CN111728957B - Tolterodine long-acting sustained-release microsphere and preparation method thereof - Google Patents
Tolterodine long-acting sustained-release microsphere and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
Abstract
The invention discloses tolterodine long-acting slow-release microspheres and a preparation method thereof. The tolterodine microspheres prepared from the polylactide-glycolide delay the release of tolterodine and have a sustained-release effect.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to tolterodine long-acting sustained-release microspheres and a preparation method thereof.
Background
Muscarinic receptors are used to signal normal bladder contractions and voiding and overactive bladder. The most widely used clinically for the treatment of urge incontinence is a muscarinic antagonist, however most drugs lack selectivity for the toxic choline receptor and the effectiveness of other drugs, besides tolterodine, may be limited by adverse effects. Tolterodine (Tolterodine) is a potent, competitive antagonist of muscarinic receptors and is widely used in the clinical treatment of overactive bladder (OAB). The mean frequency of urination after tolterodine treatment was reported to decrease.
Patent CN1164265C discloses a sustained-release tablet of tolterodine tartrate. The specific method combines tolterodine tartrate and a large amount of sustained-release materials together to achieve the sustained-release effect, and has the defects of short sustained-release period, more used auxiliary materials and no change of the characteristic of daily medicine taking.
Sustained release microspheres are a highly innovative formulation, usually administered by intramuscular or subcutaneous routes, and the active pharmaceutical ingredient is slowly released following degradation of the carrier material at the site of administration, and enters the systemic circulation by absorption. Research reports a preparation method of tolterodine microspheres, wherein tolterodine base drugs are used in the preparation process, an emulsification-solvent volatilization method is adopted to prepare slow-release microspheres, and butyl stearate is added to delay release. However, the encapsulation efficiency of the prepared microspheres is not high and does not meet the pharmacopoeia instruction requirements (preparation of lina tolterodine PLGA microspheres and research on treatment of overactive bladder [ D ] Jilin university, 2018).
The patent (CN105997887A) reports a preparation method of tolterodine sustained-release microspheres containing small-molecule additives. Specifically, tolterodine and micromolecular fatty acid/fatty acid ester are wrapped in the microsphere together, so that the effect of delaying the release of tolterodine is achieved. The disadvantages are that the drug loading is low due to the addition of small molecules, and the encapsulation rate does not reach the instruction requirement of 80 percent in pharmacopoeia.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a tolterodine long-acting sustained-release microsphere preparation which has high drug loading, can be released for one month to two months and greatly reduces the times of medication.
The invention further provides a preparation method of the tolterodine sustained-release microspheres, which is simple and feasible and can easily meet the requirements of modern industrial large-scale production.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
the invention provides tolterodine sustained-release microspheres, which are characterized by comprising the following components in percentage by weight: 5 to 50 percent of tolterodine pamoate and the balance of biodegradable medical polymer auxiliary materials.
The medical polymer auxiliary material used for the sustained-release microsphere preparation is polylactide-glycolide (PLGA). Preferably, the molar ratio of lactide units to glycolide units is 80: 20-60: 40, molecular weight of 5000-; more preferably, the molar ratio of lactide units to glycolide units is 75: 25-50: 50, the molecular weight is 5000-.
According to the purpose of the invention, the invention provides a preparation method of toltero sustained-release microspheres, which comprises the following steps: dissolving tolterodine pamoate and polylactide-glycolide in an organic solvent, and swirling to completely dissolve the tolterodine pamoate and the polylactide-glycolide to obtain an organic phase; preparing a polyvinyl alcohol (PVA) aqueous solution as a water phase; slowly adding the organic phase into the water phase, fully emulsifying by high-speed shearing, and slowly volatilizing the organic solvent by low-speed stirring to obtain a suspension of the tolterodine drug microspheres in the water phase; washing to remove the water phase; collecting and drying the obtained microspheres; thus obtaining the tolterodine sustained-release microspheres.
The organic solvent is a sufficiently volatile, low-residue, low-boiling organic solvent from the viewpoint of handling, for example, one, two or more mixed solvents of dichloromethane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, methanol, ethyl acetate, chloroform and diethyl ether.
The particle size of the tolterodine sustained-release microspheres prepared by the invention is 10-200 mu m. The advantages of this particle size range are that the efficacy of the drug is easily maintained, that the biodegradability is good, and that the blood circulation is not affected after injection into the body. If the particle size is too small, it is difficult to maintain the drug effect for a long time, and capillary vessels may be blocked, which may affect the microcirculation in vivo; the particle size is too large, the initial release is too slow, and the effective blood concentration cannot be achieved.
The content of tolterodine in the sustained-release microsphere formulation of the present invention is not particularly limited as long as it can achieve the purpose of sustained release, but from the viewpoint of ensuring a sufficiently high blood concentration and a balance of sustained-release effect, tolterodine preferably accounts for 5 to 50%, preferably not less than 10% by weight of the total weight of the microsphere formulation; the medicinal polymer auxiliary material accounts for 50-95% of the total weight of the microsphere, and preferably not higher than 90% of the total weight. If the content of tolterodine is low, a sufficiently high blood concentration cannot be ensured; on the other hand, if the total weight is too high, the smooth release of the drug cannot be ensured, which may cause side effects.
Compared with the prior art, the invention has the beneficial effects that:
1. the sustained-release microsphere prepared by replacing tolterodine tartrate with the tolterodine pamoate realizes high drug loading and high encapsulation rate of the drug, the drug loading can reach 50 percent at most, and the encapsulation rate can reach more than 80 percent.
2. The tolterodine sustained-release microsphere preparation has a unique core-shell structure, and the structure can ensure that the medicine burst release is small, the medicine is constantly released, the long-acting effect of the tolterodine medicine is realized, and the tolterodine medicine can be administrated at intervals of not less than one month, preferably not less than 45 days, and even more than 2 months.
3. The tolterodine sustained-release microsphere preparation of the invention does not add other auxiliary materials except the tolterodine pamoate and the polylactide-glycolide, and has simple and convenient operation and low cost.
4. The emulsification-solvent volatilization method adopted by the invention has the advantage of process amplification and is easy to realize industrialization.
Drawings
FIG. 1 is a scanning electron micrograph of the sustained release microspheres of tolterodine prepared in example 1.
FIG. 2 is a graph showing the laser particle size measurement of the sustained-release tolterodine microspheres prepared in example 1.
Fig. 3 is an in vitro release profile of tolterodine sustained release microspheres prepared in example 1.
FIG. 4 is a graph of laser particle size measurement of the sustained-release tolterodine microspheres prepared in this example 6.
Fig. 5 is an in vitro release profile of tolterodine sustained release microspheres prepared in example 6.
Detailed Description
The present invention will be further described with reference to specific examples, but the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.
Embodiment 1 a method for preparing tolterodine sustained release microspheres, comprising the following steps:
tolterodine pamoate (1.25 g) and PLGA (1.25 g) (LA: GA ═ 50:50) were weighed precisely, 2ml of dichloromethane was added, and vortex sonication was performed to dissolve completely, thereby obtaining an oil phase. Preparing 0.5% PVA17-88 aqueous solution as water phase, refrigerating at 0-10 deg.C for use, and controlling the volume ratio of oil phase and water phase at 1: 50-100. Preparing microsphere by emulsification-solvent evaporation method, adding oil phase into water phase, and shearing at high speed for 1 min. Solidifying the sheared microspheres at room temperature, magnetically stirring at low speed for 4h, reducing pressure to promote volatilization of the organic solvent, centrifuging, sieving with a filter screen, collecting the microspheres, washing the microspheres with water, and vacuum drying in a freeze dryer to obtain the microsphere.
Embodiment 2 a method for preparing tolterodine sustained release microspheres, comprising the following steps:
tolterodine pamoate (0.2 g) and PLGA (1.8 g) (LA: GA ═ 50:50) were weighed precisely, 2ml of dichloromethane was added, and vortex-sonication was performed to dissolve completely, thereby obtaining an oil phase. Preparing 0.8% PVA17-88 aqueous solution as water phase, refrigerating at 0-10 deg.C for use, and controlling the volume ratio of oil phase and water phase at 1: 50-100. The microspheres are prepared by an emulsification-solvent volatilization method. Adding the oil phase into the water phase, and shearing at high speed for 1 min. Solidifying the sheared microspheres at room temperature, magnetically stirring at low speed for 4h, reducing pressure to promote volatilization of the organic solvent, centrifuging, sieving with a filter screen, collecting the microspheres, washing the microspheres with water, and vacuum drying in a freeze dryer to obtain the microsphere.
Embodiment 3 a method for preparing tolterodine sustained release microspheres, comprising the following steps:
about 0.4g of tolterodine pamoate and 1.6g of PLGA (LA: GA ═ 50:50) were precisely weighed, 2.5ml of methylene chloride was added, and the mixture was vortexed and sonicated to completely dissolve the tolterodine pamoate to obtain an oil phase. Preparing 0.5% PVA17-88 aqueous solution as water phase, refrigerating at 0-10 deg.C for use, and controlling the volume ratio of oil phase and water phase at 1: 50-100. The microspheres are prepared by an emulsification-solvent volatilization method. Adding the oil phase into the water phase, and shearing at high speed for 1 min. Solidifying the sheared microspheres at room temperature, magnetically stirring at low speed for 4h, reducing pressure to promote volatilization of the organic solvent, centrifuging, sieving with a filter screen, collecting the microspheres, washing the microspheres with water, and vacuum drying in a freeze dryer to obtain the microsphere.
Embodiment 4 a method for preparing tolterodine sustained release microspheres, comprising the following steps:
about 0.6g of tolterodine pamoate and 1.4g of PLGA (LA: GA ═ 50:50) were precisely weighed, 3ml of methylene chloride was added, and the mixture was vortexed and sonicated to completely dissolve the tolterodine pamoate to obtain an oil phase. Preparing 0.8% PVA17-88 aqueous solution as water phase, refrigerating at 0-10 deg.C for use, and controlling the volume ratio of oil phase and water phase at 1: 50-100. The microspheres are prepared by an emulsification-solvent volatilization method. Adding the oil phase into the water phase, and shearing at high speed for 1 min. Solidifying the sheared microspheres at room temperature, magnetically stirring at low speed for 4h, reducing pressure to promote volatilization of the organic solvent, centrifuging, sieving with a filter screen, collecting the microspheres, washing the microspheres with water, and vacuum drying in a freeze dryer to obtain the microsphere.
Embodiment 5 a method for preparing tolterodine sustained release microspheres, comprising the following steps:
tolterodine pamoate (about 0.6 g) and PLGA (0.9 g) (LA: GA ═ 50:50) were precisely weighed, 4ml of dichloromethane was added, and vortex-sonicated to completely dissolve it, to give an oil phase. Preparing 0.5% PVA17-88 aqueous solution as water phase, refrigerating at 0-10 deg.C for use, and controlling the volume ratio of oil phase and water phase at 1: 50-100. The microspheres are prepared by an emulsification-solvent volatilization method. Adding the oil phase into the water phase, and shearing at high speed for 1 min. Solidifying the sheared microspheres at room temperature, magnetically stirring at low speed for 4h, reducing pressure to promote volatilization of the organic solvent, centrifuging, sieving with a filter screen, collecting the microspheres, washing the microspheres with water, and vacuum drying in a freeze dryer to obtain the microsphere.
Embodiment 6 a method for preparing tolterodine sustained release microspheres, comprising the following steps:
about 1.25g of tolterodine pamoate and 1.25g of PLGA (LA: GA 75:25) were precisely weighed, 2ml of dichloromethane was added, and vortex-sonicated to completely dissolve the resulting mixture to obtain an oil phase. Preparing 0.8% PVA17-88 aqueous solution as water phase, refrigerating at 0-10 deg.C for use, and controlling the volume ratio of oil phase and water phase at 1: 50-100. The microspheres are prepared by an emulsification-solvent volatilization method. Adding the oil phase into the water phase, and shearing at high speed for 1 min. Solidifying the sheared microspheres at room temperature, magnetically stirring at low speed for 4h, reducing pressure to promote volatilization of the organic solvent, centrifuging, sieving with a filter screen, collecting the microspheres, washing the microspheres with water, and vacuum drying in a freeze dryer to obtain the microsphere.
Embodiment 7a method for preparing tolterodine sustained release microspheres, comprising the following steps:
tolterodine pamoate (ca. 0.25 g) and plga2.25g (LA: GA ═ 75:25) were weighed precisely, 2ml of dichloromethane was added, and vortex-sonicated to completely dissolve it, to give an oil phase. Preparing 0.5% PVA17-88 aqueous solution as water phase, refrigerating at 0-10 deg.C for use, and controlling the volume ratio of oil phase and water phase at 1: 50-100. The microspheres are prepared by an emulsification-solvent volatilization method. Adding the oil phase into the water phase, and shearing at high speed for 1 min. Solidifying the sheared microspheres at room temperature, magnetically stirring at low speed for 4h, reducing pressure to promote volatilization of the organic solvent, centrifuging, sieving with a filter screen, collecting the microspheres, washing the microspheres with water, and vacuum drying in a freeze dryer to obtain the microsphere.
Embodiment 8 a method for preparing tolterodine sustained release microspheres, comprising the steps of:
about 0.5g of tolterodine pamoate and 2.0g of PLGA (LA: GA 75:25) were precisely weighed, 2.5ml of dichloromethane was added, and vortex-sonicated to completely dissolve the resulting mixture to obtain an oil phase. Preparing 0.8% PVA17-88 aqueous solution as water phase, refrigerating at 0-10 deg.C for use, and controlling the volume ratio of oil phase and water phase at 1: 50-100. The microspheres are prepared by an emulsification-solvent volatilization method. Adding the oil phase into the water phase, and shearing at high speed for 1 min. Solidifying the sheared microspheres at room temperature, magnetically stirring at low speed for 4h, reducing pressure to promote volatilization of the organic solvent, centrifuging, sieving with a filter screen, collecting the microspheres, washing the microspheres with water, and vacuum drying in a freeze dryer to obtain the microsphere.
Embodiment 9 a method for preparing tolterodine sustained release microspheres, comprising the steps of:
tolterodine pamoate (ca. 0.3 g) and PLGA (0.7 g) (LA: GA ═ 75:25) were weighed precisely into 3ml of dichloromethane, and vortexed and sonicated to dissolve completely to give an oil phase. Preparing 0.5% PVA17-88 aqueous solution as water phase, refrigerating at 0-10 deg.C for use, and controlling the volume ratio of oil phase and water phase at 1: 50-100. The microspheres are prepared by an emulsification-solvent volatilization method. Adding the oil phase into the water phase, and shearing at high speed for 1 min. Solidifying the sheared microspheres at room temperature, magnetically stirring at low speed for 4h, reducing pressure to promote volatilization of the organic solvent, centrifuging, sieving with a filter screen, collecting the microspheres, washing the microspheres with water, and vacuum drying in a freeze dryer to obtain the microsphere.
Embodiment 10 a method for preparing tolterodine sustained release microspheres, comprising the steps of:
tolterodine pamoate (about 0.6 g) and PLGA (0.9 g) (LA: GA ═ 75:25) were weighed precisely into 4ml of dichloromethane, and vortexed and sonicated to dissolve completely to give an oil phase. Preparing 0.8% PVA17-88 aqueous solution as water phase, refrigerating at 0-10 deg.C for use, and controlling the volume ratio of oil phase and water phase at 1: 50-100. The microspheres are prepared by an emulsification-solvent volatilization method. Adding the oil phase into the water phase, and shearing at high speed for 1 min. Solidifying the sheared microspheres at room temperature, magnetically stirring at low speed for 4h, reducing pressure to promote volatilization of the organic solvent, centrifuging, sieving with a filter screen, collecting the microspheres, washing the microspheres with water, and vacuum drying in a freeze dryer to obtain the microsphere.
The results of the products prepared by the processes of examples 1-10 are shown in Table 1:
TABLE 1
| Numbering | PLGA Specification | Drug loading | Encapsulation efficiency | Microsphere yield |
| Example 1 | 50：50 | 50％ | 80％ | 76％ |
| Example 2 | 50：50 | 10％ | 92％ | 80％ |
| Example 3 | 50：50 | 20％ | 86％ | 82％ |
| Example 4 | 50：50 | 30％ | 85％ | 78％ |
| Example 5 | 50：50 | 40％ | 82％ | 75％ |
| Example 6 | 75：25 | 50％ | 81％ | 77％ |
| Example 7 | 75：25 | 10％ | 91％ | 84％ |
| Example 8 | 75：25 | 20％ | 85％ | 82％ |
| Example 9 | 75：25 | 30％ | 86％ | 79％ |
| Example 10 | 75：25 | 40％ | 83％ | 76％ |
As can be seen from the comparison results in Table 1, PLGA materials of different specifications have no great influence on the drug loading and encapsulation efficiency of tolterodine. The encapsulation efficiency of the microspheres is gradually reduced along with the increase of the drug loading.
The tolterodine sustained release microspheres prepared in examples 1 and 4 were used for release tests by simulating in vivo conditions. It was found that the drug release behavior was similar in vivo when phosphate buffered solutions at pH 7.4 were used as release media. 10mg of microspheres were weighed precisely, placed in a lidded centrifuge vial having a volume of 50ml, placed in a constant temperature shaker, maintained at 37. + -. 0.5 ℃ and rotated at 100 rpm.
During sampling, the centrifugal tube is centrifuged for 10min at 3000rpm, 5ml of solution is accurately absorbed, 5ml of release medium is added into the centrifugal tube, and the solution is taken out and detected by HPLC.
As can be seen from the release results, the tolterodine sustained-release microspheres of the invention can stably release the drug for more than one month. Therefore, for patients suffering from unstable or excessive bladder diseases including urge incontinence, urgency or frequency, the administration frequency can be greatly reduced, and the dosage can be effectively controlled to avoid side effects.
The invention is not the best known technology.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (5)
1. The tolterodine long-acting slow-release microsphere is characterized by comprising the following components in percentage by weight: 5 to 50 percent of tolterodine pamoate and the balance of biodegradable medical polymer auxiliary material polylactide-glycolide; the preparation method comprises the following steps: dissolving tolterodine pamoate and polylactide-glycolide in an organic solvent, and swirling to dissolve the tolterodine pamoate and polylactide-glycolide to obtain an organic phase; PVA water solution is used as water phase; slowly adding the organic phase into the water phase, fully emulsifying by high-speed shearing, and volatilizing to remove the organic solvent to obtain a microsphere suspension; washing and drying; obtaining tolterodine sustained-release microspheres;
the organic solvent in the preparation is one or more than two mixed solvents selected from dichloromethane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, methanol, ethyl acetate, chloroform and diethyl ether.
2. The tolterodine long-acting slow-release microsphere according to claim 1, wherein the molecular weight of the polylactide-glycolide is 5000-.
3. The tolterodine long-acting sustained-release microsphere according to claim 2, wherein the molecular weight of the polylactide-glycolide is 5000-.
4. The tolterodine long-acting sustained-release microsphere according to claim 1, wherein the molar ratio of lactide units and glycolide units in the polylactide-glycolide is 75: 25-50: 50.
5. the tolterodine long-acting sustained-release microsphere according to claim 1, wherein the particle size of the microsphere is 10-200 μm.
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