CN105664261B - A method of preparing the injectable implant - Google Patents

A method of preparing the injectable implant Download PDF

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CN105664261B
CN105664261B CN201610091590.2A CN201610091590A CN105664261B CN 105664261 B CN105664261 B CN 105664261B CN 201610091590 A CN201610091590 A CN 201610091590A CN 105664261 B CN105664261 B CN 105664261B
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polylactic acid
particles
method according
production method
oil phase
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CN105664261A (en
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王志强
丁劲松
谭建雄
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江苏西宏生物医药有限公司
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Abstract

本发明揭示了种改进的聚乳酸注射植入剂的制备方法,该方法包括:1)、制备聚乳酸颗粒;2)、制备羧甲基纤维素的水凝胶液;3)、上述聚乳酸颗粒分散于上述凝胶液中成混悬液;4)、上述混悬液在上述步骤3之后被冷冻干燥成固态物。 The present invention discloses a method of producing an improved injectable implant polylactic acid, the method comprising: 1), polylactic acid particles; 2), carboxymethylcellulose hydrogel prepared glue; 3), the polylactic acid the gel particles are dispersed in the above solution into a suspension; 4) the suspension is freeze-dried into a solid product after step 3 above. 在制备上述聚乳酸颗粒中包含:(1)、形成聚乳酸为油相的水包油型乳剂;(2)、上述的聚乳酸油相在压力下在高于其开始固化的温度5℃以内的温度下过筛网后30秒钟内被固化成聚乳酸颗粒;(3)、再过孔径相对较小的筛,未过的部分被留用。 In the preparation of the above-described polylactic acid particles comprising: (a) forming an oil phase polylactic acid oil-in-water emulsion; (2) the oil phase polylactic acid at a pressure above its starts to solidify within a temperature 5 ℃ after through the screen at a temperature of polylactic acid is solidified into particles within 30 seconds; (3), another relatively small screen pore size, the portion had not been retained. 该方法简化了工艺,提高了工作效率,降低了浪费;此外提高该制剂的通针性及聚乳酸降解的均性。 This approach simplifies the process, improve efficiency and reduce waste; Further increase of the formulation through the needle and the average degradation of the polylactic acid.

Description

_种注射植入剂的制备方法 _ Injectable preparation methods of the implant

技术领域 FIELD

[0001]本发明涉及一种注射植入剂的制备方法。 [0001] The present invention relates to a method for implanting an injection agent. 具体来说,涉及一种改进的聚乳酸注射植入剂的制备方法。 Particularly, it relates to an improved method for preparing polylactic acid of injectable implant.

背景技术 Background technique

[0002]聚乳酸(polylactide, PLA)及其共聚物是一类高分子聚合材料,具有优良的生物相容性和生物可降解性,最终降解产物是二氧化碳和水,中间产物乳酸也是体内正常糖代谢的产物,所以不会在重要器官聚集,对人体无毒、无刺激。 [0002] The polylactic acid (polylactide, PLA) and its copolymers are a class of polymer materials with excellent biocompatibility and biodegradability, the ultimate degradation products are carbon dioxide and water, of lactic acid is an intermediate body normal glucose metabolic product, so it will not gather the vital organs of the human body non-toxic, non-irritating. 经美国食品药品管理局(FDA)批准认可,已成为一种备受关注的可生物降解的生物医用高分子材料。 Approved by the US Food and Drug Administration (FDA) approved the accreditation, it has become a concern of biodegradable biomedical polymer material. 广泛地应用于骨科内固定材料、骨替代材料、医用缝线、药物载体、组织工程支架、生物引导膜等不同领域。 Widely used in orthopedic fixation material, bone substitute material, medical sutures, drug delivery, tissue engineering scaffold, bio-guiding film in different areas.

[0003] PLA制剂Sculptra已被美国食品药品管理局(FDA)批准其美容用途,用于改善法令纹(笑纹)等皱纹的成效,其适应症包括减退法令纹(虎纹)、减退嘴角纹、减退面颊皱纹、饱满下陷额侧、抚平泪沟、收紧腮腺、饱满太阳穴、任何需填充饱满的位置。 [0003] PLA preparation Sculptra has been the United States Food and Drug Administration (FDA) approved its cosmetic use, for improving the nasolabial folds (laugh lines) such as the effectiveness of wrinkles, loss indications including nasolabial folds (tiger), loss marionette lines, loss cheek wrinkles, sagging full frontal, heal the tear trough, the tightening of the parotid gland, full of temples, no need to fill the full position. Sculptra为冻干粉针剂,每支含物料367.5mg,其中,聚乳酸150mg,聚乳酸颗粒的平均粒径为40 — 63微米,此外还有辅料甘露醇及作为助悬剂的羧甲基纤维素(钠),使用时用5ml无菌注射用水重构(复溶)成混悬液。 Sculptra is freeze-dried powder, each containing material 367.5mg, wherein the polylactic acid 150mg, polylactic acid particles have an average particle diameter of 40--63 microns, and mannitol as excipients in addition to suspending agent is carboxymethyl cellulose (sodium), using (reconstituted) into a suspension reconstituted with 5ml sterile water for injection.

[0004] PLA制剂(Sculptra)采用的方法制备一般如附图所示。 [0004] PLA formulation (Sculptra) prepared as shown in the drawings generally employed. 该方法中通过筛分除去聚乳酸颗粒粒径较大及较小的部分,仅保留中间一小部分的聚乳酸颗粒(40 — 63微米)。 The process by removing portions of larger and smaller particle size sieving polylactic acid, polylactic acid particles retain only a small fraction of intermediate (40--63 microns). 该方法产率较低,物耗、能耗较大,此外,制得的聚乳酸颗粒圆整度还有待提高,圆整度可能影响通针性及聚乳酸降解的均一性,换言之,该制剂的通针性能、降解的均一性等还有改进提高的空间。 This method is low yield, material consumption, greater power consumption, in addition, to obtain a polylactic acid particles to be improved roundness, roundness of the needle may impact on the degradation of polylactic acid and homogeneity, in other words, the formulation acupuncture performance degradation and the like as well as improved uniformity improvement.

[0005] 因此,现实中还需要性能更优异的聚乳酸注射植入剂。 [0005] Thus, in reality, more excellent properties required of polylactic acid implant injection.

发明内容 SUMMARY

[0006] 本发明涉及一种改进的聚乳酸注射植入剂的制备方法,该制备方法包括下列步骤: [0006] relates to an improved injectable implant polylactic acid production method of the present invention, the preparation process comprises the steps of:

[0007] 1)、制备聚乳酸颗粒; [0007] 1), polylactic acid particles;

[0008] 2)、制备羧甲基纤维素的水凝胶液; [0008] 2) Preparation of hydrogel glue carboxymethyl cellulose;

[0009] 3)、上述聚乳酸颗粒分散于上述凝胶液中成混悬液; [0009] 3), the polylactic acid particles are dispersed into the gel solution to the suspension;

[0010] 4)、上述混悬液在上述步骤3之后被冷冻干燥成固态物(温度25 °C下)。 [0010] 4) the suspension after the above step 3 was freeze-dried to a solid state (at a temperature of 25 ° C).

[0011] 在制备上述聚乳酸颗粒中包含: [0011] contained in the above polylactic acid particles prepared:

[0012] (1)、把聚乳酸在含乳化剂的水溶液为(w相)中形成聚乳酸为油相(〇相)的水包油型乳剂(〇/V); [0012] (1), the polylactic acid is in an aqueous solution containing an emulsifier (w phase) to form an oil-in-water emulsion is an oil phase of the polylactic acid (square phase) (square / V);

[0013] (2)、上述水包油型乳剂中的聚乳酸油相在压力下在高于上述聚乳酸油相开始固化的温度5°C (较佳地3°C,更较佳地2°C,最佳地1°C)以内的温度下(软化但未液化状态下) 通过孔径相对较大(孔径通常不高于100微米,但高于60微米)的筛网后30秒钟(较佳地10秒钟,更较佳地5秒钟,最佳地1秒钟)内被固化成聚乳酸颗粒(固化方式如把上述过筛后水包油型乳剂冲入冰水、或液态二氧化碳、或液态氮等中); [0013] (2), the above-described polylactic acid oil emulsion oil in water phase at a pressure higher than the above polylactic acid in the oil phase start curing temperature 5 ° C (preferably 3 ° C, more preferably 2 under ° C, most preferably 1 ° C temperature) within (liquefied state but softened) after 30 seconds by a relatively large pore size (pore size no greater than 100 microns typically, but greater than 60 microns) sieve ( preferably curing is 10 seconds, more preferably 5 seconds, most preferably 1 seconds) to the polylactic acid particles (the above-mentioned curing means such as oil-in-water sieving into the ice-water emulsion, or liquid carbon dioxide, liquid nitrogen or the like);

[0014] (3)、上述被固化的聚乳酸颗粒过孔径相对较小(孔径通常不高于40微米)的筛网, 未通过上述筛网的部分(用水洗涤后)被留用。 [0014] (3) the cured polylactic acid particles through a relatively small aperture (usually not higher than 40 [mu] m pore size) sieve, (washed with water) not through said screen portions are retained.

[0015] 上述制备方法中把聚乳酸颗粒的固化与筛分两步并成一步进行,简化了工艺,缩短了工作时间,提高了工作效率,更重要的是大大提高聚乳酸颗粒的产率,原来被弃用的粒径较大的部分加压过筛后切割成粒径较大小适用的部分,降低了浪费,减少了物耗、能耗。 [0015] The production method of the cured two-stage screening, and polylactic acid particles into a single step, simplifying the process, shortening the working time and improve work efficiency, more importantly, greatly increase the yield of polylactic acid particles, deprecated originally large diameters larger diameter portion is cut into small applied sieve fraction after pressurization, reduced waste, reduced material consumption, energy. 该制备方法的另一优势为大大提高了聚乳酸颗粒的圆整度,从而提高该制剂的通针性及聚乳酸降解的均一"性。 Another advantage of this preparation method is greatly improved roundness of polylactic acid particles, thereby increasing the needle through the formulation of polylactic acid degradation uniformity "sex.

[0016] 上述羧甲基纤维素的重均分子量为25万至70万,较佳地25万至60万,更佳地25万至50万,其中的羧甲基取代度为0.80至1.2 (较佳地为0.85至1.0),该羧甲基纤维素(中的羧甲基)被中和成碱土金属盐(钠盐、钾盐或锂盐,较佳地为钠盐),其中和度为90至100%。 [0016] The above-described weight average molecular weight of carboxymethyl cellulose is from 250,000 to 700,000, preferably from 250,000 to 600,000, more preferably 250,000 to 500,000, wherein the carboxymethyl degree of substitution from 0.80 to 1.2 ( preferably 0.85 to 1.0), the carboxymethyl cellulose (carboxymethyl in) is neutralized to alkaline earth metal (sodium, potassium or lithium salt, preferably a sodium salt), and wherein the degree of It is 90 to 100%.

[0017] 上述聚乳酸包括L 一聚乳酸,D—聚乳酸,及DL—聚乳酸,较佳地为L 一聚乳酸,其重均分子量为5万至30万,较佳地8万至20万,更佳地10万至15万。 [0017] The polylactic acid comprising L-polylactic acid, D- polylactic acid, polylactic acid and DL-, L is preferably a polylactic acid having a weight-average molecular weight of from 50,000 to 300,000, preferably from 80,000 to 20 million and more preferably from 100,000 to 150,000. 上述聚乳酸的(平均)粒径为1微米为至100微米,较佳地为10微米为至80微米,更佳地为20微米为至70微米,最佳地为40 微米为至65微米。 The above-described polylactic acid (average) particle size of 1 micron to 100 microns, preferably 10 microns to 80 microns, more preferably from 20 microns to 70 microns, most preferably from 40 microns to 65 microns.

[0018] 上述聚乳酸及上述羧甲基纤维素用量重量比为1:0.01至0.5,较佳地为1:0.03至0.3,更佳地为1:0.05至0.2,最佳地为1:0.1至0.2。 [0018] The above-described polylactic acid and carboxymethyl cellulose is used in an amount by weight ratio of 1: 0.01 to 0.5, preferably 1: 0.03 to 0.3, more preferably from 1: 0.05 to 0.2, most preferably 1: 0.1 to 0.2.

[0019] 上述注射植入剂还可包含一种除羧甲基纤维素以外的添加剂,特别是一种填充剂或释稀剂(如甘露醇、乳糖、甘氨酸),上述添加剂的用量为上述聚乳酸用量的1至500%,较佳地3至300%,更佳地为5至200%。 [0019] The injectable implant may further comprise an additive other than carboxymethyl cellulose, in particular a dilute release agent or filler (such as mannitol, lactose, glycine), the above amount of the additive is poly the amount of the acid 1-500%, preferably 3-300%, more preferably 5 to 200%.

[0020] 上述注射植入剂具有较高(改善)的通针性能、较高的产率、较低的产耗(物耗、能耗),及较高的降解的均一性。 [0020] The injectable implant having a higher (improved) performance through the needle, higher yields, lower production energy consumption (material consumption, energy consumption), and high uniformity degradation.

附图说明 BRIEF DESCRIPTION

[0021] 附图1:注射植入剂制备方法示意图。 [0021] Figure 1: a schematic view of an injection preparation of implant. 实施例 Example

[0022] 下非选择性实施例进一步描述了本发明范围内的优选实施例。 [0022] under non-selective examples further describe preferred embodiments within the scope of embodiments of the present invention. 在本发明的范围内这些实施例还可有许多变化。 Within the scope of the present invention to these embodiments it may have many variations.

[0023] 实施例1 [0023] Example 1

[0024] 其组成(组方)如下: [0024] The composition (prescription) as follows:

[0025] [0025]

Figure CN105664261BD00041

[0026] 其中,L 一聚乳酸:重均分子量为8〜14万; [0026] wherein, L a polylactic acid: 8~14 weight average molecular weight of ten thousand;

[0027] 其中,羧甲基纤维素:重均分子量为39万,其中羧甲基取代度为0.97,其中和度为98.8%,被中和成钠盐。 [0027] wherein, carboxymethylcellulose: weight average molecular weight of 390,000, wherein the degree of carboxymethyl substitution of 0.97, and wherein the degree of 98.8%, neutralized to the sodium salt.

[0028] 实施例1 一1制备方法: [0028] Example 1 a Preparation Method 1:

[0029] 1)、制备聚乳酸颗粒,方法如下: [0029] 1), polylactic acid particles, as follows:

[0030] (1)、把聚乳酸在含乳化剂的水溶液为(W相)中形成聚乳酸为油相(〇相)的水包油型乳剂(〇/V); [0030] (1), the polylactic acid is in an aqueous solution containing an emulsifier (W-phase) to form an oil-in-water emulsion is an oil phase of the polylactic acid (square phase) (square / V);

[0031] (2)、上述水包油型乳剂中的聚乳酸油相在压力下在高于上述聚乳酸油相开始固化的温度5°C的温度下(软化但未液化状态下)通过孔径相对较大(孔径为65微米)的筛网后10秒钟内被固化成聚乳酸颗粒; [0031] (2), the above-described oil in water emulsion of polylactic acid at a pressure in the oil phase at a temperature above the polylactic acid starts to solidify the oil phase temperature 5 ° C (the lower softening but not liquefied state) through the aperture after relatively large (pore size 65 microns) sieve to be cured within 10 seconds of the polylactic acid particles;

[0032] (3)、上述被固化的聚乳酸颗粒通过孔径相对较小(孔径为40微米)的筛网,未通过上述筛网的部分用水洗涤后被留用; [0032] (3), the above-described polylactic acid pellets cured by a relatively small pore size (pore size of 40 [mu] m) sieve, are not retained by the mesh portion after the above-described washing water;

[0033] 2)、制备羧甲基纤维素的水凝胶液; [0033] 2) Preparation of hydrogel glue carboxymethyl cellulose;

[0034] 3)、上述聚乳酸颗粒分散于上述凝胶液中成混悬液; [0034] 3), the polylactic acid particles are dispersed into the gel solution to the suspension;

[0035] 4)、上述混悬液在上述步骤3之后被冷冻干燥成固态物(温度25 °C下)。 [0035] 4) the suspension after the above step 3 was freeze-dried to a solid state (at a temperature of 25 ° C).

[0036] 实施例1 一2制备方法: [0036] Example 1 a Preparation 2:

[0037] 除以下不同外,其他均同实施例1 一1: [0037] except with the following, other embodiments are the same in Example 1 1 a:

[0038] 上述聚乳酸油在高于上述聚乳酸油相开始固化的温度3°C的温度下(软化但未液化状态下)通过上述的筛网。 [0038] The polylactic acid oil at a temperature above the polylactic acid starts to solidify the oil phase temperature of 3 ° C (softening but liquefied state) by the above screen.

[0039] 实施例1 一3制备方法: [0039] Example 3 a Preparation Method 1:

[0040] 除以下不同外,其他均同实施例1 一1: [0040] except with the following, other embodiments are the same in Example 1 1 a:

[0041] 上述聚乳酸油在高于上述聚乳酸油相开始固化的温度1°C的温度下(软化但未液化状态下)通过上述的筛网。 [0041] The polylactic acid oil at a temperature above the polylactic acid starts to solidify the oil phase temperature of 1 ° C (softening but liquefied state) by the above screen.

[0042] 实施例2 [0042] Example 2

[0043] 其组成(组方)如下: [0043] The composition (prescription) as follows:

[0044] [0044]

Figure CN105664261BD00051

[0045] 其中,L 一聚乳酸:重均分子量为13〜16万; [0045] wherein, L a polylactic acid: 13~16 weight average molecular weight of ten thousand;

[0046] 其中,羧甲基纤维素:重均分子量为55万,其中羧甲基取代度为0.96,其中和度为95%,被中和成钠盐。 [0046] wherein, carboxymethylcellulose: weight average molecular weight of 550,000, wherein the degree of carboxymethyl substitution 0.96, and wherein a degree of 95%, neutralized to the sodium salt.

[0047] 实施例2 — 1制备方法: : 1 preparation - two cases of [0047] Embodiment

[0048] 1)、制备聚乳酸颗粒,方法如下: [0048] 1), polylactic acid particles, as follows:

[0049] (1)、把聚乳酸在含乳化剂的水溶液为(w相)中形成聚乳酸为油相(〇相)的水包油型乳剂(〇/V); [0049] (1), the polylactic acid is in an aqueous solution containing an emulsifier (w phase) to form an oil-in-water emulsion is an oil phase of the polylactic acid (square phase) (square / V);

[0050] (2)、上述水包油型乳剂中的聚乳酸油相在压力下在高于上述聚乳酸油相开始固化的温度3°C的温度下(软化但未液化状态下)通过孔径相对较大(孔径为65微米)的筛网后30秒钟内被固化成聚乳酸颗粒; [0050] (2), the above-described oil in water emulsion of polylactic acid at a pressure in the oil phase at a temperature above the polylactic acid starts to solidify the oil phase temperature of 3 ° C (softened but liquefied state) through the aperture after relatively large (pore size 65 microns) sieve to be cured within 30 seconds, the polylactic acid particles;

[0051] (3)、上述被固化的聚乳酸颗粒通过孔径相对较小(孔径为30微米)的筛网,未通过上述筛网的部分用水洗涤后被留用; [0051] (3), the above-described polylactic acid pellets cured by a relatively small pore size (pore size 30 microns) sieve, are not retained by the mesh portion after the above-described washing water;

[0052] 2)、制备羧甲基纤维素的水凝胶液; [0052] 2) Preparation of hydrogel glue carboxymethyl cellulose;

[0053] 3)、上述聚乳酸颗粒分散于上述凝胶液中成混悬液; [0053] 3), the polylactic acid particles are dispersed into the gel solution to the suspension;

[0054] 4)、上述混悬液在上述步骤3之后被冷冻干燥成固态物(温度25 °C下)。 [0054] 4) the suspension after the above step 3 was freeze-dried to a solid state (at a temperature of 25 ° C).

[0055] 实施例2 — 2制备方法: : Preparation 2 - 2 [0055] Example

[0056] 除以下不同外,其他均同实施例2 — 1: [0056] In addition the following differences, others were the same as Example 2--1:

[0057] 上述的聚乳酸油相通过上述的筛网后10秒钟内被固化成聚乳酸颗粒。 [0057] The polylactic acid is solidified into the oil phase of the polylactic acid particles in the above-described 10 seconds after passing through a screen.

[0058] 实施例2 — 3制备方法: : Preparation 3 - 2 [0058] Example

[0059] 除以下不同外,其他均同实施例2 — 1: [0059] In addition the following differences, others were the same as Example 2--1:

[0060] 上述的聚乳酸油相通过上述的筛网后5秒钟内被固化成聚乳酸颗粒。 [0060] The oil phase of the polylactic acid is solidified into particles of polylactic acid within 5 seconds after the above-described screen-passing.

[0061] 实施例2 — 4制备方法: : Preparation 4 - Example 2 [0061] Embodiment

[0062] 除以下不同外,其他均同实施例2 — 1: [0062] In addition the following differences, others were the same as Example 2--1:

[0063] 上述的聚乳酸油相通过上述的筛网后1秒钟内被固化成聚乳酸颗粒。 [0063] The polylactic acid to the oil phase is solidified within 1 second polylactic acid particles described above after passing through a screen.

[0064] 实施例3 [0064] Example 3

[0065] 其组成(组方)如下: [0065] The composition (prescription) as follows:

[0066] [0066]

Figure CN105664261BD00061

[0067] 其中,L 一聚乳酸:重均分子量为14〜20万; [0067] wherein, L a polylactic acid: 14~20 weight average molecular weight of ten thousand;

[0068]其中,羧甲基纤维素:重均分子量为65万,其中羧甲基取代度为0.99,其中和度为100%,被中和成钠盐。 [0068] wherein, carboxymethylcellulose: weight average molecular weight of 650,000, wherein the degree of carboxymethyl substitution 0.99, and wherein a degree of 100%, neutralized to the sodium salt.

[0069] 制备方法: [0069] Preparation:

[0070] 1)、制备聚乳酸颗粒,方法如下: [0070] 1), polylactic acid particles, as follows:

[0071] (1)、把聚乳酸在含乳化剂的水溶液为(w相)中形成聚乳酸为油相(〇相)的水包油型乳剂(〇/V); [0071] (1), the polylactic acid is in an aqueous solution containing an emulsifier (w phase) to form an oil-in-water emulsion is an oil phase of the polylactic acid (square phase) (square / V);

[0072] (2)、上述水包油型乳剂中的聚乳酸油相在压力下在高于上述聚乳酸油相开始固化的温度2°C的温度下(软化但未液化状态下)通过孔径相对较大(孔径为40微米)的筛网后3秒钟内被固化成聚乳酸颗粒; [0072] (2), the above-described oil in water emulsion of polylactic acid at a pressure in the oil phase at a temperature above the polylactic acid starts to solidify the oil phase temperature by 2 ° C (softened but liquefied state) through the aperture after a relatively large (40 micron pore size) mesh particles are cured to the polylactic acid 3 seconds;

[0073] (3)、上述被固化的聚乳酸颗粒通过孔径相对较小(孔径为10微米)的筛网,未通过上述筛网的部分用水洗涤后被留用; [0073] (3) the cured polylactic acid particles are not retained by the relatively small pore size (pore size of 10 [mu] m) sieve, after being washed by the water above the screen portion;

[0074] 2)、制备羧甲基纤维素的水凝胶液; [0074] 2) Preparation of hydrogel glue carboxymethyl cellulose;

[0075] 3)、上述聚乳酸颗粒分散于上述凝胶液中成混悬液; [0075] 3), the polylactic acid particles are dispersed into the gel solution to the suspension;

[0076] 4)、上述混悬液在上述步骤3之后被冷冻干燥成固态物(温度25 °C下)。 [0076] 4) the suspension after the above step 3 was freeze-dried to a solid state (at a temperature of 25 ° C).

[0077] 对照例1 [0077] Comparative Example 1

[0078] 其组成(组方)与实施例1相同;其制备方法除以下不同外,其他均与实施例1相同: [0078] The same composition (prescription) of Example 1; the preparation method except the following differences, others are the same as in Example 1:

[0079] 上述聚乳酸油在高于上述聚乳酸油相开始固化的温度HTC的温度下通过上述的筛网。 [0079] In the above-described polylactic acid oil is higher than the polylactic acid starts to solidify the oil phase temperature HTC through the sieve.

[0080] 对照例2 [0080] Comparative Example 2

[0081] 其组成(组方)与实施例2相同;其制备方法除以下不同外,其他均与实施例2相同: [0081] The composition (prescription) in Example 2; preparation method except the following differences, others are same as in Example 2:

[0082] 上述的聚乳酸油相通过上述的筛网后60秒钟内在(用时60秒钟)被固化成聚乳酸颗粒。 [0082] The oil phase of the polylactic acid (for 60 seconds) to the polylactic acid pellets was cured by 60 seconds after the above-described internal screen.

[0083] 对照例3 [0083] Comparative Example 3

[0084] 其组成(组方)与实施例3相同;其制备方法除以下不同外,其他均与实施例3相同: [0084] The composition (prescription) in Example 3; the preparation method except the following differences, others are the same as in Example 3:

[0085] 上述聚乳酸油在高于上述聚乳酸油相开始固化的温度HTC的温度下通过上述的筛网; [0085] The polylactic acid oil at a temperature above the polylactic acid oil phase temperature HTC begins to solidify by the above screen;

[0086] 上述的聚乳酸油相通过上述的筛网后30秒钟内在(用时30秒钟)被固化成聚乳酸颗粒。 [0086] The oil phase of the polylactic acid (for 30 seconds) of polylactic acid is solidified into granules through the inner mesh 30 seconds after the above.

[0087] 对照例4、5、6 [0087] comparative example 4,5,6

[0088] 对照例4、5、6的组成(组方)分别与实施例1、2、3相同; [0088] the same as the composition of Example 1, 2, 4, 5 Comparative Example (prescription), respectively;

[0089] 制备方法:按如附图所示方法制备(其中制备聚乳酸颗粒时不包括上述的加压过筛固化的步骤⑵)。 Preparation [0089] Method: The preparation method shown in the accompanying drawings (not including the above-described curing step ⑵ forcing through a screen when polylactic acid particles) Press.

[0090] 市售品(Sculptra(derma veil))也作为对照例。 [0090] The commercially available product (Sculptra (derma veil)) also as a comparative example.

[0091] 测试例1 [0091] Test Example 1

[0092] 产率测试 [0092] Yield Test

[0093] 以Wo聚乳酸原料为基准,按上述实施例、对照例的组成(组方)及制备方法制备注射植入剂,测定注射植入剂中的聚乳酸的重量W,按下列公式计算产率P: [0093] In the polylactic acid Wo reference material, prepared by the above-described embodiments of the composition of Comparative Example (prescription) and the preparation of injectable implants, implants injection by weight of the polylactic acid W, is calculated by the following formula yield P:

[0094] P=W^ff0X 100%〇 [0094] P = W ^ ff0X 100% square

[0095] 结果见表1〜3。 [0095] The results are shown in Table 1~3.

[0096] 测试例2 [0096] Test Example 2

[0097] 通针性能测试 [0097] Performance Test Acupuncture

[0098] 原理: [0098] Principle:

[0099] 通针性能越好,相同量的混悬液在同一条件下通过同一针头所需时间越少。 [0099] Acupuncture better performance, the same amount of the suspension under the same conditions, the less the time required by the same needle.

[0100] 方法: [0100] Method:

[0101] 取相同重量的上述实施例及对照例加入用相同量的医用注射用水经相同时间相同方式(如同一振摇方法)复溶(重构)成混悬液,取相同量混悬液装于同一注射器(针头也不变)中,用同等的恒定压力推注射器使其中混悬液排完,测定所需时间。 [0101] Example embodiments described above take the same weight and the suspension was added into a suspension of Comparative Example with the same amount of water for injection medical over the same time in the same way (as a shaking method) reconstitution (reconstituted), take the same amount installed in the same syringe (needle does not change), and pushes with the same syringe so that a constant pressure wherein the suspension drained, the measurement time required. 最后计算上述实施例及对照例测得的时间与市售品(Sculptra (derma veil))或对照例6测得的时间的比值,以该比值衡量上述实施例及对照例的通针性能,该比值越小,通针性能越强,该比值越大,通针性能越弱。 And commercially available product (Sculptra (derma veil)), or ratio of the measured time for Comparative Example Comparative Example 6 measured last time is calculated, and the above-described embodiment, in order to measure the ratio of the above-described embodiments and comparative example of the performance through the needle, the the smaller the ratio, the stronger the performance through the needle, the larger the ratio, the weaker performance through the needle.

[0102] 测试结果见表1〜3。 [0102] The test results are shown in Table 1~3.

[0103] 测试例3 [0103] Test Example 3

[0104] 降解的均一性测试 [0104] Degradation homogeneity test

[0105] (体外)降解实验:PLA注射植入剂(1支)完全浸没于5ml NaCl-NaH2P〇4_Na2HP〇4缓冲系的I3BS溶液中(pH=7.2),每支试管中放含W〇(约150mg)PLA的注射植入剂,封口,置于37 °C恒温水浴箱,100转/min,于24周后测定试管中PLA的量Wt。 [0105] (in vitro) degradation experiments: PLA injectable implant (1) is completely immersed in the solution I3BS 5ml NaCl-buffer system in NaH2P〇4_Na2HP〇4 (pH = 7.2), place each tube containing W〇 ( about 150 mg of) PLA implants injected, and sealed in a 37 ° C constant temperature water bath, 100 rpm / min, measuring the amount of PLA in Wt tube 24 weeks. 按下列公式计算降解率P: Degradation rate is calculated by the following formula P:

[0106] P= (1-fft^ffo) X100%〇 [0106] P = (1-fft ^ ffo) X100% billion

[0107] 按上述方法(同时)重复测定10次(同一批次的PLA注射植入剂),然后计算(降解率P的)标准差(SD),以标准差反映PLA注射植入剂(批内)降解的均一性。 [0107] as described above (simultaneous) measurement was repeated 10 times (same batch injectable implant PLA), is then calculated (degradation rate P) of standard deviation (the SD), standard deviation to reflect PLA injectable implants (Batch Endo) uniformity degradation. 标准差值越小,降解的均一性越好。 The smaller the standard deviation, the better the uniformity degradation.

[0108] 测试结果见表1〜3。 [0108] The test results are shown in Table 1~3.

[0109] 表1-1 [0109] Table 1-1

[0110] [0110]

Figure CN105664261BD00081

Claims (14)

1. 一种改进的聚乳酸注射植入剂的制备方法,该制备方法包括下列步骤: 1) 、制备聚乳酸颗粒; 2) 、制备羧甲基纤维素的水凝胶液; 3) 、上述聚乳酸颗粒分散于上述凝胶液中成混悬液; 4) 、上述混悬液在上述步骤3)之后被冷冻干燥成固态物; 且,在制备上述聚乳酸颗粒中包含: (1) 、把聚乳酸在含乳化剂的水溶液中形成聚乳酸为油相的水包油型乳剂; (2) 、上述水包油型乳剂中的聚乳酸油相在压力下在高于上述聚乳酸油相开始固化的温度5°C以内的温度下,通过孔径相对较大的筛网后30秒钟内被固化成聚乳酸颗粒; (3) 、上述被固化的聚乳酸颗粒过孔径相对较小的筛网,未通过上述筛网的部分被留用。 1. An improved method for preparing polylactic acid an injection of the implant, the preparation process comprises the following steps: 1), polylactic acid particles; 2), carboxymethylcellulose hydrogel prepared glue; 3) the the polylactic acid particles are dispersed in the above solution into the gel suspension; 4) the suspension is freeze-dried to a solid material after said step 3); and, contained in the above polylactic acid particles prepared: (1), the formed polylactic acid is polylactic oil phase oil in water type emulsion in an aqueous solution containing an emulsifier; and (2) the oil-in-water emulsion the oil phase polylactic acid at a pressure higher than the above polylactic acid in the oil phase begins to solidify at a temperature within a temperature 5 ° C, through a relatively large pore size of the sieve is cured within 30 seconds into a polylactic acid particles; (3), the above-described polylactic acid is solidified particles through a relatively small aperture sieve network, is not retained by the portion of the screen.
2. 根据权利要求1的制备方法,其特征在于所述聚乳酸及所述羧甲基纤维素用量重量比为1:0.01 至0.5。 2. The production method according to claim 1, wherein the polylactic acid and the carboxymethyl cellulose is used in an amount by weight ratio of 1: 0.01 to 0.5.
3. 根据权利要求1的制备方法,其特征在于所述聚乳酸包括L 一聚乳酸,D—聚乳酸,及DL—聚乳酸,其重均分子量为5万至30万。 3. The production method according to claim 1, wherein said polylactic acid comprising L-polylactic acid, D- polylactic acid, and poly-DL- lactic acid having a weight-average molecular weight of from 50,000 to 300,000.
4. 根据权利要求1的制备方法,其特征在于所述聚乳酸的平均粒径为1微米为至100微米。 4. The production method according to claim 1, wherein an average particle size of the polylactic acid is 1 micron to 100 microns.
5. 根据权利要求1的制备方法,其特征在于所述羧甲基纤维素的重均分子量为25万至70万。 The production method according to claim 1, wherein the weight average molecular weight of carboxymethyl cellulose is from 250,000 to 700,000.
6. 根据权利要求1的制备方法,其特征在于该注射植入剂还包含一种除羧甲基纤维素以外的添加剂。 6. The production method according to claim 1, characterized in that the injectable implant further comprises an additive other than the carboxymethyl cellulose.
7. 根据权利要求6的制备方法,其特征在于所述添加剂的用量为所述聚乳酸用量的1至500% 〇 7. The production method according to claim 6, characterized in that the additive amount of the polylactic acid used in an amount of 1-500% billion
8. 根据权利要求1的制备方法,其特征在于该注射植入剂基本上不加入除羧甲基纤维素以外的任何添加剂,但10%以内的水分除外,上述水分的量是基于上述聚乳酸的用量。 8. The production method according to claim 1, characterized in that the injectable implant substantially not adding any additives other than carboxymethyl cellulose, except for water of less than 10%, the amount of the water is based on the polylactic acid amount.
9. 根据权利要求1的制备方法,其特征在于所述孔径相对较大的筛网的孔径不高于100 微米,但高于60微米,所述孔径相对较小的筛网的孔径不高于40微米。 9. The production method according to claim 1, wherein said aperture is a relatively large pore size screen is not higher than 100 microns but greater than 60 microns, the pore size is relatively small screen pore diameter of not greater than 40 microns.
10. 根据权利要求1的制备方法,其特征在于所述聚乳酸颗粒固化方式为把所述过筛后水包油型乳剂冲入冰水、或液态二氧化碳、或液态氮中。 10. The production method according to claim 1, wherein said polylactic acid particle after said curing methods sieved into the water-in-oil type emulsion ice water, or liquid carbon dioxide or liquid nitrogen.
11. 根据权利要求1的制备方法,其特征在于所述水包油型乳剂中的聚乳酸油相在压力下在高于所述聚乳酸油相开始固化的温度3°C以内的温度下,通过孔径相对较大的筛网后10秒钟内被固化成聚乳酸颗粒。 The production method according to claim 1, wherein said oil in water emulsion the oil phase polylactic acid at a temperature higher than the pressure within the oil phase polylactic temperature starts to solidify 3 ° C, by the relatively large pore size screen cured to a polylactic acid particles within 10 seconds.
12. 根据权利要求6的制备方法,其特征在于所述水包油型乳剂中的聚乳酸油相在压力下在高于所述聚乳酸油相开始固化的温度3°C以内的温度下,通过孔径相对较大的筛网后5 秒钟内被固化成聚乳酸颗粒。 12. The production method according to claim 6, wherein said oil in water emulsion the oil phase polylactic acid at a temperature higher than the pressure within the oil phase polylactic temperature starts to solidify 3 ° C, by the relatively large pore size screen it is solidified into particles of polylactic acid within 5 seconds.
13. 根据权利要求6的制备方法,其特征在于所述水包油型乳剂中的聚乳酸油相在压力下在高于所述聚乳酸油相开始固化的温度1°C以内的温度下,通过孔径相对较大的筛网后1 秒钟内被固化成聚乳酸颗粒。 13. A production method according to claim 6, wherein said oil in water emulsion the oil phase polylactic acid at a temperature higher than the pressure within the oil phase polylactic temperature starts to solidify 1 ° C, by the relatively large pore sieve it is solidified into particles in a second polylactic acid.
14. 一种根据权利要求1至13所述的任意一种制备方法制备的注射植入剂。 14. A method of preparing any one of claim 1 to claim 13 Preparation of injectable implant.
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