Filling method of medicine crystal suspension

Abstract

The invention discloses a filling method of a medicine crystal suspension, and relates to the technical field of pharmacy. Comprising the following steps: mixing a sterile API crystal with a sterile auxiliary material buffer solution to prepare a target content of suspension liquid medicine, and storing the suspension liquid medicine in a liquid medicine storage tank; the suspension liquid medicine is conveyed into a buffer tank in an isolator, the liquid medicine in the buffer tank is conveyed into a filling machine to be filled, and a filled finished product is obtained; in the filling process, the suspension liquid medicine flows back to the liquid medicine storage tank and keeps circulation in the tank from the liquid medicine storage tank through the circulating pump 1, the other path is conveyed to the buffer tank, and the suspension liquid medicine in the buffer tank is subjected to liquid medicine circulation through the circulating pump 2; the uniformity of the liquid medicine content of the non-final sterilized suspension in the filling process is effectively ensured by adopting a liquid medicine double-circulation mode, the filling effect is improved, the API content of a final filled finished product is ensured, the requirement of large-scale production is met, meanwhile, the production cost is reduced, and meanwhile, the limitation of traditional shaking table equipment is overcome.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceuticals, and in particular to a filling method for a drug crystal suspension. Background Art

[0002] Since suspensions are non-uniformly dispersed liquid medicines in which poorly soluble solid drugs are dispersed in the dispersion medium in the form of microparticles, the API crystal particles in the suspensions will settle due to gravity. Therefore, in the pharmaceutical industry, the aseptic filling process of non-terminally sterilized suspension products faces some technical challenges, especially during the long filling process of several hours, when it is necessary to ensure the uniformity of the drug solution content.

[0003] To prevent sedimentation, traditional shaking equipment is widely used in the suspension production and filling process. However, this technology has some limitations:

[0004] ① Limited production batch: The shaking table equipment is mainly suitable for small batches of suspension liquid, with a capacity of about 20 to 30 liters. For large batches of suspension liquid, the mixing effect of the shaking table equipment may not be uniform, and the uniformity of the liquid content of the entire batch cannot be guaranteed.

[0005] ② Limited application scenarios: Shaker equipment is usually suitable for the design of restricted access barrier systems (RABS) in Class B background environments. Due to the large size of the shaker equipment and the limited internal space of the isolator, it is generally not applicable to the isolator.

[0006] ③High operational complexity: The operating interface of traditional shaker equipment is relatively complex, and cumbersome operations may increase new sterility risks.

[0007] ④ Expensive: High-performance shaking table equipment is usually expensive, and its operation and maintenance costs affect the economic benefits of the enterprise.

[0008] Based on the limitations of non-terminally sterilized suspensions in the prior art during filling, the present invention proposes a new filling method for drug crystal suspensions. Summary of the invention

[0009] The invention aims to solve the technical problem that during the filling process of non-terminally sterilized suspensions, due to long-term filling, the drug solution is prone to sedimentation and the uniformity of the drug solution content cannot be ensured. The invention aims to provide a filling method for drug crystal suspensions. By adopting a double circulation mode of drug solution, the uniformity of the drug solution content of the non-terminally sterilized suspensions during the filling process is effectively ensured, the filling effect is improved, the API content of the final filled product is guaranteed, the needs of large-scale production are met while reducing the production cost, and at the same time, the limitations of traditional shaking table equipment are overcome.

[0010] The present invention is achieved through the following technical solutions:

[0011] A filling method for a drug crystal suspension comprises the following steps:

[0012] Mixing sterile API crystals with sterile excipient buffer solution to prepare a suspension solution with a target content, and storing it in a solution storage tank;

[0013] The suspended drug solution is transported to a buffer tank in the isolator, and the drug solution in the buffer tank is sent to a filling machine for filling to obtain a finished filled product;

[0014] During the filling process, the suspended liquid medicine flows from the liquid medicine storage tank through the circulation pump 1, one way is returned to the liquid medicine storage tank to maintain the circulation in the tank, and the other way is transported to the buffer tank, and the suspended liquid medicine in the buffer tank is circulated by the circulation pump 2.

[0015] As a further technical solution of the present invention, before the sterile API crystals are mixed with the sterile auxiliary material buffer solution, the sterile API crystals need to be pretreated, including:

[0016] The drug crystals were sieve filtered and washed 3 to 10 times.

[0017] As a further technical solution of the present invention, the pretreatment is carried out in a filtering, washing and drying all-in-one machine.

[0018] As a further technical solution of the present invention, the specific method of filtering and washing includes:

[0019] Introduce sterile filtered water for injection and clean compressed air into the filtering, washing and drying machine, control the pressure at 0.02-0.20 MPa, and filter and wash the drug crystals through a sieve for 3-10 times to prepare API crystals.

[0020] As a further technical solution of the present invention, when the suspended drug solution is stored in a drug solution storage tank, the drug solution storage tank needs to be kept in a stirring state.

[0021] As a further technical solution of the present invention, the stirring speed of the drug solution storage tank is controlled at 200-400 rpm.

[0022] As a further technical solution of the present invention, the step of conveying the suspended drug solution to the buffer tank in the isolator comprises:

[0023] Introduce clean compressed air into the drug liquid storage tank, control the pressure at 0.02-0.20MPa, and transport the suspended drug liquid to the buffer tank in the isolator for preparation of filling.

[0024] As a further technical solution of the present invention, when the suspended drug solution is stored in a buffer tank, the buffer tank needs to maintain a self-circulating state.

[0025] As a further technical solution of the present invention, the rotation speed of the circulation pump 2 is controlled at 300-500 rpm.

[0026] As a further technical solution of the present invention, after the filling is completed, it is necessary to visually check whether there are crystal particles attached to the stirring device at the bottom of the liquid medicine storage tank, the bottom of the buffer tank, and the hoses of the circulating pump 1 and the circulating pump 2.

[0027] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0028] 1. The present invention fills the drug liquid in a dual circulation flow mode of circulating inside and outside the isolator. On the one hand, through the process of circulating the drug liquid outside the isolator, the drug liquid can be self-circulated outside the isolator, thereby maintaining the uniformity of the content of the drug liquid to be filled and preventing sedimentation problems caused by standing still for a long time. On the other hand, through the process of circulating the drug liquid inside the isolator, the drug liquid circulates in the buffer tank in the isolator, which can further ensure the uniformity of the drug liquid during the filling process, especially the drug liquid near the filling point; at the same time, the drug liquid storage tank and the buffer tank are kept in a stirring state, ultimately ensuring the uniformity of the drug liquid content of the non-terminally sterilized suspension during the filling process.

[0029] 2. The present invention effectively ensures the uniformity of the drug liquid content of non-terminally sterilized suspensions during the filling process by adopting a double circulation method of drug liquid, improves the filling effect, ensures the API content of the final filled product, adapts to the needs of large-scale production while reducing production costs. At the same time, it overcomes the limitations of traditional shaking table equipment and provides a new aseptic filling solution for the pharmaceutical industry. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and should not be regarded as limiting the scope. For those of ordinary skill in the art, other relevant drawings can be obtained based on these drawings without creative work. In the drawings:

[0031] Figure 1 It is a schematic diagram of the connection structure of the filling system of the present invention. DETAILED DESCRIPTION

[0032] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the technical solutions in the embodiments of the present invention are clearly and completely described below in combination with the embodiments and drawings. Obviously, the schematic implementation modes of the present invention and their description are only used to explain the present invention and are not intended to limit the present invention.

[0033] The following is a detailed description of an embodiment of a new method for filling a pharmaceutical crystal suspension of the present invention with reference to the accompanying drawings as appropriate. However, there may be cases where unnecessary detailed descriptions are omitted. For example, there may be cases where detailed descriptions and repeated descriptions of well-known matters are omitted. This is to avoid the following description from becoming unnecessarily lengthy and to facilitate understanding by those skilled in the art.

[0034] The "range" disclosed in this application is defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of the particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a range.

[0035] Unless otherwise specified, all embodiments and optional embodiments of the present application can be combined with each other to form a new technical solution.

[0036] Unless otherwise specified, all technical features and optional technical features of this application can be combined with each other to form a new technical solution.

[0037] Unless otherwise specified, the terms "include" and "comprising" mentioned in this application may be open-ended or closed-ended. For example, the terms "include" and "comprising" may mean that other substances not listed may also be included or only the listed substances may be included.

[0038] If there is no special explanation, all the steps of the present application can be performed sequentially or randomly, preferably sequentially.

[0039] In order to solve the technical problem that during the filling process of non-terminally sterilized suspensions, due to long-term filling, the drug solution is prone to sedimentation and the uniformity of the drug solution content cannot be ensured, the technical solution of the present invention is to provide a filling method for drug crystal suspensions, comprising the following steps:

[0040] (1) Preparation of suspension solution

[0041] The drug crystals are filtered through a sieve and washed with water for injection to prepare sterile, uniformly sized and highly pure active pharmaceutical ingredient (API) crystals; the sterile API crystals are mixed with a sterile excipient buffer solution to prepare a suspension solution with a target content, which is stored in a drug solution storage tank; aseptic sampling is performed through a movable sampling port of the drug solution storage tank to detect the API content.

[0042] In order to prevent the drug crystals from settling, the suspension drug solution needs to be kept in a stirring state when it is stored in the drug solution storage tank, so that the liquid remains in a slightly suspended state, and the stirring speed is controlled at 200-400 rpm, thereby ensuring that a suspension drug solution with uniform content is prepared.

[0043] Preferably, the drug crystals are screen filtered and washed 3 to 10 times. Impurities are effectively removed through multiple filtrations and washings to obtain sterile API crystals with uniform particle size distribution and high purity.

[0044] Among them, filtration and washing are carried out in a filtering, washing and drying machine, and the sterile auxiliary material buffer solution is transported to the filtering, washing and drying machine to be mixed with the sterile API crystals.

[0045] (2) Preparation before filling

[0046] The isolator chamber has been bio-purified to ensure a sterile internal environment.

[0047] The filling system inside the isolator includes a buffer tank and liquid medicine pipeline, which are cleaned (CIP) and sterilized (SIP).

[0048] The drug liquid storage tank and filling machine are connected to the outside of the isolator through stainless steel pipes. The connecting pipes also pass CIP and SIP, and the entire system is in a sterile state.

[0049] (3) Liquid drug delivery

[0050] Clean compressed air is introduced into the drug storage tank, and the pressure is controlled to be 0.02-0.20MPa, and the suspended drug liquid is transported to the buffer tank in the isolator for filling. When the suspended drug liquid is stored in the buffer tank, the drug liquid in the buffer tank needs to be kept in a self-circulating state by the circulation pump 2, and the speed of the circulation pump 2 is controlled at 300-500rpm.

[0051] (4) Filling

[0052] The suspension is filled by using a double circulation method inside and outside the isolator to prevent the liquid from settling during the filling process.

[0053] Circulation outside the isolator: The suspended drug solution flows from the drug solution storage tank through the circulation pump 1 and flows back to the drug solution storage tank to maintain the circulation inside the drug solution storage tank. During the circulation outside the isolator, the bottom of the drug solution storage tank is opened for continuous stirring to achieve the circulation of the drug solution in the tank. The drug solution is self-circulated outside the isolator through the circulation pump 1 and the circulation pipeline, thereby maintaining the uniformity of the content of the drug solution to be filled and preventing sedimentation problems caused by long-term standing.

[0054] Circulation in the isolator: The suspended liquid medicine coming out of the liquid medicine storage tank is transported to the buffer tank by another route through the circulation pump 1. The suspended liquid medicine in the buffer tank is self-circulated in the isolator through the circulation pump 2. In the process of circulation in the isolator, the liquid medicine circulates in the buffer tank in the isolator through the circulation pump 2, which can further ensure the uniformity of the liquid medicine during the filling process, especially the liquid medicine near the filling point.

[0055] Under the double-circulation stirring mode, the drug solution is quantitatively filled and vacuum stoppered to obtain a pre-filled needle product with uniform content.

[0056] (5) Inspection after filling

[0057] Visually inspect the system where the drug solution comes in direct contact with the patient for any crystal particles.

[0058] (6) Inspection

[0059] Take appropriate amount of finished products from the front, middle and back stages of filling and test the API content.

[0060] The present invention fills the drug liquid in a dual circulation flow mode of circulating inside and outside the isolator. On the one hand, through the process of circulating the drug liquid outside the isolator, the drug liquid can be self-circulated outside the isolator, thereby maintaining the uniformity of the content of the drug liquid to be filled and preventing sedimentation problems caused by standing still for a long time. On the other hand, through the process of circulating the drug liquid inside the isolator, the drug liquid circulates in the buffer tank in the isolator, which can further ensure the uniformity of the drug liquid during the filling process, especially the drug liquid near the filling point; at the same time, the drug liquid storage tank is always kept in a stirring state, ultimately ensuring the uniformity of the drug liquid content of the non-terminally sterilized suspension during the filling process.

[0061] Therefore, the present invention effectively ensures the uniformity of the drug liquid content of non-terminally sterilized suspensions during the filling process by adopting a double circulation method of drug liquid, improves the filling effect, ensures the API content of the final filled product, adapts to the needs of large-scale production while reducing production costs, and at the same time overcomes the limitations of traditional shaking table equipment, providing a new aseptic filling solution for the pharmaceutical industry.

[0062] The technical solution of the present invention is further described in detail below in conjunction with embodiments.

[0063] It should be noted that the experimental methods used in the examples are conventional methods unless otherwise specified. The materials, reagents, methods and instruments used are conventional materials, reagents, methods and instruments in the art unless otherwise specified, and can be obtained by those skilled in the art through commercial channels.

[0064] Example 1

[0065] Raw materials: API crystals, water for injection, excipient buffer solution.

[0066] Equipment: Filter, wash and dryer, liquid medicine storage tank, filling machine, isolator, auxiliary material preparation tank. Figure 1 shown.

[0067] A filling method for a drug crystal suspension comprises the following steps:

[0068] (1) Preparation of suspension solution:

[0069] Sterile filtered water for injection and clean compressed air were introduced into the filtering, washing and drying machine, and the pressure was controlled at 0.02-0.20 MPa. After the drug crystals were filtered and washed through a sieve for 5 times, active pharmaceutical ingredient (API) crystals (white) with uniform particle size were prepared, and the volume average particle size (Dv50) was 20 μm.

[0070] The prepared auxiliary material buffer solution is filtered through two-stage sterilization from the auxiliary material preparation tank to the filtering, washing and drying machine, and the stirring is turned on. The stirring speed is controlled at 15 rpm to resuspend the crystals and finally transported to the drug solution storage tank through a closed pipeline.

[0071] The drug solution storage tank was kept stirring, and the stirring speed was controlled at 300 rpm to prepare a suspension drug solution with uniform content. After testing, the API content was 100 mg / mL.

[0072] (2) Preparation before filling:

[0073] The isolator chamber has been bio-purified to ensure a sterile internal environment.

[0074] The filling system inside the isolator, including the buffer tank and liquid medicine pipeline, has been cleaned (CIP) and sterilized (SIP).

[0075] The drug liquid storage tank and filling machine are connected to the outside of the isolator through stainless steel pipes. The connecting pipes also pass CIP and SIP, and the entire system is in a sterile state.

[0076] (3) Drug delivery:

[0077] Introduce clean compressed air into the drug liquid storage tank, control the pressure at 0.02-0.20MPa, and transport the drug liquid to the buffer tank in the isolator for preparation of filling.

[0078] (4) Filling:

[0079] The liquid medicine storage tank outside the isolator is kept stirred at a speed of 300rpm to prevent the liquid medicine to be filled from settling after being left still for a long time. During the filling process, the liquid medicine flows back from the liquid medicine storage tank through the circulation pump 1 to the liquid medicine storage tank, keeps circulating in the tank, and is transported to the filling buffer tank. The suspension in the buffer tank is circulated by the circulation pump 2, and the speed of the circulation pump 2 is 400rpm to ensure uniform liquid medicine content near the filling point.

[0080] The liquid medicine in the buffer tank is filled into the prefilled needle container, and the filling time is about 3 hours. After vacuum stoppering, the finished filled product is obtained.

[0081] (5) Inspection after filling:

[0082] After filling, visually inspect the stirring device at the bottom of the liquid storage tank, the bottom of the buffer tank, and the hoses of circulating pump 1 and circulating pump 2. No obvious white crystals are attached.

[0083] (6) Inspection:

[0084] Samples were taken from the front, middle and back stages of filling, and the API concentrations were detected to be 99 mg / mL, 101 mg / mL and 100 mg / mL respectively.

[0085] Comparative Example 1

[0086] Raw materials: API crystals, water for injection, excipient buffer solution

[0087] Equipment: Filter, wash and dryer, liquid medicine storage tank, filling machine, isolator, auxiliary material preparation tank.

[0088] A filling method for a drug crystal suspension, which differs from Example 1 in that the suspension in the buffer tank is not circulated, specifically comprising the following steps:

[0089] (1) Preparation of suspension drug solution: Sterile filtered water for injection and clean compressed air were introduced into a filter-washing-drying machine, and the pressure was controlled at 0.02-0.20 MPa. The drug crystals were filtered and washed 5 times to obtain active pharmaceutical ingredient (API) crystals (white) with uniform particle size and a volume average particle size (Dv50) of 20 μm.

[0090] The prepared auxiliary material buffer solution is filtered through two-stage sterilization from the auxiliary material preparation tank to the filtering, washing and drying machine, and the stirring is turned on. The stirring speed is controlled at 15 rpm to resuspend the crystals and finally transported to the drug solution storage tank through a closed pipeline.

[0091] The tank was kept stirred and the stirring speed was controlled at 300 rpm to prepare a suspension solution with uniform content. After testing, the API content was 100 mg / mL.

[0092] (2) Preparation before filling:

[0093] The isolator chamber has been bio-purified to ensure a sterile internal environment.

[0094] The filling system inside the isolator, including the buffer tank and liquid medicine pipeline, has been cleaned (CIP) and sterilized (SIP).

[0095] The drug liquid storage tank and filling machine are connected to the outside of the isolator through stainless steel pipes. The connecting pipes also pass CIP and SIP, and the entire system is in a sterile state.

[0096] (3) Drug delivery:

[0097] Introduce clean compressed air into the drug liquid storage tank, control the pressure at 0.02-0.20MPa, and transport the drug liquid to the buffer tank in the isolator for preparation of filling.

[0098] (4) Filling

[0099] The liquid medicine storage tank outside the isolator is kept stirred at 300rpm to prevent the liquid medicine to be filled from settling after a long period of static state. The suspension in the buffer tank is not circulated and is directly filled into the prefilled needle container. The filling time is about 3h. After vacuum plugging, the finished filling product is obtained.

[0100] (5) Inspection after filling:

[0101] After filling, a visual inspection revealed obvious white crystals adhering to the liquid hose.

[0102] (6) Inspection:

[0103] Samples were taken from the front, middle and back stages of filling, and the API test results were 99 mg / mL, 92 mg / mL and 87 mg / mL respectively.

[0104] The filling processes of Example 1 and Comparative Example 1 were subjected to relevant tests, and the results are shown in Table 1.

[0105] Table 1 Comparison of relevant test data of filling process of Example 1 and Comparative Example 1

[0106] Detection point API content of Example 1 (mg / mL) API content of comparative example 1 (mg / mL) Preparation completed 100 100 Filling front section 99 99 Filling middle section 101 92 After filling 100 87 Inspection after filling No obvious white crystals attached to the filling system There are obvious white crystals attached to the filling system

[0107] As can be seen from Table 1, for the suspension with an API content of 100 mg / mL, the embodiment of the present invention performs a double circulation of the liquid medicine. During the aseptic filling process of about 3 hours, the API content of the finished product before, during and after filling is uniform, and there is no significant change compared with the API content after the preparation, and the content uniformity is guaranteed; while the comparative example does not design a liquid medicine circulation. During the aseptic filling process of about 3 hours, as the filling time increases, the API content shows a significant downward trend. After the filling is completed, visual inspection shows that there are obvious white crystals attached to the liquid medicine hose. It can be seen that the present invention adopts a double circulation system design for double circulation filling of the liquid medicine, which can effectively prevent crystal sedimentation, improve the uniformity of the liquid medicine content during the filling process, and ensure the stability of the API content of the finished liquid medicine.

[0108] Finally, it should be noted that the above specific embodiments are only used to explain in detail the purpose, technical solutions and beneficial effects of the present invention. It should be understood that the above description is only a specific implementation method of the present invention and is not used to limit the protection scope of the present invention. Although the present invention is described in detail with reference to the above specific embodiments, ordinary technicians in this field should understand that it is still possible to modify the technical solutions recorded in the above embodiments, or to replace or improve some or all of the technical features therein. These modifications, equivalent replacements and improvements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the scope of the claims and description of the present invention.

Claims

1. A filling method for a drug crystal suspension, characterized in that: The following steps are involved: Mixing sterile API crystals with sterile excipient buffer solution to prepare a suspension solution with a target content, and storing it in a solution storage tank; The suspended drug solution is transported to a buffer tank in the isolator, and the drug solution in the buffer tank is sent to a filling machine for filling to obtain a finished filled product; During the filling process, the suspended liquid flows from the liquid storage tank through the circulation pump 1, one way is returned to the liquid storage tank to maintain the circulation in the tank, and the other way is transported to the buffer tank. The suspended liquid in the buffer tank is circulated by the circulation pump 2.

2. A filling method for a pharmaceutical crystal suspension according to claim 1, characterized in that: Before the sterile API crystals are mixed with the sterile excipient buffer solution, the sterile API crystals need to be pretreated, including: The drug crystals were sieve filtered and washed 3 to 10 times.

3. A filling method for a pharmaceutical crystal suspension according to claim 2, characterized in that: The pretreatment is carried out in a filtering, washing and drying integrated machine.

4. A filling method for a pharmaceutical crystal suspension according to claim 2, characterized in that: The specific method of filtering and washing comprises: Introduce sterile filtered water for injection and clean compressed air into the filtering, washing and drying machine, control the pressure at 0.02-0.20 MPa, and filter and wash the drug crystals through a sieve for 3-10 times to prepare API crystals.

5. A filling method for a pharmaceutical crystal suspension according to claim 1, characterized in that: When the suspended drug solution is stored in the drug solution storage tank, the drug solution storage tank needs to be kept in a stirring state.

6. A filling method for a pharmaceutical crystal suspension according to claim 5, characterized in that: The stirring speed of the drug solution storage tank is controlled at 200-400 rpm.

7. A filling method for a pharmaceutical crystal suspension according to claim 1, characterized in that: The method of conveying the suspended drug solution to the buffer tank in the isolator comprises: Introduce clean compressed air into the drug liquid storage tank, control the pressure at 0.02-0.20MPa, and transport the suspended drug liquid to the buffer tank in the isolator for preparation of filling.

8. A filling method for a pharmaceutical crystal suspension according to claim 1, characterized in that: When the suspended drug solution is stored in the buffer tank, the drug solution in the buffer tank needs to maintain a self-circulating state.

9. A filling method for a pharmaceutical crystal suspension according to claim 8, characterized in that: The rotation speed of the circulating pump 2 is controlled at 300-500 rpm.

10. The filling method of a pharmaceutical crystal suspension according to claim 1, characterized in that: After the filling is completed, it is necessary to visually check the stirring device at the bottom of the liquid medicine storage tank, the bottom of the buffer tank, and the hoses of the circulation pump 1 and the circulation pump 2 to see if there are crystal particles attached.

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