized microspheres and the ordinary-sized microspheres according to a certain proportion, for example, the release period of example 1 is 30 days, the delayed release period is 10 days, and the release period of example 2 is 10 days, and no delayed release period exists. Then embodiment 1 may be used in combination with embodiment 2. Just as the microspheres of example 2 are responsible for the early release of the combination, the microspheres of example 1 are responsible for the late release. If the required dose of drug is 3 parts for the entire release cycle, example 1 provides two parts and example 2 provides one part. Specifically, if the drug dosage required for the entire release cycle is 30mg, then example 1 needs to provide 20mg of drug, i.e. 72.73mg of microspheres (microsphere weight ═ required drug amount/content); example 2 required 10mg of drug to be provided, i.e. 37.17mg of microspheres; by analogy, three portions of example 3 were mixed with one portion of example 4 (about 5.7 weeks of release period), three portions of example 5 were mixed with one portion of example 6 (about 8.6 weeks of release period), two portions of example 7 were mixed with one portion of example 8 (about 12 weeks of release period), five portions of example 9 were mixed with one portion of example 8 (about 6 weeks of release period), three portions of example 11 were mixed with two portions of example 12 (about 7 weeks of release period), and then in vitro release experiments were performed to obtain a pharmaceutical composition with a release period of 4-12 weeks, no burst release period, and no delayed release period. The mixing is performed on the premise that the release period of the nano-to submicron microspheres can be just overlapped with the delayed release period of the microspheres with the common particle size. Examples 2/4/6/8/10/12 correspond to the nano-to submicron size microspheres of example 1/3/5/7/9/11, respectively, which when combined achieve a longer release period without a delayed release period.
TABLE 5
TABLE 6
In conclusion, in the conventional particle size range of the microspheres, the release period and the delayed release period of the microspheres are actually shortened with the decrease of the particle size of the microspheres, but the change is not obvious. In addition, the creative discovery shows that when the microspheres are prepared into a submicron level, the release behavior of the microspheres is obviously changed, firstly, the release period is not delayed and not burst, and secondly, the release period is obviously shortened. It has also been unexpectedly found that the release period of the submicron-sized microspheres of the present invention is the same as the delayed release period of conventional particle-sized microspheres. By mixing two microspheres with different particle sizes, a product with a longer release period is obtained, and the delayed release period is avoided. By using the technical scheme, the microspheres with high drug loading capacity and high encapsulation rate can be obtained, and the proper combination of 2 microspheres with different particle sizes is used in the pharmaceutical composition disclosed by the invention, so that the fluctuation of the concentration of rasagiline in blood plasma can be obviously reduced, and no obvious delayed release period exists. Meanwhile, the invention has no burst release of the medicine under the condition of high medicine-loading rate.
Claims (8)
1. A long-acting sustained-release preparation of a drug for treating Parkinson's disease, which is characterized in that the long-acting sustained-release preparation is microspheres, the microspheres comprise rasagiline or a pharmaceutically acceptable salt thereof and a biodegradable biocompatible high polymer, the microspheres comprise microspheres with an average particle size of 0.5-5 μm and microspheres with an average particle size of 20-150 μm, the microspheres with an average particle size of 0.5-5 μm account for 10-50wt% of the long-acting sustained-release preparation, the microspheres with an average particle size of 20-150 μm account for 50-90 wt%, and the biodegradable biocompatible high polymer is poly (lactide-glycolide).
2. The long-acting sustained-release formulation according to claim 1, wherein rasagiline or a pharmaceutically acceptable salt of rasagiline accounts for 10-50wt% of the long-acting sustained-release formulation.
3. The long-acting sustained-release formulation according to claim 1, wherein the poly (lactide-glycolide) has a molar ratio of lactide to glycolide of 65: 35-100: 0.
4. the long-acting sustained-release formulation according to claim 3, wherein the poly (lactide-glycolide) has a viscosity in the range of 0.2 to 0.8 dl/g.
5. The long-acting sustained-release formulation according to claim 3, wherein the poly (lactide-glycolide) has a molecular weight in the range of 21kDa to 89 kDa.
6. The long-acting sustained-release preparation according to claim 1, wherein the release period of the long-acting sustained-release preparation is 4 to 12 weeks.
7. The method for preparing a long-acting sustained-release preparation of a drug for treating Parkinson's disease according to claim 1, which comprises the following steps:
a) dissolving biodegradable biocompatible polymer in a first organic solvent to obtain a uniform solution A; wherein, the first organic solvent is selected from any one of dichloromethane, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide or dimethylacetamide;
b) dissolving rasagiline or a pharmaceutically acceptable salt thereof in a second organic solvent which is mutually soluble with the first organic solvent to obtain a uniform solution B; wherein the second organic solvent is selected from any one of ethanol, acetic acid, hydrochloric acid, dimethyl sulfoxide, dimethylformamide or dimethylacetamide;
c) adding the uniform solution B obtained in the step B) into the uniform solution A obtained in the step a) to obtain a uniform emulsion C;
d) adding the uniform emulsion C obtained in the step C) into a continuous aqueous phase solution prepared from a medicinal water-soluble polymer to form microspheres;
e) removing the organic solvent in the microspheres in the step d), filtering and washing;
f) freezing and drying the microspheres obtained in the step e) to obtain the slow release microspheres.
8. The method of claim 7, 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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| Controlled release of rasagiline mesylate promotes neuroprotection in a rotenone-induced advanced model of Parkinson"s disease;M.Fernandez;《International Journal of Pharmaceutics》;20121115;第438卷(第1-2期);266-278 * |
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