CN217908365U - Continuous production system of triptorelin sustained-release preparation - Google Patents
Continuous production system of triptorelin sustained-release preparation Download PDFInfo
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- CN217908365U CN217908365U CN202220389694.2U CN202220389694U CN217908365U CN 217908365 U CN217908365 U CN 217908365U CN 202220389694 U CN202220389694 U CN 202220389694U CN 217908365 U CN217908365 U CN 217908365U
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Abstract
The utility model discloses a serialization production system of triptorelin slowly-releasing preparation, including the oil phase storage tank, the colostrum jar, outer aqueous phase liquid storage pot, the online cutter of multiple emulsion, retort group in the liquid, continuous flow centrifuge and freeze dryer, the colostrum jar is connected to the oil phase storage tank, colostrum jar and outer aqueous phase liquid storage pot are connected to the online cutter of multiple emulsion respectively, retort group in the online cutter of multiple emulsion connects the liquid, retort group link continuous flow centrifuge's feed inlet in the liquid, retort group's import in dry circulation tube coupling liquid is passed through on the one hand to continuous flow centrifuge's discharge gate, centrifuge's discharge gate on the other hand still passes through the tube coupling freeze dryer feed inlet. The utility model discloses but linear amplification, serialization production, be fit for the production of hydrophilicity pharmaceutic preparation, save the industrialization production time by a wide margin, be particularly suitable for the industrialization and enlarge production.
Description
Technical Field
The utility model relates to a pharmacy technical field, in particular to serialization production system of triptorelin sustained-release preparation.
Background
Triptorelin is an artificially synthesized decapeptide, and the D-trp is adopted to replace the sixth Gly on the basis of natural Luteinizing Hormone Releasing Hormone (LHRH) to obtain an LHRH analogue (LHRHa) with stronger biological activity. The triptorelin effect is characterized by positive promotion and negative inhibition due to different administration modes and doses, when the triptorelin is administered with physiological pulse frequency in a short period and in a small dose, the triptorelin effect has a promoting effect on a pituitary-gonad axis, can be clinically used for treating symptoms such as sexual hypofunction, anovulation, delayed puberty and the like, and when the triptorelin is administered with non-physiological frequency in a long period and in a large dose, the triptorelin effect has an inhibiting effect on the pituitary-gonad axis, so that the hormone secretion capacity of the gonad is reduced, and the triptorelin effect is clinically used for treating hormone-dependent diseases such as prostatic cancer, uterine myoma, breast cancer, endometriosis and precocious puberty.
The triptorelin sustained release preparations which are developed and marketed at the earliest time comprise Diphereline @ (Daphthin) and Decapeptyl @ (Daphthin),
were developed contemporaneously by Ipsen, france (Yipusheng) and Ferring GmbH, germany, respectively, and were first marketed in 1986. The active ingredients are triptorelin acetate, each triptorelin acetate contains 3.75mg triptorelin, and the triptorelin acetate is embedded in a biodegradable polymer. The long-acting preparation has the action period of 1 month and excellent slow release performance, greatly prolongs the half-life period of triptorelin in a human body, obviously improves the treatment effect and improves the compliance of patients. The 1-month triptorelin preparation has great success in the market, and more long-acting dosage forms with triptorelin pamoate as an active ingredient for 3 months (11.25 mg) and 6 months (22.5 mg) are developed and marketed successively.
The commercially available triptorelin 1-month preparation is prepared by a complex coacervation method (phase separation method) by using lactide-glycolide copolymer (PLGA) 5050 (Mw 40000-60000) as a slow-release auxiliary material, specifically, triptorelin acetate powder with certain particle size distribution and a polymer are dissolved and dispersed in an organic solvent (dichloromethane) together, and a coagulant (silicone oil) immiscible with the polymer is added to initiate phase separation and formForming embryo capsule, adding hardener (n-heptane) to extract the above solvent to accelerate polymer precipitation to form preparation, cleaning, vacuum drying, and mixing with the above solvent 60 Co irradiation sterilization to obtain the sterile preparation. The hydrophilic medicinal preparation prepared by the complex coacervation method has high encapsulation efficiency, high yield, obvious defects, wide particle size distribution, high solvent residue, large environmental pressure, high cost and small batch, and is calculated by the formula ratio of the commercially available triptorelin: the yield ratio of solvent per volume (L) to formulation mass (g) was about 1 per thousand (1 g/L), with 2 thousand production scales requiring 340L of solvent (450L of coacervation tank) and 2 thousand production scales requiring 3400L of solvent (4500L) of coacervation tank. The production batch expansion to tens of thousands is obviously unrealistic, and the production can be expanded only by building a new line.
At present, common preparation methods of triptorelin acetate preparations also comprise a multiple emulsion method (Lizhu medicines CN105169366B, shandong green leaf CN104010629B and Beijing Boentte CN 104523605A), a hot melt extrusion method (Changchun Jinsai CN102048699B and Shanghai Su Haoyi Ming CN 105267153A), and the problems of sudden release of the triptorelin acetate preparation, small initial release amount of the preparation, small drug loading amount, short drug effect time and the like are only solved through the processes, and the process batch is small and the cost is high. The current production method has obvious amplification effect and great change of product properties, so that the amplification production is greatly limited. The FDA also encourages Hot Melt Extrusion (HME) as a continuous production process, which has many advantages (continuous production, few steps, no solvent) and is more applied to increasing the dissolution rate of poorly soluble drugs, and HME technology is used to encapsulate polypeptide drugs. However, the high temperature and final irradiation sterilization during extrusion will inevitably increase the amount of polypeptide-related substances (CN 102048699B, < 5%), and then the amount of expensive API used is large, i.e., large equipment is required in the product development stage to avoid the risk of amplification, and it is difficult to produce a small amount of samples on production equipment.
According to the existing research, how to realize continuous preparation (re-emulsifying shearing) is to change the various disadvantages of in-kettle shearing (batch change brings frequent replacement of core equipment, change of volume of material liquid, change of height-diameter ratio of material liquid, change of diameter ratio of shearing head to tank body, change of internal structure of shearing head, change of gap between shearing head and stator and rotor, change of linear speed of shearing head) into pipeline shearing, although the possibility of continuous production is increased, the negative effect brought by prolonging of each process link time brought by batch amplification when the re-emulsifying technology is amplified can not be solved, such as: the problem of colostrum stability change after the compound emulsion shearing time is prolonged, and how to remove a large amount of solvent in a short time in the drying process in the liquid after the volume of the material liquid is increased, so that the medicine distribution is prevented from changing, and the release behavior of the preparation is directly influenced.
Disclosure of Invention
An object of the utility model is to provide a serialization production system of triptorelin sustained-release preparation, but linear amplification, serialization production, the production that is fit for hydrophilicity pharmaceutic preparation save the industrialization production time by a wide margin, be particularly suitable for the industrialization and enlarge production.
The utility model provides a technical scheme that its technical problem adopted is:
a continuous production system of a triptorelin slow-release preparation comprises an oil phase storage tank (1), a colostrum tank (2), an outer water phase liquid storage tank (3), an online multiple emulsion shearing machine (4), a middle liquid drying tank set (5), a continuous flow centrifugal machine (6) and a freeze-drying machine (7), wherein the oil phase storage tank is connected to the colostrum tank through a pipeline, a discharge port of the colostrum tank and a discharge port of the outer water phase liquid storage tank are respectively connected to the online multiple emulsion shearing machine through a pipeline, a discharge port of the online multiple emulsion shearing machine is connected to an inlet of the middle liquid drying tank set through a pipeline, an outlet of the middle liquid drying tank set is connected to a feed port of the continuous flow centrifugal machine through a pipeline, a discharge port of the continuous flow centrifugal machine is connected to an inlet of the middle liquid drying tank set through a middle liquid drying circulation pipeline (8), a discharge port of the continuous flow centrifugal machine is further connected to a feed port of the freeze-drying machine through a pipeline, and a discharge port of the outer water phase liquid storage tank is further connected to the middle liquid drying circulation pipeline.
The utility model discloses encapsulate hydrophilic pharmaceutical preparation's research based on multiple emulsion method, to multiple emulsion method in the process of enlarging the product process link that changes, provided new technological means, show to reduce the preparation behavioural difference that batch variation brought, developed a production technology that can linearly enlarge, serialization production, be fit for hydrophilic pharmaceutical preparation in the true sense, save the industrialization production time by a wide margin, be particularly suitable for the industrialization production that enlarges. Further, the utility model discloses a production system has still solved the production and has shown the problem that the change brought in batches, can enlarge the production and produce in batches, can realize on the production line again that the production technology of experimental development stage even the production stage of trying on a small number of samples is regulated and control, and is simple and easy, and stable controllable, very big saving the time and the cost of regulating and controlling.
The utility model discloses the researcher is to the process link that the product changes in the multiple emulsion method amplification process, like link such as colostrum shearing back stability, multiple emulsion shearing, liquid in dry carries out the linear design that enlargies, through midbody and the preparation finished product that acquires different batches of preparations, collects data, carries out each item index contrast, has verified that current technical scheme has the feasibility, can realize the different batches, the link up of enlargiing or reducing between different equipment.
A colostrum jacket (14) for cooling is arranged outside the colostrum tank.
The colostrum jar still is equipped with colostrum circulation splice pipeline (9) outward, is equipped with colostrum online shear (10) on the colostrum circulation splice pipeline, and the one end of colostrum circulation splice pipeline is connected with the discharge gate of colostrum tank bottom, and the other end is connected with the circulation material access connection at colostrum tank top.
An online viscometer (11) is arranged in the colostrum tank.
The in-liquid drying tank group comprises a plurality of in-liquid drying tanks (12), and the plurality of in-liquid drying tanks are arranged in a single group and are connected in series.
The drying cylinder group in liquid includes a plurality of drying cylinders in liquid, and a plurality of drying cylinders in liquid equally divide into the multiunit, and multiunit drying cylinder in liquid adopts the parallelly connected series connection setting in the group of intergroup.
The liquid drying tank is internally provided with a stirring paddle (13).
The beneficial effects of the utility model are that:
(1) The utility model discloses all design into the pipeline type with each process step of multiple emulsion method, including colostrum shearing, multiple emulsion shearing, dry in the liquid, centrifugation collection, for realizing continuous type production, the at utmost reduces batch effect. Especially in the dry process in the liquid, the utility model discloses pioneering nature adopts 2 above dryer cans in the liquid to shift in succession, behind preliminary treatment (drying) preparation, collects in succession, returns the dryer can afterwards and carries out the liquid and dry, has guaranteed per unit volume feed liquid processing step, time highly uniform.
(2) The utility model discloses a production process is from throwing the material to obtaining the wet preparation after the washing, and the process is long can shorten to in 1 to 2h, greatly improves production efficiency.
(3) The utility model discloses production, when enlargiing in batches, only need increase drying can quantity, need not change the core equipment.
(4) The triptorelin sustained release preparation produced by the utility model has various indexes which are highly consistent among different batches.
Drawings
Fig. 1 is a schematic structural diagram of the present invention.
Fig. 2 is another schematic structural diagram of the present invention.
Detailed Description
The technical solution of the present invention is further specifically described below by way of specific examples.
In the utility model, if not, the adopted raw materials and equipment can be purchased from the market or commonly used in the field. The methods in the following examples are conventional in the art unless otherwise specified.
Example 1:
the continuous production system of the triptorelin sustained release preparation shown in figure 1 comprises an oil phase storage tank 1, a colostrum tank 2, an external water phase storage tank 3, a multiple emulsion online shearing machine 4, a liquid-medium drying tank group 5, a continuous flow centrifuge 6 and a freeze dryer 7.
The oil phase storage tank is connected to the colostrum tank through a pipeline, and a colostrum jacket 14 for cooling is arranged outside the colostrum tank. Be equipped with online viscometer 11 and overhead head of cuting 15 in the colostrum jar, the colostrum jar still is equipped with colostrum circulation splice pipeline 9 outward, is equipped with colostrum online shearing machine 10 on the colostrum circulation splice pipeline, and the one end of colostrum circulation splice pipeline is connected with the discharge gate of colostrum tank bottoms portion, and the other end is connected with the circulation material access connection at colostrum tank deck portion.
The discharge port of the colostrum tank and the discharge port of the external water phase liquid storage tank are respectively connected to the compound milk on-line shearing machine through pipelines, and the discharge port of the colostrum tank is connected with the pipeline part of the compound milk on-line shearing machine and shares with the colostrum circulating splicing pipeline.
The discharge port of the compound emulsion on-line shearing machine is connected with the inlet of the in-liquid drying tank group through a pipeline, the outlet of the in-liquid drying tank group is connected with the feed port of the continuous flow centrifugal machine through a pipeline, the discharge port of the continuous flow centrifugal machine is connected with the inlet of the in-liquid drying tank group through an in-liquid drying circulation pipeline 8, the discharge port of the continuous flow centrifugal machine is connected with the feed port of the freeze dryer through a pipeline, and the discharge port of the outer water phase liquid storage tank is connected with the in-liquid drying circulation pipeline through a pipeline.
The drying tank group in liquid comprises a plurality of drying tanks in liquid 12, in this embodiment, three drying tanks in liquid are arranged in a single group and are sequentially connected in series. The drying tank in liquid is provided with a stirring paddle 13.
Example 2:
the continuous production system of the triptorelin sustained release preparation shown in fig. 2 comprises an oil phase storage tank 1, a colostrum tank 2, an external water phase storage tank 3, a multiple emulsion online shearing machine 4, a liquid-medium drying tank group 5, a continuous flow centrifuge 6 and a freeze dryer 7.
The oil phase storage tank is connected to the colostrum tank through a pipeline, and a colostrum jacket 14 for cooling is arranged outside the colostrum tank. Be equipped with online viscometer 11 and overhead head of cuting 15 in the colostrum jar, the colostrum jar still is equipped with colostrum circulation splice pipeline 9 outward, is equipped with colostrum online shearing machine 10 on the colostrum circulation splice pipeline, and the one end of colostrum circulation splice pipeline is connected with the discharge gate of colostrum tank bottoms portion, and the other end is connected with the circulation material access connection at colostrum tank deck portion.
The discharge port of the colostrum tank and the discharge port of the external water phase liquid storage tank are respectively connected to the multiple-emulsion on-line shearing machine through pipelines, and the discharge port of the colostrum tank is connected with the pipeline part of the multiple-emulsion on-line shearing machine and shares with a colostrum circulating splicing pipeline.
The discharge port of the compound emulsion on-line shearing machine is connected with the inlet of the in-liquid drying tank group through a pipeline, the outlet of the in-liquid drying tank group is connected with the feed port of the continuous flow centrifugal machine through a pipeline, the discharge port of the continuous flow centrifugal machine is connected with the inlet of the in-liquid drying tank group through an in-liquid drying circulation pipeline 8, the discharge port of the continuous flow centrifugal machine is connected with the feed port of the freeze dryer through a pipeline, and the discharge port of the external water phase liquid storage tank is connected with the in-liquid drying circulation pipeline through a pipeline.
The liquid middle drying tank group comprises a plurality of liquid middle drying tanks 12, in the embodiment, six liquid middle drying tanks are equally divided into two groups, and the two groups of liquid middle drying tanks are arranged in parallel between the groups and in series. The drying tank in the liquid is provided with a stirring paddle 13.
The utility model discloses a use method does:
in a colostrum tank, triptorelin acetate is heated and dissolved in water to prepare an inner water phase, and the inner water phase is cooled to room temperature through a colostrum jacket; dissolving degradable polymer (such as PLGA 7525) in dichloromethane to obtain oil phase; and (3) conveying the oil phase into the inner water phase of the colostrum tank, opening an overhead shearing head in the colostrum tank to premix in the colostrum tank, then opening an online colostrum shearing machine to circularly shear the colostrum, monitoring the viscosity of the colostrum by the online viscometer until the viscosity of the colostrum does not increase, and opening a colostrum jacket to cool.
Then, opening a multiple emulsion on-line shearing machine, and simultaneously inputting the colostrum and the external water phase in the external water phase liquid storage tank into the multiple emulsion on-line shearing machine for multiple emulsion shearing; transferring the newly formed multiple emulsion into each liquid drying tank in sequence at a certain flow rate, stirring by a stirring paddle in each liquid drying tank to enable the feed liquid to stay for a fixed time in each liquid drying tank, then entering a continuous flow centrifuge for concentration, centrifuging to remove supernatant, mixing the concentrated feed liquid with fresh external water phase again in equal proportion through a liquid drying circulation pipeline, returning to the first liquid drying tank, repeating the steps of liquid drying circulation until the liquid drying is finished, centrifuging for collection, sampling to detect the solid content of the preparation, adding mannitol serving as a freeze-drying protective agent, freezing and drying in a freeze dryer, and collecting the finished product of the preparation.
Use the triptorelin acetate about 2g as the raw materials, adopt the utility model discloses a production system produces and obtains the preparation finished product, and the triptorelin preparation drug-loading capacity is 10.2%, among the pH7.4PBS, 1d burst release 10.3%, and steady release 30d. When enlargiing 10 times, use acetate triptorelin about 22g as the raw materials, under the same conditions, adopt the utility model discloses a production system production obtains the preparation finished product, obtains the triptorelin preparation drug-loading capacity and is 9.9%, among the pH7.4PBS, 1d burst release 9.5%, steadily release 30d. It can be seen that the indexes of the triptorelin sustained release preparation produced by the utility model are highly consistent between batches with significant differences.
The above-described embodiment is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and other variations and modifications may be made without departing from the scope of the invention as set forth in the claims.
Claims (8)
1. A continuous production system of a triptorelin sustained release preparation is characterized in that: the device comprises an oil phase storage tank (1), a colostrum tank (2), an outer water phase liquid storage tank (3), an online multiple emulsion shearing machine (4), a middle liquid drying tank group (5), a continuous flow centrifugal machine (6) and a freeze-drying machine (7), wherein the oil phase storage tank is connected to the colostrum tank through a pipeline, a discharge port of the colostrum tank and a discharge port of the outer water phase liquid storage tank are respectively connected to the online multiple emulsion shearing machine through pipelines, a discharge port of the online multiple emulsion shearing machine is connected with an inlet of the middle liquid drying tank group through a pipeline, an outlet of the middle liquid drying tank group is connected with a feed inlet of the continuous flow centrifugal machine through a pipeline, the discharge port of the continuous flow centrifugal machine is connected with the inlet of the middle liquid drying tank group through a middle liquid drying circulating pipeline (8), the discharge port of the continuous flow centrifugal machine is further connected with the feed inlet of the freeze-drying machine through a pipeline, and the discharge port of the outer water phase liquid storage tank is further connected with the middle liquid drying circulating pipeline through a pipeline.
2. The continuous production system of a triptorelin extended release formulation as claimed in claim 1, wherein: a colostrum jacket (14) for cooling is arranged outside the colostrum tank.
3. The continuous production system of a triptorelin extended release formulation as claimed in claim 1, wherein: the colostrum jar still is equipped with colostrum circulation splice pipeline (9) outward, is equipped with colostrum online shear (10) on the colostrum circulation splice pipeline, and the one end of colostrum circulation splice pipeline is connected with the discharge gate of colostrum tank bottom, and the other end is connected with the circulation material access connection at colostrum tank top.
4. The continuous production system of a triptorelin extended release formulation as claimed in claim 1, wherein: an online viscometer (11) is arranged in the colostrum tank.
5. The continuous production system of a triptorelin extended release formulation as claimed in claim 1, wherein: the in-liquid drying tank group comprises a plurality of in-liquid drying tanks (12), and the plurality of in-liquid drying tanks are singly arranged and are arranged in series.
6. The continuous production system of a triptorelin extended release formulation as claimed in claim 1, wherein: the drying cylinder group in liquid includes a plurality of drying cylinders in liquid, and a plurality of drying cylinders in liquid equally divide into the multiunit, and multiunit drying cylinder in liquid adopts the parallelly connected series connection setting in the group of intergroup.
7. The continuous production system of a triptorelin extended release formulation of claim 5 or 6, wherein: the number of the drying tanks in the liquid is 2-10.
8. The continuous production system of a triptorelin extended release formulation of claim 5 or 6, wherein: the drying tank in liquid is provided with a stirring paddle (13).
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| CN202220389694.2U CN217908365U (en) | 2022-02-25 | 2022-02-25 | Continuous production system of triptorelin sustained-release preparation |
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