METHOD OF PREPARING AQUEOUS DISPERSION OF HYDROXYPROPYL METHYLCELLULOSE PHTHALATE NANOPARTICLE COMPOSITION BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to a method of preparing an aqueous dispersion of hydroxypropyl methylcellulose phthalate (hereunder referred to as "HPMCP") nanoparticle composition, more particularly to a method of preparing an environment-friendly aqueous dispersion of HPMCP nanoparticle composition wherein the aqueous neutralization-emulsification of HPMCP is performed under optimum conditions selectively using an emulsifier and a plasticizer, so that superior physical properties such as disintegration and dissolution can be obtained when used for enteric films or coatings without an ion exchange process, thereby significantly reducing processing time and the amount of additives to be used.

Description of Related Art To date, HPMCP and acryl copolymers (e. g. , Eudragit; Degussa, USA) have been mainly used for enteric coatings. However, HPMCP is not considered advantageous because it may cause environmental problems due to the use of an organic solvent. Although aqueous dispersions of acryl copolymers are commercially available, they are not natural products but synthetic polymers and have physical properties for films inferior to HPMCP. Accordingly, there has been an increasing demand on the development of novel environment-friendly products.

As a way to meet the above need, aqueous dispersions of HPMCP have been developed. According to the conventional method of preparing an aqueous dispersion of HPMCP, HPMCP is completely dissolved, in an organic solvent and

then diffused in water. Then, the organic solvent is removed from the solution to obtain an aqueous dispersion of HPMCP. However, the aqueous dispersion prepared by this method has poor product stability and also the production cost is relatively high because an organic solvent is used. Especially, it is difficult to remove the organic solvent from the solution after emulsification. Further, there is a danger that the organic solvent remaining in the product may cause environmental problems.

US Patent No. 5,560, 930 discloses a method of preparing nanoparticles of about 0.2 pm in size by dissolving HPMCP in acetone, emulsifying it in water and removing the organic solvent through vacuum distillation.

US Patent No. 5,512, 092 discloses a method of dissolving HPMCP in ethanol and emulsifying it in water.

US Patent No. 5,346, 542 discloses a method of dissolving carboxymethyl ethyl cellulose, a cellulose derivative, in methyl acetate and emulsifying it in water.

Although the above methods have little problem with regard to latex particle size or its dispersion, the products show problems in stability after emulsification.

Also, the organic solvent remains in the final product because it is hardly removed.

To test the above methods, 1 cm x 1 cm films were prepared from the aqueous dispersions of HPMCP prepared according to above methods. When they were immersed in a pH 1.2 buffer solution for 2 hours, they were almost disintegrated and the shape of the films were almost unidentifiable. The aqueous dispersions of HPMCP were diluted to 7 wt% with ultrapure water and coated on tablets using Hi-Coater (HCT Labo). Then, the disintegration test (using Pharmatest PTZ E) result showed that disintegration occurs within 2 hours in pH 1.2. For the above reasons, there has not been as yet any aqueous dispersion of HPMCP that has been successfully commercialized.

The present inventors have prepared stable and environment-friendly

aqueous dispersion of HPMCP nanoparticles, having superior physical properties such as dissolution and disintegration to be used for enteric coatings, via aqueous emulsification of HPMCP and controlled content of remaining electrolytes through ion exchange process, as disclosed in Korea Patent Publication No. 2003-40616 (WO 03/42248).

Although the aqueous dispersions of HPMCP nanoparticles have superior properties for enteric coatings, they have been considered disadvantageous with respect to productivity and cost-effectiveness due to the requirement of using an expensive emulsifier and a relatively long ion exchange process which lasts for about 4 to 8 hours to offer superior properties to be used as films and enteric coatings.

SUMMARY OF THE INVENTION Hence, the present inventors have made extensive efforts to develop a method of preparing an aqueous dispersion of HPMCP nanoparticles that can offer physical properties for enteric coatings without an ion exchange process, which is the cause of increased manufacture cost. In doing so, they found out that an HPMCP nanoparticle composition prepared by an aqueous neutralization-emulsification process, in which use of an emulsifier and a plasticizer is selectively controlled, can solve the solid content decrease and a problem of long process time due to the ion exchange process and offer physical properties such as dissolution and disintegration for use as enteric films and coatings.

Thus, it is an object of the present invention to provide a method of preparing an aqueous dispersion of HPMCP nanoparticle composition, which is more economical and commercially advantageous and having good properties for use as enteric materials.

DETAILED DESCRIPTION OF THE PERFERRED EMBODIMENTS The present invention relates to a method of preparing an aqueous dispersion of hydroxypropyl methylcellulose phthalate (HPMCP) composition comprising the steps of: dispersing hydroxypropyl methylcellulose phthalate, an emulsifier selected from sodium lauryl sulfate and polysorbate and a hydrophilic plasticizer in purified water; and performing a reaction for 2 to 4 hours at 40 to 60 °C after adding a neutralization agent.

Hereinafter, the present invention is described in more detail.

The present invention relates to a method of preparing an environment-friendly aqueous dispersion of HPMCP nanoparticle composition wherein the aqueous neutralization-emulsification of HPMCP is performed under optimum conditions by selectively using an emulsifier and a plasticizer, so that superior physical properties such as dissolution and disintegration can be obtained when used for enteric films or coatings without an ion exchange process, thus significantly reducing processing time and the amount of additives to be used.

A striking feature of the present invention lies in that the aqueous neutralization-emulsification is proceeded in a single step and an HPMCP nanoparticle composition having superior properties for enteric materials can be prepared without an ion exchange process.

Hereinafter, the preparing method of the present invention is described in more detail.

In the present invention, HPMCP is comprised in purified water in the amount of 10 to 30 wt%, and an emulsifier, a plasticizer and a neutralizing agent are comprised in 1 to 5 wt%, 1 to 5 wt% and 7 to 14 wt%, respectively, for the amount of HPMCP.

The emulsifier, which is used to offer emulsion stability, is comprised in 1 to 5 wt% for the amount of HPMCP, more preferably in 2 to 4 wt%. If the

emulsifier content is below 1 wt%, precipitation occurs due to poor emulsion stability. In contrast, if it exceeds 5 wt%, excessive use of an emulsifier generates much foam and degenerates physical properties for enteric coatings.

To be specific, sodium lauryl sulfate, polysorbate and the like can be used as an emulsifier.

Coatings for drug are prepared by dissolving or dispersing a coating agent, a plasticizer, a pigment, etc. in a mixed solvent. In general, the plasticizer is used in 10 to 30 wt% for the coating agent. However, according to the present invention, superior properties for coatings can be obtained with a small amount of a plasticizer.

That is, in the present invention, the plasticizer is comprised in 1 to 5 wt% for the amount of HPMCP, more preferably in 2 to 3 wt%. If the plasticizer content is below 1 wt%, swelling occurs at pH 1.2 after coating. In contrast, if it exceeds 5 wt%, the coating efficiency drops significantly due to adhesion, etc. For the plasticizer, a hydrophilic plasticizer, specifically at least one compound selected from the group consisting of polyethylene glycol, glycerine, propylene glycol and polyvinyl alcohol, may be used.

The neutralizing agent is an important factor in forming nanoparticles.

For the neutralizing agent, 25 to 30 % aqueous ammonia solution can be used.

Preferably, the neutralizing agent is comprised in 7 to 14 wt% for the amount of HPMCP, more preferably 8 to 12 wt%. If the neutralizing agent content is below 7 wt%, a large portion of HPMCP remains as particles, which causes decrease of production yield, and the particle becomes large, so that layer separation may occur during storage due to particle sedimentation. In contrast, if it exceeds 14 wt%, nanoparticles are not formed and the product gives out offensive odor.

Such HPMCP nanoparticle composition can be prepared by adding purified water, an emulsifier, HPMCP, a plasticizer and a neutralizing agent in a 20 L jacket

reactor, for example, heating to 40 to 60 °C and performing neutralization-emulsification for 2 to 4 hours.

The resultant composition has a pH ranging from 4.0 to 7.0, conductivity from 6.0 to 10.0 uS, solid content from 10 to 30 % and particle size from 50 to 300 nm.

When a disintegration test was performed on a tablet coated with the composition at pH 1.2 for 2 hours, no disintegration was observed, which suggests that it has superior physical properties for enteric coatings.

Hereinafter, this invention is further illustrated by the following examples.

However, these examples should not be construed as limiting the scope of this invention in any manner.

EXAMPLES Examples 1 to 14 Purified water, HPMCP (AnyCoat-P, Samsung Fine Chemicals, Korea), an emulsifier and a plasticizer were put in a 20 L jacket reactor. After slowly adding an aqueous ammonia solution for 30 minutes, a reaction was performed at 40 to 60 °C for 2 to 4 hours to prepare a 10 to 30 % aqueous dispersion of HPMCP.

Contents of purified water, HPMCP, the emulsifier and the plasticizer were the same as shown in Table 3 below.

Comparative Example 1 Purified water, an emulsifier and HPMCP were put in a 25 L reactor equipped with a stirrer and stirred at 300 to 350 rpm. A 28 % aqueous ammonia solution was slowly added and the temperature was increased to 60 °C.

Keeping the temperature at to 60 °C, the mixture was stirred for 4 to 5 hours and the content of remaining electrolytes was controlled to 2.0 mS using ion exchange resin (Dowex MR-3, Sigma-Aldrich, USA) to prepare an aqueous dispersion of HPMCP

nanoparticles.

Comparative Example 2 Purified water and HPMCP were put in a reactor equipped with a stirrer and stirred at 300 rpm. Aqueous ammonia solution was slowly added to prepare an aqueous dispersion of HPMCP nanoparticles containing 10.0 to 12.0 mS of electrolytes. After 1 to 2 hours, the content of remaining electrolytes was controlled to a pH of 7.0 to 9.0 using ion exchange resin (Dowex MR-3, Sigma-Aldrich, USA). Then, 10 g of polyvinyl alcohol was added as a plasticizer and stirred to prepare an aqueous dispersion of HPMCP nanoparticles.

Test Example Physical properties of aqueous dispersion of HPMCP nanoparticles prepared in Examples 1 to 14 and Comparative Examples 1 to 2 were tested as follows.

The result is shown in Table 4 below.

1) pH: pH of a 2% solution was measured with a pH meter.

2) Solid content: Measured at 60 °C for 4 hours.

3) Conductivity: Measured with a conductivity meter.

4) Evaluation of enteric property: A diclofenac sodium tablet, which is widely used as anti-inflammatory drug, was prepared with the content of Table 1 below and under the condition of Table 2 below. The tablet was coated with the prepared aqueous dispersions of HPMCP and evaluation of enteric property was performed.

If no disintegration occurred at pH 1.2 for 2 hours, the coating was evaluated to have enteric property. PTZ E Disintegrator (Pharmatest, Germany) was used in the disintegration test.

Table 1. Diclofenac naked tablet formulation Components Contents (mg) Diclofenac sodium 52.5 200 mesh lactose 217.25 Amorphous cellulose 15 Magnesium stearate 3 Calcium carboxymethylcellulose 3 Hydroxypropylcellulose 9.25 Ethanol 9.25 Table 2 Variables Conditions Coating machine Hi-Coater (HCT Labo) Tablet weight (g) 400 Fan speed (rpm) 20 Air intake temperature (°C) 55 to 60 Air outlet temperature (°C) 37 to 39 Coating nozzle spray pressure (bar) 2 Preheating time (min) 5 Coating time (min) 30 Drying time (min) 5 Coating amount (% to the tablet weight) 7.0 to 7.7

Table 3 Purified Neutralizing Emulsifier HPMCP Plasticizer Water Agent Classification Amount Amount Amount Amount Amount (kg) (kg) (kg) (kg) (kg) Example 1 13. 2 SLS 0. 072 2. 4 PEG 0. 048 0. 216 Example 2 13. 2 PS 0. 072 2. 4 PEG 0. 048 0. 224 Example 3 13. 2 SLS 0. 072 2. 4 Gly 0. 048 0. 224 Example 4 13. 2 PS 0. 072 2. 4 Gly 0. 048 0. 240 Example 5 13. 3 SLS 0. 072 2. 4 PG 0. 048 0. 228 Example 6 13. 2 PS 0. 120 2. 4 PG 0. 072 0. 238 Example 7 13. 2 SLS 0. 072 2. 4 PVA 0. 048 0. 240 Example 8 13. 3 PS 0. 072 2. 4 PVA 0. 048 0. 216 Example 9 12. 3 SLS 0. 096 3. 2 PEG 0. 064 0. 304 Example 10 11. 4 SLS 0. 120 4. 0 PEG 0. 080 0. 372 Example 11 11. 1 SLS 0. 130 4. 32 PEG 0. 086 0. 401 Example 12 10. 5 SLS 0. 144 4. 8 PEG 0. 096 0. 446 Example 13 12. 4 SLS 0. 064 3. 2 PEG 0. 064 0. 304 Example 14 12. 3 SLS 0. 096 3. 2 PEG 0. 096 0. 304 Comparative 12. 0 F-68 0. 040 3. 0--0. 320 Example 1 Comparative 12. 0--3. 0 0. 400 PVA 0. 320 Example 2 SLS: Sodium lauryl sulfate PS: Polysorbate PEG: Polyethylene glycol Gly: Glycerine PG: Propylene glycol PVA: Polyvinyl alcohol F-68: Flutonic 68 Table 4 Solid content Conductivity Disintegration pH (%) (mS) at pH 1. 2, 2 hr No Example 1 5. 2 15. 7 7. 8 disintegration No Example 2 5. 8 15. 7 8. 7 disintegration No Example 3 5. 9 15. 7 8. 8 disintegration No Example 4 6. 4 15. 7 9. 5 disintegration No Example 5 6. 0 15. 7 8. 9 disintegration No Example 6 6. 1 15. 7 9. 2 disintegration No Example 7 6. 3 15. 7 9. 3 disintegration No Example 8 5. 3 15. 7 8. 0 disintegration No Example 9 6. 3 21. 0 9. 4 disintegration No Example 10 5. 9 26. 2 8. 9 disintegration No Example 11 6. 0 28. 3 9. 0 disintegration No Example 12 5. 9 31. 5 8. 7 disintegration No Example 13 5. 8 20. 8 8. 9 disintegration No Example 14 5. 5 21. 2 8. 4 disintegration Comparative No 4. 7 25. 3 2. 0 Example 1 disintegration Comparative No 4. 8 28. 3 7. 0 Example 2 disintegration

As described above, the present invention can prepare an aqueous dispersion of HPMCP nanoparticles having superior enteric properties economically by excluding an ion exchange process, thereby significantly reducing the processing time and also minimizing the use of an emulsifier and a plasticizer.

While the present invention has been described with reference to the preferred embodiments, those skilled in the art will appreciate that various modifications and substitutions can be made thereto without departing from the spirit and scope of the present invention as set forth in the appended claims.