METHOD FOR PRODUCING AN AMORPHOUSE SOLID DISPERSION AND PHARMACEUTICAL COMPOSITION FOR STABILIZING ACTIVE PHARMACEUTICAL INGREDIENTS

Abstract

The present invention relates to a method for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polymer matrix. The Invention further relates to a pharmaceutical composition using polymers as an excipient and particularly to an improved pharmaceutical composition comprising polyvinyl alcohol grades with different degrees of hydrolysis, which is suitable to stabilize active pharmaceutical ingredients.

Claims

1. A method for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polymer matrix, wherein the polymer matrix comprises polyvinyl alcohol, comprising selecting a first polyvinyl alcohol having a first degree of hydrolysis, selecting a second polyvinyl alcohol having a second degree of hydrolysis which is lower than the first degree of hydrolysis, mixing the first polyvinyl alcohol, the second polyvinyl alcohol and the active pharmaceutical ingredient at a temperature above the glass transition temperature or melting temperature of the polymer matrix, thereby forming an amorphous solid dispersion of the active pharmaceutical ingredient.

2. The method according to claim 1, wherein the degree of hydrolysis is measured by determining the saponification value of the polyvinyl alcohol.

3. The method according to claim 1, wherein the temperature is at least the melting temperature of the active pharmaceutical ingredient.

4. The method according to claim 1, wherein the amorphous solid dispersion is produced by hot-melt extrusion, melt extrusion, injection molding, compression molding, or additive manufacturing.

5. The method according to claim 1, wherein the first hydrolysis degree of the first polyvinyl alcohol is at least 5 percentage points by weight higher than the second hydrolysis degree of the second polyvinyl alcohol.

6. The method according to claim 1, wherein the first polyvinyl alcohol is a PVA having a hydrolysis degree of 98% to 99%, and a viscosity of a 4% solution at 20° C. of 2 mPas to 50 mPas, and the second polyvinyl alcohol is a PVA having a hydrolysis degree of 70% to 88%, and a viscosity of a 4% solution at 20° C. of 2 mPas to 50 mPas.

7. The method according to claim 1, wherein the weight ratio of the first PVA and the second PVA is from 1:1 to 1:8.

8. The method according to claim 1, wherein the weight ratio of the first PVA and the second PVA is from 1:3.5 to 1:8.

9. The method according to claim 1, wherein the active pharmaceutical ingredient is poorly soluble in water.

10. A pharmaceutical composition for oral administration comprising an amorphous solid dispersion of at least one active pharmaceutical ingredient in a pharmaceutically acceptable polymer matrix comprising a first polyvinyl alcohol having a first degree of hydrolysis, and a second polyvinyl alcohol having a second degree of hydrolysis, wherein the amorphous solid dispersion is obtainable by a method according to claim 1.

11. An oral dosage form comprising a pharmaceutical composition according to claim 10 in form of tablets, beads, granules, pellets, capsules, suspensions, emulsions, gels or films.

12. A method for stabilizing the amorphous form of an active pharmaceutical ingredient in a polymer matrix comprising polyvinyl alcohol, said method comprising a step of mixing a first polyvinyl alcohol having a first degree of hydrolysis, a second polyvinyl alcohol having a second degree of hydrolysis which is lower than the first degree of hydrolysis and the active pharmaceutical ingredient at a temperature above the glass transition temperature or melting temperature of the polymer matrix, thereby forming an amorphous solid dispersion of the active pharmaceutical ingredient, whereas the weight ratio of the first PVA and the second PVA is between 1:1 and 1:10.

13. The method according to claim 12, wherein the temperature is at least the melting temperature of the active pharmaceutical ingredient.

14. The method according to claim 12, wherein the stability of the amorphous form of the active pharmaceutical ingredient in the amorphous solid dispersion is enhanced as compared to the stability of the amorphous form of the active pharmaceutical ingredient in the amorphous solid dispersion comprising a first PVA and a second PVA in a ratio outside the weight ratio between 1:1 and 1:10.

15. A method for stabilizing the amorphous form of an active pharmaceutical ingredient in an amorphous solid dispersion comprising mixing a first polyvinyl alcohol having a first degree of hydrolysis, a second polyvinyl alcohol having a second degree of hydrolysis which is lower than the first degree of hydrolysis and an active pharmaceutical ingredient at a temperature above the glass transition temperature or melting temperature of the polymer matrix, thereby forming an amorphous solid dispersion of the active pharmaceutical ingredient, wherein the weight ratio of the first PVA and the second PVA is between 1:1 and 1:10.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0070] FIG. 1 shows a table summarizing extrusion parameters for preparing model ternary matrix systems with varying ratios of PVA 5-74 and PVA 4-98 and itraconazole (ITZ) as a lipophilic model API.

[0071] FIG. 2 shows X-ray diffractograms of extruded matrices with varying ratios of PVA and PVA 4-98 and a constant load of the model API itraconazole (ITZ) at 10% by weight.

[0072] FIG. 3 shows dissolution profiles of ternary systems containing PVA 4-98, PVA 5-74 and ITZ.

EXAMPLES

Example 1: Preparation of Ternary Compositions

[0073] Five ternary compositions comprising different ratios of PVA 4-98 (Poval 4-98, Kuraray Europe GmbH) and PVA 5-74 (Poval 5-74, Kuraray Europe GmbH) and to comparative compositions comprising solely PVA 4-98 or PVA 5-74 as the polymer matrix were prepared by hot-melt extrusion with 10% by weight itraconazole (ITZ) according to Table 1 as follows:

TABLE-US-00001 TABLE 1 Ternary compositions PVA 4-98:PVA 5-74:API PVA 4-98:PVA 5-74 10:80:10 1:8 20:70:10 .sup. 1:3.5 45:45:10 1:1 70:20:10 3.5:1.sup.  80:10:10 8:1 0:90:10 0:1 90:0:10 1:0

[0074] The quantities of the first polyvinyl alcohol Poval 4-98, the second polyvinyl alcohol Poval 5-74 and the active ingredient itraconazole (ITZ) required for a total mass of 200 g powder mixture according to the weight ratios shown in Table 1 and FIG. 1 were weighed into a 1 L mixing vessel and then mixed by means of a tubular mixer for 5 min.

[0075] The powder mixture was then filled into the gravimetric twin-screw feeder of a Brabender KETSE 12/36 extruder and a determination of the maximum feed rate was performed.

[0076] The heating zones were heated at the respective target temperatures as shown in FIG. 1.

[0077] After the heating zones had reached their respective temperatures, the speed and, analogously, the dosing rate of the powder mixture was increased step by step in units of 50 until the target speed and target dosing rate of 200 rpm and 200.0 g/h, respectively, were reached. The extrudate was discarded for about 5 minutes until nozzle pressure and torque stabilized. The extrudate was then allowed to cool on the conveyor belt at room temperature and thereby conveyed to the pelletizer, where the extrudate was crushed to 1.5 mm pellets using a Brabender pelletizer. The process was continued until the powder mixture in the feeder was used up. This was reflected in incipient fluctuations in the dosing rate. Afterwards, the dosing was stopped and the screw speed was gradually reduced to 10 rpm and held for another 10 minutes to feed residual polymer from the extruder barrel, which was then discarded.

[0078] The so obtained extruded ternary composition pellets were used for further x-ray diffractometry analysis and dissolution experiments.

Example 2: X-Ray Diffractometry Analysis (XRD) of Ternary Compositions

[0079] The extruded polymer matrices obtained according to Example 1 were further characterized by X-ray diffractometry analysis. X-ray diffraction is a well-established technology in pharmaceutical sciences that can be used to identify the polymorphic form of the API as well as the remaining crystallinity of a polymer.

[0080] Samples were measured in transmission mode at 40 KV and 40 mA. Copper was used as an anode material at a wavelength of 1.54060 A. The stepsize was 0.015 at 15.0 sec/step.

[0081] The stabilizing effect of the low hydrolysed PVA 5-74 on the amorphous state of ITZ was evaluated. The X-ray diffractograms of the extruded matrices are shown in FIG. 2. It was observed that in a pure PVA 4-98 based polymer matrix, crystalline peaks of ITZ were still detected. With an increasing percentage of PVA 5-74 corresponding to a weight ratio of PVA 4-98 to PVA 5-74 from 8:1 to 1:8 in the polymer matrix, the crystalline peaks were more and more reduced and showed only two minor peaks for a ternary composition having a weight ratio of PVA 4-98 to PVA 5-74 of 1:1. Ternary compositions having a weight ratio of PVA 4-98 to PVA 5-74 from 1:3, 5 to 1:8 showed no distinct crystalline peaks. From the results, it can be confirmed hat an increasing amount of the acetate groups induced by an increasing percentage of the lower hydrolysed PVA 5-74 in the polymer matrix improves the stability of the amorphous state of ITZ. Thus, the addition of PVA 5-74 in a weight ratio of PVA 4-98 to PVA 5-74 from 1:1 to 1:8 was sufficient to effectively reduce the crystalline content of the polymer matrix indicating a successful stabilization of the amorphous ITZ within the polymer matrix.

Example 3: Drug Release of Ternary Compositions

[0082] Drug release experiments were performed using the extruded polymer matrices obtained according to Example 1.

Sample Preparation

[0083] The ternary composition extrudates were ground in an IKA Tubemill 100 with a 40 ml disposable grinding cup for 20 sec at 25000 rpm. 3 samples of each extrudate were prepared. For each sample, 500 mg of extrudate were weighed corresponding to 50 mg ITZ per sample.

[0084] Dissolution Method:

[0085] The dissolution rates of ITZ from the ternary composition extrudates were measured using a Sotax AT7 smart measuring system equipped with an online Agilent photometer 8453. The samples were placed in dissolution vessels containing 900 mL SGF.sp (20 g NaCl, 800 mL 0.1 M HCl ad 10.0 L deionized water) equilibrated to a temperature of 37±0.5° C. with a paddle rotation of 75 rpm. Samples were taken at 5, 20, 35, 50, 65, 95, 125, 155, 185 and 240 min, filtered and analyzed by HPLC.

[0086] The dissolution profiles of the ternary compositions are shown in FIG. 3. Dissolution data show that the release profiles of ternary compositions having weight ratios of PVA 4-98 to PVA 5-74 of 1:3.5 to 1:8 were very similar showing more than 80% release of ITZ within 90 min dissolution time.

[0087] Therefore, varying the weight ratios of PVA 4-98 to PVA 5-74 and enables a tailored release formulation.