HK1218395B - Coating composition - Google Patents

Description

Coating composition

Technical Field

The present invention discloses a coating composition comprising, on a dry weight basis, at least 20 wt% of polyvinyl alcohol and 0.1 to 20 wt% of a water-insoluble (meth)acrylate copolymer containing quaternary ammonium groups, based on the weight of the polyvinyl alcohol, wherein an aqueous dispersion containing the coating composition and having a solid content of 25 wt% has a viscosity of 200 mPa·s or less at 22°C.

Background Art

WO 2010/132204A1 describes an immediate-release film coating composition with enhanced moisture barrier properties, comprising polyvinyl alcohol, a polymer with pH-dependent solubility, and optionally a plasticizer and/or a glidant. The polymer with pH-dependent solubility may be, for example, hydroxypropylmethylcellulose acetate succinate (HPMC-AS) or L100-55.

Summary of the Invention

Purpose of the Invention

WO 2010/132204 A1 describes an immediate-release film-coating composition with enhanced moisture barrier properties. However, it has been found that the viscosity of the polymer composition is relatively high, which is considered disadvantageous in spray applications. In addition, it has been found that the presence of a polymer with pH-dependent solubility in the coating of the coated core may adversely affect the stability of acid-labile compounds in the core due to its acidic nature. Therefore, while proceeding from WO 2010/132204 A1, the present invention aims to provide an alternative composition having improved viscosity parameters and improved conditions for influencing the stability of the included active ingredient.

The problem is solved as claimed in the claims.

Detailed Description of the Invention

Coating composition

The present invention relates to a coating composition comprising, on a dry weight basis, at least 20% by weight of polyvinyl alcohol and 0.1 to 20% by weight, based on the weight of the polyvinyl alcohol, of a water-insoluble (meth)acrylate copolymer containing quaternary ammonium groups, wherein an aqueous dispersion containing the coating composition having a solids content of 25% by weight (% (w/w)) has a viscosity of 200 mPa·s or less at 22° C.

The present invention relates to a coating composition, which may comprise at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80 weight percent of polyvinyl alcohol based on dry weight. The coating composition may comprise 20 to 80, 30 to 70, 40 to 60 weight percent of polyvinyl alcohol.

The coating composition, on a dry weight basis, may comprise 0.1 to 20, 0.2 to 10, 0.5 to 5 wt% of a water-insoluble (meth)acrylate copolymer containing quaternary ammonium groups, based on the weight of the polyvinyl alcohol.

The coating composition may be in the form of a powder having, for example, a particle size or particle size distribution of less than 1000, less than 850, less than 150 μm, preferably 5-1000, 5 to less than 1000, 10-850, 10 to less than 850, 10-150 or 150 to less than 150 μm. The particle size or particle size distribution of the powder component may preferably be determined according to the United States Pharmacopoeia (USP), preferably USP 29, method <786> by analytical sieving for particle size distribution estimation. Another highly suitable measurement method is laser diffraction for determining particle size distribution. Commercially available instruments allow measurement in air (Malvern Co. S3.01 Particle Sizer) or preferably in a liquid medium (LOT Co., Galai CIS 1).

The powder can be dispersed in water to give an aqueous dispersion.

The coating composition may be in the form of an aqueous dispersion having, for example, a solids content of 5-60, 10-40 or 15 or 40% (weight/volume).

The polyvinyl alcohol and the water-insoluble (meth)acrylate copolymer containing quaternary ammonium groups can add up to 100% (dry weight). However, the coating composition can also contain additional excipients. In this case, the polyvinyl alcohol, the water-insoluble (meth)acrylate copolymer containing quaternary ammonium groups, and the additional excipients can add up to 100% (dry weight).

Disintegration

Tablets, e.g., tablets having a diameter of 5-15 mm and having a coating of 2 to 8% based on the tablet core, which are coated with an aqueous dispersion comprising a coating composition of the present invention, disintegrate in an aqueous medium in 30 minutes or less, 20 minutes or less, 10 minutes or less, or within 1 to 30 minutes.

Additional auxiliary materials

The coating composition may further comprise additional excipients selected from antioxidants, brighteners, binders, flavorings, glidants, fragrances, slip agents, penetration enhancers, pigments, plasticizers, polymers other than polyvinyl alcohol or water-insoluble (meth)acrylate copolymers, pore formers or stabilizers.

Disintegration

Tablets coated with an aqueous dispersion comprising the coating composition disintegrate in an aqueous medium in 30 minutes or less, in 20 minutes or less, in 15 minutes or less, or in 1 to 30 minutes.

Viscosity

The viscosity of the aqueous dispersion having a solid content of 25% by weight at 22° C. is 200 mPa·s or less, 180 mPa·s or less, 150 mPa·s or less, 120 mPa·s or less, or 100 mPa·s or less. The viscosity can preferably be measured at 22° C. using a Brookfield viscometer. A 500 ml glass beaker and spindle S61 can be used in the study, and the measurement can be performed at 20 RPM.

Water-insoluble (meth)acrylate copolymers containing quaternary ammonium groups

Water-insoluble (meth)acrylate copolymers within the meaning of the present invention are polymers which are insoluble in water over the entire pH range from 1 to 14 or are only swellable in water.

The water-insoluble (meth)acrylate polymer may be composed of 85 to 98 wt % of free-radically polymerized C ₁ - to C ₄ -alkyl acrylic acid or methacrylic acid esters and 2 to 15 wt % of alkyl (meth)acrylate monomers having a quaternary amino group in the alkyl group.

The water-insoluble (meth)acrylate copolymer may be composed of 50 to 70 wt% methyl methacrylate, 20 to 40 wt% ethyl acrylate, and greater than 7 and up to 15 wt% 2-trimethylammoniumethyl methacrylate chloride (RL type).

The water-insoluble (meth)acrylate copolymer may be composed of 55 to 75 wt % of methyl methacrylate, 20-40 wt % of ethyl acrylate, and 2 to 7 wt % of 2-trimethylammoniumethyl methacrylate chloride (RS type).

Active pharmaceutical or nutritional ingredient

Embodiments of the present invention are applicable to all types of active pharmaceutical ingredients or nutritional ingredients. Preferably, embodiments of the present invention are applicable to acid-labile active pharmaceutical ingredients or nutritional ingredients. Acid-labile pharmaceutical ingredients or nutritional ingredients within the meaning of the present invention may be characterized by the presence of acidic components that produce impurities by degradation. An example of an acid-labile pharmaceutical ingredient is atorvastatin. The acidic compound (under the influence of which the acid-labile pharmaceutical ingredient or nutritional ingredient produces impurities by degradation) may be the acidic substance in the coating. The acidic substance in the coating may be an acid added to the coating, or may be a film coating polymer having acidic or carboxylic acid groups.

Active nutrient ingredients or nutrients can generally be defined as extracts from foods that are claimed to have a medicinal effect on human health. The nutrients are usually contained in a pharmaceutical format, such as a capsule, tablet or powder, in a prescribed dosage. Examples of nutrients are resveratrol from grape products as an antioxidant, soluble dietary fiber products such as psyllium husk for lowering hypercholesterolemia, broccoli (sulfanes) as a cancer protectant, and soy or clover (isoflavonoids) for improving arterial health. Other examples of nutrients are flavonoids, antioxidants, α-linoleic acid from flaxseed, β-carotene from marigold petals or anthocyanins from berries. Sometimes, the expression "neutraceuticals" is used as a synonym for "nutraceuticals."

Dosage form

The present invention discloses a dosage form, preferably an orally absorbable dosage form, comprising a core comprising an active pharmaceutical or nutraceutical ingredient and a coating obtained from a coating composition described herein.

The dosage form may preferably contain an active pharmaceutical or nutraceutical ingredient that is acid labile.

Atorvastatin pills

The coating composition can be characterized in that, when used to coat pellets containing atorvastatin, the increase in impurities measured as lactones from the initial stage (day 0) to 45 days of storage in an open petri dish at 40°C and 75% relative humidity is less than 1000, less than 500, less than 250, less than 200, less than 150 or less than 100%.

The (relative) increase in impurities was calculated by subtracting the initial value of the impurities from the coated atorvastatin-containing pellets from the impurity value of the coated atorvastatin-containing pellets after storage for 45 days in open petri dishes at 40°C and 75% relative humidity and calculating the percentage of this difference compared to the initial value (100%).

The lactone impurities of the coated formulation can be measured by HPLC or other suitable analytical methods.

use

Disclosed herein is the use of a coating composition as described herein for preparing a dosage form as also described herein.

method

The present invention discloses a method of preparing a dosage form as described herein by first preparing a core comprising an active pharmaceutical or nutraceutical ingredient, and then applying a coating composition as described herein to the core.

DETAILED DESCRIPTION

Example

Examples with "C" are comparative examples. Examples without "C" are examples of the present invention.

Materials and methods

PVA: Polyvinyl alcohol

205S: is a commercially available product containing polyvinyl alcohol.

L 100-55 is a copolymer composed of polymerized units of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.

RL 30D is a 30% (dry matter) aqueous dispersion of a copolymer composed of polymerized units of 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammoniumethyl methacrylate chloride.

NE 30D and NM 30D are 30% (dry matter) aqueous dispersions of a copolymer composed of polymerized units of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate.

EUDRAGIT® 200 is a commercially available product comprising polyvinyl alcohol, EUDRAGIT L 100-55, sodium bicarbonate, talc, titanium dioxide and/or colorants.

AMB is a commercially available product containing polyvinyl alcohol, lecithin, talc, titanium dioxide and/or colorants.

Parts A and B:

The viscosity was measured using a Brookfield viscometer at 22° C. A 500 ml glass beaker and spindle S61 were used in the study, and the measurements were performed at 20 RPM.

Part C:

Impurities measured as lactones in the coated formulations were measured by HPLC.

The increase in impurities was calculated by subtracting the initial value of the impurities obtained from the coated atorvastatin-containing pellets from the impurity value of the coated atorvastatin-containing pellets after storage for 45 days in an open petri dish at 40°C and 75% relative humidity, and calculating the percentage of the difference compared to the initial value (100%).

Related substances (by HPLC):

Chromatographic conditions:

Mobile phase A: Tetrahydrofuran, acetonitrile, and ammonium acetate solution were mixed in a ratio of (12:21:67).

Mobile phase B: Tetrahydrofuran, ammonium acetate solution, and acetonitrile were mixed in a ratio of (12:27:61).

Preparation of ammonium acetate solution: Weigh approximately 3.9 g of ammonium acetate and dissolve in 1000 ml of water and adjust the pH to 5.00 with acetic acid.

Test Solution: Weigh a sample equivalent to 0.050 g of atorvastatin and transfer it to a 50 ml volumetric flask. Add 30 ml of diluent and sonicate for 30 minutes with intermittent shaking. Allow to cool to room temperature. Dilute to volume with diluent.

Reference Solution: Accurately weigh approximately 0.050 g of atorvastatin calcium working standard into a 50 ml volumetric flask, dissolve it in diluent, and dilute to volume (stock solution). Dilute 1 ml of the stock solution to 100 ml with diluent. Further, dilute 1 ml of this solution to 10 ml with diluent.

name Relative retention time Response Factor (RF) Atorvastatin lactone About 1.72 1.0

calculate:

The relevant substance % was calculated by using the following calculation formula.

Area of impurity in test solution × weight of standard × 1 × 1 × 50 × 100 × RF × average weight

_____________________________________________________________________

Average area of reference solution × 50 × 100 × 10 × sample weight × label claim

Part D:

Moisture protection of the formulation of the present invention at 84% relative humidity (RH)

Part A: Examples C1 and 2: Processing Advantages of the Formulations of the Invention

Operation process of Examples C1 and 2

25% by weight (% w/w) dispersions were prepared using the PVA (205S) + L100-55 formulation (Example C1, comparative example according to WO 2010/132204A1, Table 1) and the PVA + RL combination (Example 2, according to the present invention) with overhead stirring for 1 hour. The prepared coating dispersions were filtered through a 60# sieve and sprayed onto placebo tablets using an 18" perforated coating pan (Neocota).

Table 1

Table 2

result:

Table 3

Compared to the comparative formulation of Example C1 (L100-55 according to WO 2010/132204 A1), the formulation according to the invention of Example 2 (RL formulation) has a lower viscosity and can be sprayed at a higher spray speed without any processing problems.

Part B: Examples 3, 4, C5 and C6: Viscosity Advantages of the Formulations of the Invention

Operation process:

1. Accurately weigh and mix all ingredients together to prepare a homogeneous blend.

2. The prepared blend was then added to the required amount of water with overhead stirring.

3. Stirring was carried out for 60 minutes.

4. Add the required amount of pH-independent EUDRAGIT (NE/NM/RS/RL) under stirring.

5. Filter the dispersion through a 60# sieve.

6. The viscosity of the prepared dispersion was measured using a Brookfield viscometer at 22° C. A 500 ml glass beaker and spindle S61 were used in the study and the measurement was performed at 20 RPM.

formula

Table 4 Solid content (weight %) = 25

result:

Table 5

Part C: Examples 7 and C8: Active Pharmaceutical Ingredient (API) Advantages of the Formulations of the Invention

Preparation details:

1. Preparation of Atorvastatin Drug-Loaded Pills:

Formulation: 10% Atorvastatin coating on 400gm sugar spheres

Table 6/Solid content = 10 wt%

Operation process:

1. Dissolve PVP K 90 and BHA in methanol with overhead stirring.

2. Then add atorvastatin calcium trihydrate to the above solution under stirring.

3. A clear solution was obtained, which was used for drug loading on sugar spheres (20/25#).

4. Take 400 gm sugar spheres in GPCG Glatt 1.1 Wuster coater for drug loading.

5. Spray the prepared solution onto the sugar spheres using the following parameters:

2. Preparation of RL 30D (dry basis) coated atorvastatin pellets:

PVA+RL preparation

Table 7

Operation process:

1. Combine all ingredients together with overhead stirring and add to required amount of water.

2. Stir for 60 minutes.

3. The prepared dispersion was filtered through a 60# sieve. The pH of the dispersion was 7.10.

4. For 15 wt% solids coating on 70 gm of drug loaded atorvastatin pellets, take 70 gm of coating dispersion.

5. Coating was performed on a Mycrolab Huttlin using the following parameters:

3. Preparation of Opadry 200-coated atorvastatin pellets:

200 preparations

Table 8

Operation process:

1. Add Opadry 200 to the required amount of water with overhead stirring.

2. Stir for 60 minutes

3. The prepared dispersion was filtered through a 60# sieve. The pH of the dispersion was 5.79.

4. For 15 wt% solids on 70 g drug loaded atorvastatin pellets

Coating, take 70g coating dispersion.

5. Coating was performed on a Mycrolab Huttl in using the following parameters:

result:

Analysis of Atorvastatin Lactone in Coated Formulations:

Procedure: For this study, uncoated drug-loaded pellets, 205S-RL 30D (dry basis) coated pellets, and 200 coated pellets were analyzed for initial atorvastatin lactone impurities. All three pellets were also exposed to accelerated storage conditions, 40°C/75% RH in open petri dishes for 45 days, and the production of atorvastatin lactone was determined. The following are the results of this study:

Table 9

Examples of powder compositions:

Example-P1

Example-P2

1. Mix RL 30D, talc and titanium dioxide together.

2. Mix PEG 6000 uniformly with the above blend, followed by PVA.

3. Dry the blend at 50°C for 30 minutes

Particle size analysis was performed using USP Method 29 (<786> Particle Size Distribution Estimation by Analytical Sieving) with mechanical agitation.

Minimum pore size, through which 90% of particles pass Example-P1 150μm (US mesh #100) Example-P2 850μm (US mesh #20)

Part D: Examples C9, C10, C11, 12, 13 and C14: Moisture Protection of Formulations of the Invention at 84% Relative Humidity (RH)

Table 11

Discussion: The 205S+RS (PVA+RS) and 205S+RL (PVA+RL) formulations achieved moisture protection comparable to that of the 200 formulation.

Claims (12)

1. A coating composition, on a dry weight basis, comprising at least 20% by weight of polyvinyl alcohol and 0.1 to 20% by weight of a water-insoluble (meth)acrylate copolymer containing quaternary ammonium groups based on the weight of said polyvinyl alcohol, wherein an aqueous dispersion comprising the coating composition having a solid content of 25% by weight has a viscosity of 200 mPa·s or less at 22°C. The other excipients, together with the polyvinyl alcohol and the water-insoluble (meth)acrylate copolymer, total 100% by weight; The additional excipients are selected from antioxidants, brighteners, binders, flavoring agents, flow aids, fragrances, slip agents, penetration enhancers, pigments, plasticizers, pore-forming agents, or stabilizers; and The water-insoluble (meth)acrylate copolymer consists of 85 to 98 wt% of free radical polymerized _C1- to _C4 -alkyl esters of acrylic acid or methacrylic acid and 2 to 15 wt% of (meth)acrylate alkyl ester monomers having quaternary ammonium groups in the alkyl groups. 2. The coating composition according to claim 1, wherein the water-insoluble (meth)acrylate copolymer comprises 55 to 75% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and 2 to 7% by weight of 2-trimethylammonium methacrylate chloride. 3. The coating composition of claim 1, wherein the water-insoluble (meth)acrylate copolymer comprises 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and greater than 7% and up to 15% by weight of 2-trimethylammonium methacrylate chloride. 4. The coating composition according to any one of claims 1 to 3, wherein when used for coating pills containing atorvastatin, the increase in impurities as measured by lactone is less than 1000% from the initial stage to 45 days of storage in an open petri dish at 40°C and 75% relative humidity. 5. The coating composition according to any one of claims 1 to 3, wherein the tablet coated with an aqueous dispersion comprising the coating composition disintegrates in an aqueous medium in a time of 30 minutes or less. 6. The coating composition according to any one of claims 1 to 3, wherein it is in powder form. 7. The coating composition according to any one of claims 1 to 3, wherein it is in the form of an aqueous dispersion. 8. A dosage form comprising a core containing an active pharmaceutical or nutrient ingredient and a coating derived from a coating composition according to any one of claims 1 to 7. 9. The dosage form according to claim 8, wherein the active pharmaceutical or nutrient component is acid-labile. 10. The dosage form according to claim 8 or 9, wherein the active ingredient is atorvastatin. 11. Use of the coating composition according to any one of claims 1 to 7 for the preparation of a dosage form according to any one of claims 8 to 10. 12. A method for preparing a dosage form according to any one of claims 8 to 10, the method being carried out by first preparing a core comprising an active pharmaceutical ingredient or a nutrient component and subsequently applying a coating composition in the form of an aqueous dispersion according to claim 7 onto the core.