Perampanel sustained release microsphere, pharmaceutical preparation and preparation method based on membrane emulsification

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a perampanel sustained release microsphere, a pharmaceutical preparation and a preparation method based on membrane emulsification. The invention firstly provides a preparation method which comprises the following steps: (1) dissolving perampanel and a polylactic acid-glycolic acid copolymer in an organic solvent to prepare an oil phase; (2) preparing a water phase; (3) adding the oil phase into the water phase to prepare a pre-emulsion; (4) adding the pre-emulsion into a membrane emulsifier, and dispersing to obtain an emulsion; and (5) curing to obtain the drug microspheres. By strictly controlling the membrane emulsification process, the drug microspheres with uniform size and stable quality are obtained.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a perampanel sustained-release microsphere, a pharmaceutical formulation, and a preparation method based on membrane emulsification. Background Technology

[0002] Perampanel is a novel antiepileptic drug. Epilepsy patients need to take it for a long time, and stable blood drug concentrations are expected to reduce the incidence of adverse reactions. Therefore, the development of long-acting sustained-release formulations of perampanel has important clinical significance.

[0003] Perampanel is prone to drug escape, forming drug crystals on the surface of microspheres or in aqueous solutions, making the preparation of stable, long-acting sustained-release perampanel microspheres challenging. Patent CN120241620A, entitled "A Donepezil Sustained-Release Microsphere and its Preparation Method, Pharmaceutical Formulation, and Use," discloses a process in which an aqueous and oil phases are prepared separately, the oil phase is then added to the aqueous phase for dispersion to form a pre-emulsion, the pre-emulsion is further emulsified through a membrane to form an emulsion, and finally, the pre-emulsion is solidified to form donepezil sustained-release microspheres. Patent CN113018277A, entitled "Sustained-Release Formulation for Injection and its Preparation Method," discloses a method for preparing an oil-in-water pre-emulsion, followed by membrane emulsification to obtain a secondary emulsion, and finally solidification to obtain semaglutide sustained-release microspheres for injection.

[0004] The preparation of drug-loaded microspheres via membrane emulsification is influenced by numerous factors, easily leading to problems such as uneven microsphere size and unstable drug loading. Therefore, strict control of process conditions is necessary, but this process is often time-consuming and labor-intensive due to the large number of conditions requiring adjustment. Therefore, in-depth research is needed on the influence of process parameters in the preparation of drug microspheres using membrane emulsification methods. Summary of the Invention

[0005] The purpose of this invention is to provide a perampanel sustained-release microsphere, a pharmaceutical formulation, and a membrane emulsification-based preparation method, which partially solves or alleviates the above-mentioned deficiencies in the prior art. The specific technical solution adopted by this invention is as follows.

[0006] A first aspect of the present invention is to provide a method for preparing drug microspheres based on a membrane emulsification process.

[0007] A method for preparing perampanel sustained-release microspheres based on membrane emulsification process includes the following steps: S01: The oil phase is prepared by dissolving perampanel and polylactic acid-glycolic acid copolymer in an organic solvent; S02: Prepare an aqueous phase containing surfactant; S03: The oil phase is added to the aqueous phase and a preemulsion is obtained by mechanical stirring; S04: The pre-emulsion is added to a membrane emulsifier for emulsification and dispersion to obtain an emulsion; S05: The emulsion is solidified under heating and stirring to obtain the perampanel sustained-release microspheres.

[0008] Furthermore, the molar ratio of LA to GA in the polylactic acid-glycolic acid copolymer ranges from 50:50 to 85:15; the intrinsic viscosity of the polylactic acid-glycolic acid copolymer ranges from 0.15 to 0.7 dL / g.

[0009] Furthermore, the organic solvent used to prepare the oil phase includes dichloromethane, ethyl acetate, chloroform, or acetone.

[0010] Furthermore, the surfactant used to prepare the aqueous phase includes polyvinylpyrrolidone, polyvinyl alcohol, or Tween 80; the mass ratio of the surfactant ranges from 1% to 5%.

[0011] Furthermore, the membrane pore size of the membrane emulsifier ranges from 8 to 25 μm.

[0012] Furthermore, an operating pressure is applied during the membrane emulsification process, the operating pressure being in the range of 0.1-1.0 kPa.

[0013] In some preferred embodiments, the operating pressure ranges from 0.1 to 0.5 or from 0.5 to 1.0 kPa.

[0014] Furthermore, the temperature for heating and stirring is set to 4℃ ~ 40℃.

[0015] Furthermore, in SO3, the volume ratio of the oil phase to the aqueous phase is 1:10; or, in SO4, the volume ratio of the preemulsion to the aqueous phase ranges from 1:10 to 1:50.

[0016] In some preferred embodiments, the volume ratio of the preemulsion to the aqueous phase in S04 includes 1:10, 1:25, or 1:50.

[0017] Another aspect of the present invention is to provide perampanel sustained-release microspheres prepared by the above-described preparation method.

[0018] A final aspect of the present invention is to provide a pharmaceutical formulation comprising the above-described perampanel sustained-release microspheres.

[0019] Beneficial technical effects: This invention first provides a method for preparing perampanel sustained-release microspheres based on a membrane emulsification process. This invention, through strict control of the membrane emulsification process, first obtains a pre-emulsion by mechanically stirring a dispersed phase (oil phase) and a continuous phase (aqueous phase). The pre-emulsion is then passed through a membrane emulsifier to obtain an emulsion, which is then heated and solidified to obtain uniform and stable drug microspheres. This invention discovers that membrane parameters (pore size, material), process parameters (flow rate, pressure, temperature), and material properties affect the effectiveness of membrane emulsification. Furthermore, this invention also provides perampanel sustained-release microspheres prepared based on this membrane emulsification process and drug formulations comprising these microspheres. Attached Figure Description

[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. In all the drawings, similar elements or parts are generally identified by similar reference numerals. The elements or parts in the drawings are not necessarily drawn to scale. Obviously, the drawings described below are some embodiments of the present invention, and those skilled in the art can obtain other drawings based on these drawings without any creative effort.

[0021] Figure 1 The cumulative release rate of the perampanel microspheres prepared in one embodiment of the present invention is shown below. Figure 2 This illustrates the effect of operating pressure on the particle size of membrane emulsified microspheres in one embodiment of the present invention. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0023] In this document, "and / or" includes any and all combinations of one or more of the listed related items.

[0024] In this article, "multiple" means two or more, that is, it includes two, three, four, five, etc.

[0025] As used in this specification, the term "about" typically means + / -5% of the value, more typically + / -4% of the value, more typically + / -3% of the value, more typically + / -2% of the value, even more typically + / -1% of the value, and even more typically + / -0.5% of the value.

[0026] In this specification, certain embodiments may be disclosed in a range-bound format. It should be understood that this "range-bound" description is merely for convenience and brevity and should not be construed as a rigid limitation on the disclosed range. Therefore, the description of a range should be considered as having specifically disclosed all possible subranges and the individual numerical values ​​within those ranges. For example, a description of the range 1-6 should be considered as having specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and the individual numbers within those ranges, such as 1, 2, 3, 4, 5, and 6. This rule applies regardless of the breadth of the range.

[0027] Example 1 This embodiment provides an example of preparing perampanel sustained-release microspheres based on a membrane emulsification method.

[0028] The microsphere preparation steps are as follows: (1) Weigh appropriate amounts of perampanel and PLGA, dissolve them in dichloromethane, and prepare an oil phase; prepare an aqueous phase using a 1.0% polyvinyl alcohol (PVA) aqueous solution. Add the oil phase to the aqueous phase and prepare a pre-emulsion by mechanical stirring; the stirring time is about 30s, and the speed is set to 300rpm.

[0029] (2) The pre-emulsion was poured into a rapid membrane emulsifier for emulsification and dispersion. The organic solvent was removed from the pre-emulsion at a stirring speed of 200 rpm and a temperature of 40°C. The pre-emulsion was allowed to evaporate and solidify for about 3 hours. After solidification, the pre-emulsion was washed and freeze-dried to obtain perampanel sustained-release microspheres.

[0030] The key processes in the microsphere preparation were explored through different experimental examples, as shown in Table 1.

[0031] Table 1 Experimental Groups Remark: (1) LA and GA represent two monomers of polylactic acid-glycolic acid copolymer: LA represents lactide and GA represents glycolide.

[0032] (2) Determination of intrinsic viscosity: Ubbelohde viscometer method, according to the specified method (method 2) for determining intrinsic viscosity in the Chinese Pharmacopoeia.

[0033] (3) Membrane pore size refers to the pore size of the membrane used in the membrane emulsification process.

[0034] (4) Operating pressure refers to the operating pressure during the membrane emulsification process.

[0035] The average particle size of the sustained-release microspheres was determined using particle size and particle size distribution assays. The drug loading and encapsulation efficiency of the prepared sustained-release microspheres were determined using high-performance liquid chromatography (HPLC).

[0036] In vitro cumulative release assay: 10 mg of microspheres and PBS buffer (pH 7.4) from Examples 1-4 were placed in 250 mL Erlenmeyer flasks and incubated at 37 °C on a water bath shaker. At the sampling time, 1 mL of solution was taken from each Erlenmeyer flask and the same amount of PBS buffer was added. The pH of the release medium was monitored and maintained at approximately pH 7.4. The samples were analyzed by high-performance liquid chromatography (HPLC), the cumulative release percentage was calculated, and a release rate curve was plotted as a cumulative release percentage versus time.

[0037] The in vitro release results of the microspheres prepared in Examples 1-4 above are shown in the figure. Figure 1 It is evident that the choice of PLGA type has a significant impact on the release of drug microspheres.

[0038] Furthermore, with the same membrane pore size (15 μm), increasing the operating pressure resulted in an increase in drug particle size.

[0039] Comparative Example 1 An experimental procedure for a traditional emulsification method is provided: (1) Weigh appropriate amounts of perampanel and PLGA, dissolve them in dichloromethane, and prepare an oil phase; prepare an aqueous phase using a 1.0% aqueous solution of polyvinyl alcohol (PVA). Add the oil phase to the aqueous phase and prepare an emulsion by mechanical stirring; the stirring time is about 30s, and the speed is set to 300rpm.

[0040] (2) Remove the organic solvent from the emulsion by stirring at 200 rpm and at 40°C, and allow it to evaporate and solidify for about 3 hours. After solidification, wash and freeze dry to obtain perampanel sustained-release microspheres.

[0041] The average particle size of the sustained-release microspheres was determined using particle size and particle size distribution assays. The drug loading and encapsulation efficiency of the prepared sustained-release microspheres were determined using high-performance liquid chromatography (HPLC). The results are shown in Table 2.

[0042] Table 2 Table 3 Table 4 Table 5 The main difference between Experimental Examples 20-23 and Experimental Example 1 is the theoretical drug loading. The difference in theoretical drug loading is mainly achieved through the difference in feed amount. A lower theoretical drug loading results in higher microsphere encapsulation efficiency, more uniform particle size distribution, and a more controllable preparation process.

[0043] Table 6 The main difference between Experimental Examples 24-26 is the curing temperature. The results show that when the curing temperature is 40℃, the resulting microspheres have a more uniform particle size distribution.

[0044] in conclusion: (1) By Figure 1 It is known that the perampanel sustained-release microspheres prepared by this invention have the ability to release stably over a long period of time. Different types of PLGA have different release cycles, and the higher the proportion of LA, the longer the release cycle of the microspheres.

[0045] (2) By Figure 2 It is evident that operating pressure is a crucial preparation condition in microporous membrane emulsification. Membrane pressure significantly influences emulsion droplet size and distribution, as well as droplet morphology. Higher operating pressure results in greater dispersed phase flux, faster droplet formation rate, larger droplet size, and a wider droplet size distribution.

[0046] (4) As can be seen from the results in Table 2, compared with the traditional emulsification method, the selective permeability of the membrane allows the dispersed phase and the continuous phase to be emulsified through the membrane pores, which can form more uniform droplets.

[0047] (5) As can be seen from the results in Table 3, the size of the membrane pores is an important factor affecting the size of the microspheres. As the pore size of the microporous membrane increases, the particle size of the resulting microspheres increases. The ratio of the average particle size of the microspheres to the pore size of the microporous membrane used is between 3 and 4. (6) To prevent drug escape of perampanel, drug crystals were formed on the surface of the microspheres or in the aqueous solution. Factors such as emulsification temperature and solidification process were controlled. The addition of long chains of polymeric stabilizers such as PVP (polyvinylpyrrolidone) and PVA (polyvinyl alcohol) can physically block crystal growth or compete with drug molecules for binding sites. As shown in Table 2, the concentration and type of aqueous stabilizer have little effect on the drug loading and encapsulation efficiency of perampanel microspheres.

[0048] (7) The theoretical drug loading is an important factor affecting drug crystallization. The higher the loading, the easier it is for drug molecules to approach each other and nucleate and crystallize. As shown in Table 3, reducing the drug loading can effectively improve the microsphere encapsulation efficiency, and make them more uniform with a narrower particle size distribution.

[0049] (8) Lowering the curing phase temperature (4℃) can reduce the diffusion rate of the drug and solvent, thereby reducing drug escape. Increasing the curing phase temperature (40℃) can rapidly solidify the microspheres, thereby reducing drug crystallization. As shown in Table 4, when the curing phase temperature is 40℃, the encapsulation efficiency of the microspheres is higher and the particle size distribution is narrower, indicating that increasing the curing phase temperature can rapidly solidify the microspheres, thereby effectively reducing drug crystallization.

[0050] The embodiments of the present invention have been described above with reference to the accompanying drawings. However, the present invention is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of the present invention without departing from the spirit and scope of the claims. All of these forms are within the protection scope of the present invention.

Claims

1. A process for the preparation of pirfenidone sustained release microspheres based on membrane emulsification process, characterized by, The method comprises the following steps: S01: preparing an oil phase by dissolving pirfenidone in an organic solvent and polylactic acid-glycolic acid copolymer; S02: preparing an aqueous phase containing a surfactant; S03: adding the oil phase into the aqueous phase to obtain a pre-emulsion by mechanical stirring; S04: emulsifying and dispersing the pre-emulsion in a membrane emulsifier to obtain an emulsion; S05: solidifying the emulsion under heating and stirring to obtain the pirfenidone sustained-release microspheres.

2. The method of claim 1, wherein, The molar ratio of LA to GA in the polylactic acid-glycolic acid copolymer ranges from 50:50 to 85:15; and the intrinsic viscosity of the polylactic acid-glycolic acid copolymer ranges from 0.15 to 0.7 dL / g.

3. The method of claim 1, wherein, The organic solvent for preparing the oil phase includes dichloromethane, ethyl acetate, chloroform or acetone.

4. The method of claim 1, wherein, The surfactant for preparing the aqueous phase includes polyvinylpyrrolidone, polyvinyl alcohol or Tween 80; and the mass ratio of the surfactant ranges from 1% to 5%.

5. The method of claim 1, wherein, The membrane aperture of the membrane emulsifier ranges from 8 to 25 μm.

6. The method of claim 1, wherein, An operating pressure is applied in the process of membrane emulsification, and the operating pressure ranges from 0.1 to 1.0 kPa.

7. The method of claim 1, wherein, The temperature of the heating and stirring is set to range from 4 to 40℃.

8. The method of claim 1, wherein, The volume ratio of the oil phase to the aqueous phase in S03 is 1:10; or the volume ratio of the pre-emulsion to the aqueous phase in S04 ranges from 1:10 to 1:

50.

9. The pirfenidone sustained-release microspheres prepared by the method of any one of claims 1-8.

10. A pharmaceutical preparation comprising the pirfenidone sustained-release microspheres of claim 9.

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