WO2000013666A1

WO2000013666A1 - Biodegradable particulate polymeric preparation and process for producing thereof

Info

Publication number: WO2000013666A1
Application number: PCT/KR1999/000512
Authority: WO
Inventors: Seung Jin Lee
Original assignee: Seung Jin Lee
Priority date: 1998-09-05
Filing date: 1999-09-03
Publication date: 2000-03-16
Also published as: AU5532699A

Abstract

The present invention relates to a biodegradable particulate polymeric preparation that can be locally applicable to the affected site of patients when subjected to a prolonged treatment; and process for producing thereof. More particularly, the present invention relates to the biodegradable particulate polymeric preparation and process for producing thereof, wherein a drug, being incorporated in a porous particulate formed by polymer and organic solvent, is slowly released to the affected site of patients for a longer period of time. The particulate-type preparation, so prepared according to the present invention, has some advantages in that since a polymeric solution containing drugs is dried at room temperature followed by a pulverization, the manufacturing process is not only more simple without any loss of drugs, but also the homogeneous incorporation of drugs can be ensured. Further, the release amount of drugs incorporated in a matrix can be easily controlled due to the fact that the size of micro-holes can be changed depending on the use of organic solvent and its mixing ratio. Therefore, the drug-containing porous particulate-type preparation of the present invention can maintain its therapeutic effect in the local affected site for a prolonged time.

Description

BIODEGRADABLE PARTICULATE POLYMERIC PREPARATION AND PROCESS FOR PRODUCING THEREOF

TECHNICAL FIELD The present invention relates to a biodegradable particulate polymeric preparation that can be locally applicable to the affected site of patients when subjected to a prolonged treatment; and process for producing thereof. More particularly, the present invention relates to the biodegradable particulate polymeric preparation and process for producing thereof, wherein a drug, being incorporated in a porous particulate formed by polymer and organic solvent, is slowly released to the affected site of patients for a longer period of time.

BACKGROUND ART The locally limited lesions are treated via local-administration of various injectable formulations using antibiotics, anti-inflammatory agents, local anaesthetic, protein drugs and opioid antagonists in the injectable forms. Hence, the introduction of the sustained-release technique of drugs may achieve the enhancement of therapeutic effects due to more extended retention of drug in the local site.

For an antibiotics, which is used for the treatment of gingival periodontitis, neuritis, cystitis, ophthalmic diseases, etc., the applications of particulate drug delivery system have been disclosed in some literatures including J. Microencapsul., 13, 195-205(1996) and J. Microencapsul., 11, 445(1994). Some particulate-type anti-inflammatory agents have been disclosed in some literatures including Biomaterials, 15, 49-54(1994). Local anesthetics have been also suggested in a manner such that they are incorporated to polymeric particulate for therapeutic use [Chem. Pharma. Bull., 29, 3363(1981)]. Protein drugs (e.g., vaccines, growth hormones, tissue growth factor, etc.) are being utilized as an incorporated-type in a polymeric particulate.

Two methods of incorporating a drug to a particulate have been reported as follows: (1) a method of manufacturing a particulate-type preparation by removal of a solvent from an o/w emulsion state, and (2) a spray-drying method of a mixing solution of drug and polymer solution. The first method, which has been frequently applicable in the related field, is directed to formulating a polymeric particulate containing a drug in a manner such that a drug and a solution of polymer in an organic solvent are mixed homogeneously to obtain a mixing solution; the mixing solution is dispersed in water to prepare an o/w emulsion; and then, the organic solvent in the emulsion is removed by heat or in a method of solvent substitution. However, this method is somewhat complicated in the manufacturing process. Furthermore, in a process where the mixing solution of polymer and drug is dispersed in water, the drug contained in a minute droplet is leaked or released in water, thus reducing the contents of drug in a final particulate. Under such circumstances, it has been reported that the incorporation rate of drug is less than 20% (International J. Pharmaceutics 98(1993), 157-164; J. Controlled Release 16(1991), 177-186). This method has recognized some disadvantages in that unstable leakage or -releasing of drug from the minute droplet (i.e., unstable contents of drug in a final particulate) makes it more difficult to ensure the reproducibility of drug incorporation and to establish the - j -

manufacturing conditions hereto.

To avoid the leaking phenomenon of drug into water phase, therefore, the w/o/w emulsion technique - emulsifying the drug-aqueous solution in a polymeric solution and then, re-dispersing the resultant emulsion in water - has been proposed, but has failed to maintain the constant contents of drug.

To overcome the shortcomings that the first method has encountered, the second method is also directed to formulating a polymeric particulate containing a drug in a manner such that a drug and a solution of polymer in an organic solvent are mixed homogeneously to obtain a mixing solution; and then, the mixing solution is sprayed and simultaneously dried at a very high temperature.

Nevertheless, this method has also several disadvantages in that any highly viscous solution is not suitable for spraying and even in the spraying process, particles are accumulated so that their size cannot be easily controlled. Furthermore, the spraying process at a very high temperature is not suitable for heat-labile drugs, such as protein drugs, some antibiotics, etc.

An object of the present invention is to provide a biodegradable particulate polymeric preparation and a process for preparing thereof, wherein the biodegradable particulate polymeric preparation, which is designed for administration of a drug towards a local affected site, shows an optimal therapeutic effect in patients when subjected to prolonged treatment, in a manner such that the drug incorporated is released over the prolonged period of time, and wherein the preparing process produces a particulate having the reproducible contents of drug without any degradation or loss of drug as well as the preparing process is very simple.

DISCLOSURE OF THE INVENTION

The inventor et al. have conducted intensive researches to develop a method by which a drug is more effectively incorporated in a particulate. In the result, they come to know that more effective incorporation of drug into a particulate could be achieved via a method in which drug is dissolved or dispersed in the solution of polymer in organic solvent, followed by drying the resultant mixing solution at room temperature; then, the matrix, so obtained, is pulverized by a pulverizer to prepare particulates. Thus, the present invention has been completed.

The present invention relates to a process for preparing a biodegradable particulate polymeric preparation, wherein a polymeric material is dissolved in an organic solvent to yield a polymeric solution and with the addition of a drug, the mixture is dried at room temperature; then, the matrix, so obtained, is pulverized by a pulverizer to prepare particulates. The present invention relates to also a biodegradable particulate polymeric preparation obtained by the said process. Examples of the polymeric material used for the manufacture of the biodegradable particulate according to the present invention may include polylactic acid, polylactic acid-glycolic acid copolymer and polycaprolactone. The preferred molecular weight of the polymer is in the range of 50,000-400,000 Da. It is preferred that when the polymeric material is dissolved in an appropriate organic solvent, its concentration is in the range of 0.5~20%w/v based on the organic solvent. If the concentration of the polymeric material is less than 0.5%w/v, the controlling capacity of drug release is reduced in forming a particulate but in case of exceeding 20%w/v, the solution is highly viscous so that the polymeric solution itself cannot be prepared. Any kind of solvents, which can well dissolve the polymeric material and is easily dried at room temperature for the manufacture of a particulate-type preparation, may be selected as the organic solvent used for dissolving the polymeric material. The preferred example of the polymeric material may include methylene chloride. In a certain preferred embodiment, a mixed-solvent may be used as the organic solvent. More specifically, one solvent (primary solvent), which can well dissolve the polymeric material and is easily evaporated with a low boiling point, is mixed with the other solvent (secondary solvent) having higher boiling point and poor solubility to the polymeric material than the primary solvent. Since the secondary solvent serves to facilitate the formation of porosity in the matrix of particulate-type preparation, the release rate can be adequately controlled so that the particulate-type preparation having an optimal release profile can be easily prepared. The preferred examples of the secondary solvent may include ethylacetate, N-methylpyrroline and ethanol. The preferred mixing ratio between the primary and secondary solvents may be determined depending on the physicochemical properties and pharmacokinetics of drug, the kind of polymer selected, etc. It is preferred that the mixing ratio of the mixed- solvent is adjusted in a matter such that the drug is released for 1-4 weeks. When the amount of the secondary solvent is increased, the release rate of particulate-type preparation becomes facilitated. According to the present invention, it is preferred that the mixed-solvent is prepared in the mixing ratio of 1 : 0.25-1 (primary solvent : co-solvent).

The formation process of particulate polymeric preparation using the mixed-solvent is explained by the following example: After polylactic acid, a polymeric material, is dissolved in the mixed-solvent containing methylene chloride (a primary solvent) and ethylacetate (a secondary solvent) and dried, methylene chloride begin to evaporate before ethylacetate. It is contemplated that the boiling point of methylene chloride (39.75 ^°C) is lower than that of ethylacetate (77 ^°C ). As methylene chloride is evaporating, the formation of a polylactic acid matrix begins to be progressed. A compact matrix is formed at the area where the readily evaporated methylene chloride is present, while small holes or cracks are formed at the area where ethylacetate is present, since ethylacetate has less solubility to polylactic acid than methylene chloride does. With the lapse of 24 hours at room temperature, volatile ethylacetate is completely evaporated. Then, fine-pores are being formed at the area where ethylacetate is present, thus fabricating a porous intra-structure.

More specifically, in case where the particulate-type preparation is prepared using methylene chloride, the particulate-type preparation with a compact matrix structure is formed. By contrast, the present invention is characterized by the particulate-type preparation with a porous matrix structure using the co-solvent.

Any drug, which can enhance the therapeutic effect by applying the biodegradable particulate polymeric preparation of the present invention, can be used regardless of physicochemical properties of drugs. The fact that any drug can be applicable in the present invention can be found in that the preparing process according to the present invention, unlike the prior arts, (1) does not include any step of emulsifying or suspending the mixture of drug and polymeric solution in water so that there is no loss of drug, (2) has little possibility that drugs are inactivated or degenerated because of the absence of heating step. The examples of drugs in the present inventions include antibiotics indicated for periodontitis, cystitis, sinusitis, bone diseases, ophthalmic diseases, prostatitis, etc.; antitumor agents; anti-inflammatory agents indicated for arthritis, etc.; and, steroidal drugs indicated for endocrine disease, etc. However, the present invention is not limited to these drugs. The detailed examples of drugs include antibiotics such as tetracyclines, cephalosporins, penicillins, ofloxacins, erythromycins, etc.; anti-inflammatory agents such as flurbiprofen, ketoprofen, indomethacin, piroxicam, mefenamic acid, etc.; protein drugs such as vaccines, growth hormone, insulin, platelet-derived growth factor, epithelium growth factor, transforming growth factor, etc.; antitumor agents such as methotroxate, adriamycin, 5-fluorouracil, taxol, etc. It is preferred that except for protein drugs, the application content of drug for the preparation according to the present invention is in the range of 0.1-0.3 parts per part by weight of polymer. Meantime, the application content of protein drugs may quite vary depending on a single dose and their activity. In the case of platelet-derived growth factor, it is preferred particularly that a single-dose preparation contains 100-5,000 ng of platelet-derived growth factor. Therefore, the application content of the platelet-derived growth factor is in the range of I x l0^"7~5xl0^"6 parts per part by weight of polymer.

In the preparing process according to the present invention, the drug may be added to the polymeric solution after the polymer is dissolved in an organic solvent. Otherwise, the drug may be also added to organic solvent with the polymer simultaneously.

The particulate-type preparation according to the present invention may be prepared with the further addition of a hydrophilic material to the polymeric solution. When the hydrophilic material is added, a matrix is well harmonious with water molecules in the body and its water infiltration is enhanced. Then, the drug is easily released from the particulate, thus improving the affinity with adjacent tissues during administration. Examples of the hydrophilic material include polyethylene glycol, polyethylene glycol-polypropylene glycol copolymer (Poloxamer: BASF of Germany), glycerin, etc. It is preferred that the amount of hydrophilic material is in the range of 0.1-0.3 parts per part by weight of polymer.

Further, a nonionic surfactant may be added to the polymeric solution. In case where the hydrophilic material is used or in the case where water-soluble drug, which does not dissolved in an organic solvent, is used, the particulate polymeric preparation may be preferably prepared using the said mixing solution comprising a nonionic surfactant (more preferably, further comprising water along with a nonionic surfactant). A w/o emulsion may be formed by the addition of water along with a nonionic surfactant to the polymeric solution, and then next step is progressed, thereby to prepare the particulate-type preparation preferably in accordance with the preparing process of the present invention. With the increase of emulsification and dispersion using the nonionic surfactant, the water affinity of the particulate polymeric preparation becomes enhanced. The release profile of drug may be also controlled by an emulsification technique. Any nonionic surfactant meeting the above objectives may be employed. Span 80 (Showa Chem. Co. of Japan) was used as one example of the nonionic surfactant according to the present invention.

In the preparing process, the mixing solution containing each component according to the present invention is dried at room temperature to form a matrix. Then, the matrix is pulverized by a pulverizer to prepare particulates having the particle size of micron. The preferred particle size in the range of 45 ~ 150 μm, more preferably in 100 μm. Any pulverizer meeting the above objectives may be employed. Example of pulverizer include micromill, jet mill, etc.

The particulate-type preparation according to the present invention may be dispersed in saline solution and then applied to the affected site of patients using a syringe. Further, to enhance the retention of particulate- type preparation in the local affected site, the particulate-type preparation may be dispersed in gel-phase vehicle prior to use. It is expected that the particulate-type preparation dispersed in such gel exhibits significantly improved therapeutic effect through sustained-release of drug from the preparation at the affected site for a prolonged period of time. The examples of the gel-phase vehicle includes adhesive polymers such as polycarbophyl, chitosan, alginic acid and etc.; proteins such as fibrin, etc.; plastibase; glycerin; etc.

The process for manufacturing the biodegradable particulate polymeric preparation according to the present invention has several advantages in that (1) since the present invention does not adopt the conventional step of preparing an o/w emulsion by dispersing in water the mixing solution of polymer and drug in an organic solvent, lower incorporation rate of drug associated with the leaking phenomenon of drug in water and and poor reproducibility thereof can be overcome, (2) since the mixing solution containing drug is dried and pulverized without dispersion in water, the incorporation rate of drug is closed to nearly 100%> and homogeneous preparation can be easily prepared, (3) heat-unstable drugs can be applicable, since there is no increase in temperature during the manufacture, (4) a prolonged treatment can be expected through sustained release drug within a matrix, and (5) the porous structure of matrix can be adequately controlled by the use of a mixed-solvent so that a particulate-type preparation, so obtained, showing an optimal release rate of drug can provide the maximization of treatment. The merits of the mixed-solvent is explained in more detail in the following Experimental example.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. la is a scanning electron microscopic photograph showing the particle distribution of a biodegradable polymeric particulate prepared by Particulate-Manufacturing Example 1 ; Fig. lb is a scanning electron microscopic photograph showing the surface of the biodegradable polymeric particulate having a porous structure prepared by Particulate-Manufacturing Example 1 ;

Fig. 2 is a graph showing the release profile of tetracycline from the biodegradable particulate polymeric preparation prepared by Example 2 (•, polylactic acid : methylene chloride : ethylacetate = 1 : 9 : 0), Example 5 (A, polylactic acid : methylene chloride : ethylacetate = 1 : 6 : 3), and Example 4 (■, polylactic acid : methylene chloride : ethylacetate = 1 : 4.5 : 4.5);

Fig. 3 is a graph showing the release profile of flurbiprofen from the biodegradable particulate polymeric preparation prepared by Example 1 (•, polylactic acid : methylene chloride : ethylacetate = 1 : 9 : 0), Example 7 (A, polylactic acid : methylene chloride : ethylacetate = 1 : 6 : 3), and Example 6 (■, polylactic acid : methylene chloride : ethylacetate = 1 : 4.5 : 4.5);

Fig. 4 is a graph showing the release profile of methotraxate from the biodegradable particulate polymeric preparation prepared by Example 3 (•, polylactic acid : methylene chloride : ethylacetate = 1 : 9 : 0), and Example 8 (A, polylactic acid : methylene chloride : ethylacetate = 1 : 4.5 : 4.5), while comparing that from methotraxate powder.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained in more detail as for its Examples but it is contemplated that various Examples and modifications may be available with the concept and scope of the present invention.

Particulate-Manufacturing Example 1 lg of polylactic acid with the molecular weight of 360,000 Da was dissolved in a mixed-solvent containing 4.5ml of methylene chloride and 4.5ml of ethylacetate 4.5 ml. The solution was dried at room temperature for 24 hours to form a matrix. The matrix, so formed, was pulverized by a micromill to prepare a particulate having the particle size of 100 μm. Fig. la and Fig. lb is a differential scanning microscopic photograph showing the biodegradable polymeric particulate having a porous structure. The particulate-type preparations containing the drugs prepared from the following Examples shows the same structure.

Examples 1 ~39

As shown in the following Tables 1-4, each component (e.g., polymer, solvent, drug, Span 80 and hydrophilic material) was mixed and then dried at room temperature for 24 hours. The matrix, so formed, was pulverized by a micromill to prepare a particulate having the particle size of 100 μm.

Table 1.

Table 2.

Table 3.

Table 4.

Experimental example 1. Dissolution test Each particulate-type preparation prepared from Examples 1-8 was placed in 0.1M phosphate buffer solution (pH 7.4) and stirred in a water bath at 37 ^°C and 15rpm. Then, each sample of dissolution medium was collected at predetermined time intervals to measure its absorbance using an ultraviolet absorption spectrophotometer. The absorbances of tetracycline, flurbiprofen and methotroxate were measured at 274 nm, 247 nm and 280 nm, respectively, to calculate the released amounts. The results were shown in Figs. 2, 3 and 4.

Fig. 2 is a graph showing the release profile of tetracycline from the biodegradable particulate polymeric preparation containing tetracycline according to the present invention. It is contemplated that the initial amount of tetracycline was rapidly released but thereafter, a small amount of the drug was slowly released for 10 days. Since tetracycline was not dissolved in polylactic acid but dispersed within a porous structure, tetracycline particles exposed to the outer area was initially released, followed by the release of drug within the matrix. Further, the release profile of drug from the particulate-type preparation showed that the release amount of drug from the particulate-type preparation prepared using a mixed-solvent (■, Example 4; and A, Example 5) was more increased than that from particulate-type preparation prepared using only primary solvent (•, Example 2). It is contemplated that the porous structure of polymeric particulate, so formed by a co-solvent, increased the contact surface with the releasing solution. Further, the fact that the increased addition of ethylacetate (a secondary solvent) was in parallel with the increase of drug release amount lies in the fact that ethylacetate in the solution of polylactic acid acts as an internal coagulant, thereby to increase the porous structure significantly. From the above results, it is contemplated that the release amount of drug can be controlled by varying the ratio of organic solvent to optimize the drug effect for the conditions that must be treated.

Fig. 3 is a graph showing the release profile of flurbiprofen from the biodegradable particulate polymeric preparation. It was observed that like tetracycline, the release amount of the drug from the particulate-type preparation prepared using a mixed-solvent (■, Example 6; and A, Example 7), particularly using more amount of ethylacetate (Example 6), was more increased than that from particulate-type preparation prepared using only primary solvent (•, Example 1). After the release of flurbiprofen for one day, its release amount was increased continuously for 10 days. It is contemplated that flurbiprofen dissolved in the polylactic acid matrix was slowly and continuously diffused and released from the inner part of the matrix of polylactic acid.

Fig. 4 is a graph showing the release profile of methotroxate from the biodegradable particulate polymeric preparation. It was observed that the release pattern of drug incorporated in the polylactic acid particulate (A, Example 8; and #, Example 3) was more delayed than using methotroxate powder (■). It is contemplated that the drug was slowly and continuously released by controlling its dispersion from the matrix. Further, like other drugs, the release amount of methotroxate from the particulate- type preparation using a mixed-solvent was increased due to formation of porous structure.

As described above, the present invention relates to a biodegradable particulate polymeric preparation that can be locally applicable for achieving an optimal therapeutic effect in patients when subjected to prolonged treatment. The present invention has several advantages in that (1) since the present invention does not adopt the steps of preparing an o/w emulsion or suspension and of heating the polymeric solution to remove the organic solvent, a drug is completely incorporated in a porous particulate with reproducibility and homogeneity, while preventing any loss of activity or degeneration related to drug induced by heat, and 2) the porous structure of matrix can be adequately controlled in the presence of a mixed-solvent so that a particulate-type preparation showing an optimal release rate of drug can provide the maximization of treatment.

Claims

1. A process for manufacturing a biodegradable particulate polymeric preparation comprising the steps of: Forming a mixing solution of a drug and a polymeric solution, wherein the said polymeric solution is formed by dissolving a polymer in an organic solvent;

Drying the organic solvent from the said mixing solution to obtain a matrix; and Pulverizing the said matrix.

2. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 1 , wherein the said polymer is at least one member selected from the group consisting of polylactic acid, a copolymer of polylactic acid-glycolic acid and polycaprolactone.

3. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 2, wherein molecular weight of the said polymer is included in the range of 50,000-400,000 Da.

4. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 1, wherein the concentration of the said polymer in the polymeric solution is in the range of 0.5~20%w/v.

5. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 1 , wherein the said organic solvent is methylene chloride.

6. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 1, wherein the said organic solvent is a mixed-solvent having one or more selected from the group consisting of ethylacetate, N-methylpyrroline and ethanol, together with methylene chloride.

7. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 6, wherein the said mixed- solvent is prepared in the mixing ratio of methylene chloride: (ethylacetate, N-methylpyrroline and/or ethanol) = 1 :0.25~1.

8. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 1, wherein the said drug is selected from the group consisting of an antibiotic, antitumor agent, anti- inflammatory agent and steroidal drug.

9. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 8, wherein the said drug is employed by 0.1-0.3 parts per part by weight of polymer.

10. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 1, wherein the said drug is at least one member selected from the group consisting of protein drugs.

11. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 10, wherein the said protein drug is platelet-derived growth factor.

12. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 11, wherein the said platelet- derived growth factor is employed by Ix l0^"7-5xl0^"6 parts per part by weight of polymer.

13. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 1, wherein one or more hydrophilic material(s) selected from the group consisting of polyethylene glycol, poloxamer and glycerin is/are further added into the said polymeric solution.

14. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 1 , wherein a nonionic surfactant is further added into the said polymeric solution.

15. The process for manufacturing a biodegradable particulate polymeric preparation according to claim 1, wherein the particle size of particulate prepared from the said pulverizing step is in the range of 45-150 m.

16. A biodegradable particulate polymeric preparation prepared by claim 1.