Direct tablet supplement ingredients

Abstract

The present invention relates to a direct compression aid composition based on lactose powder intimately mixed with water soluble polyethylene glycol-polyvinyl alcohol graft copolymer as a binder, a lubricant, a colorant and optionally crosslinked insoluble polyvinylpyrrolidone as a tablet disintegrant.

Description

[Technical field]

[0001] The present invention relates to a direct compression aid composition based on lactose powder intimately mixed with water soluble polyethylene glycol-polyvinyl alcohol graft copolymer as a binder, a lubricant, a colorant and optionally crosslinked insoluble polyvinylpyrrolidone as a tablet disintegrant. [Background technology]

[0002] In the pharmaceutical industry, the most commonly used means for delivering APIs (active pharmaceutical ingredients) are tablets, which can be obtained by compressing properly formulated powders. Traditionally, compressible mixtures are typically obtained by blending the APIs with suitable excipient materials. These excipients may include diluents or fillers, binders or adhesives, disintegrants, glidants or flow enhancers, colorants, flavors, and mixtures thereof.

[0003] Colored tableting aids are highly suitable for the manufacture of bilayer or multilayer tablets. It may be desired to indicate the presence of two different active ingredients or compositions in one tablet and to increase patient compliance through this appearance. Clear separation of their individual layers is often desirable but difficult to achieve. By simply physically mixing up to 10% by weight of coloring agent with tableting aid, the powder powderous composition does not show a homogenous appearance, but a mottled blend and poor turbidity (Figure 1).

[0004] However, there is a continuing need in the art for further optimization of processes for producing novel excipient compositions and ready-to-use co-processed excipient compositions. In particular, the industry still needs continuous manufacturing concepts for pharmaceutical excipients that exhibit good flow properties while allowing acceptable ejection forces during tableting, increasing hardness of compressed dosage forms, and shortening disintegration times. Such performance is required for various drug-containing tablets, such as painkillers. Summary of the Invention

[0005] Thus, in one aspect, the present invention provides a direct compression aid composition comprising at least one lactose component, at least one water soluble polyethylene glycol-polyvinyl alcohol graft copolymer, at least one lubricant, at least one colorant, and optionally at least one water insoluble cross-linked polyvinylpyrrolidone.

[0006] Lactose belongs to the group of disaccharides and consists of two molecules, β-D-galactose and α / β-D-glucose, which are linked together by a β-1,4 glycosidic bond. According to the present invention, the lactose component can be anhydrous lactose or lactose monohydrate. Lactose monohydrate is preferred because it is less hygroscopic compared to anhydrous lactose and is therefore more suitable for compositions containing water-sensitive active pharmaceutical ingredients. Lactose monohydrate with a content of amorphous lactose monohydrate of less than 5% by weight is more preferred.

[0007] Polyethylene glycol-polyvinyl alcohol graft copolymer is a white to yellowish powder, which has the advantages of being easily soluble in water, having low viscosity, not being oxygen sensitive, and not generating hydrogen peroxide like other polymers. It is a graft polymer containing polyethylene glycol and polyvinyl alcohol combined in a ratio of 25:75. The molecular weight is approximately 45000. The addition of polyethylene glycol-polyvinyl alcohol graft copolymer makes it possible to both optimize the particle size distribution and, surprisingly, to keep the tablet disintegration time short despite the use of a water-soluble binder. The polyethylene glycol-polyvinyl alcohol graft copolymer powder is commercially available as Kollicoat® IR and contains approximately 0.3% colloidal silica. The polyethylene glycol and polyvinyl alcohol graft copolymer used in the present invention does not contain any colloidal silica. The direct compression aid composition is unusual in that it does not contain any glidants / flow enhancers and yet shows extremely high flowability.

[0008] Crosslinked insoluble polyvinylpyrrolidone is widely used in the pharmaceutical industry due to its swelling properties. Therefore, it is mainly used as a disintegrant in tablets. Furthermore, its use as a pharmaceutical additive is triggered by its ability to hydrophilize insoluble drugs, stabilize suspensions, and form complexes, as well as its adsorption properties. According to the present invention, the crosslinked polyvinylpyrrolidone can be Kollidon CL and / or Kollidon CL-SF and / or Kollidon CL-F, with Kollidon CL-F being preferred.

[0009] The lubricant used according to the present invention is sodium stearyl fumarate, magnesium stearate, stearic acid and / or poloxamer 407 (Kolliphor P407micro), preferably it is sodium stearyl fumarate and magnesium stearate, most preferably it is magnesium stearate.

[0010] The colorants used in the present invention are classified into three groups: A. organic dyes and their lakes, B. inorganic or mineral pigments, and C. natural or vegetable or animal pigments.

[0011] A.) Organic dyes are synthetic compounds that develop their coloring or tinting power when dissolved in a solvent; examples include erythrosine, patent blue V, and the azo dyes tartrazine and sunset yellow. Lakes are defined by the FDA as "aluminum salts of FD&C water-soluble dyes spread on an alumina substrate." Lakes, unlike dyes, are insoluble and pigmented by dispersion. As a result, the particle size of a lake is crucial to its coloring and tinting power. Lakes are generally water-insoluble forms of common synthetic water-soluble dyes. Some examples of aluminum lakes are brilliant blue lake, sunset yellow lake, amaranth lake, allura red lake, indigo carmine lake, and quinoline yellow lake.

[0012] B.) Perhaps the most important use of mineral color in modern pharmaceuticals is the use of mixtures of red and yellow iron oxides. Titanium dioxide is used to color and opacify hard gelatin capsules.

[0013] C.) Natural or plant and animal colors are a chemically and physically diverse group of materials. Some of these colorants are the product of chemical synthesis rather than extraction from natural sources; for example, commercially available β-carotene is usually synthetic in origin.

[0014] Of the three groups, colorants in Group A are preferred. Preferred among the colorants in Group A are the FD&C dyes and D&C dyes, which are dyes approved for use in Food, Drugs, and Cosmetics (FD&C) or in Drugs and Cosmetics (D&C).

[0015] The direct compression aid composition according to the present invention preferably contains a lactose component in an amount of 75-98.75% by weight, more preferably 80-95% by weight, and even more preferably 83-92% by weight, based on the total weight of the composition.

[0016] The crosslinked insoluble polyvinylpyrrolidone component is preferably present in an amount of from 0 to 15% by weight, more preferably from 2 to 12% by weight, and even more preferably from 3 to 10% by weight, based on the total weight of the composition.

[0017] The polyethylene glycol-polyvinyl alcohol graft copolymer may be contained in the composition in an amount of 0.5 to 10% by weight, more preferably 1 to 10% by weight, and even more preferably 2 to 9% by weight, based on the total mass of the composition.

[0018] The composition of the present invention preferably has a total amount of lubricant of 0.5-10% by weight, more preferably 1-10% by weight, even more preferably 2-9% by weight, based on the total mass of the composition. According to the present invention, the lubricant is sodium stearyl fumarate, magnesium stearate, stearic acid and / or poloxamer 407 (Kolliphor P407micro), preferably it is sodium stearyl fumarate and magnesium stearate, most preferably it is magnesium stearate.

[0019] The colorant is preferably present in an amount of from 0.25 to 12% by weight, more preferably from 1 to 11% by weight, and even more preferably from 2 to 9% by weight, based on the total mass of the composition, the sum of all components of the composition adding up to 100% by weight.

[0020] The direct compression auxiliary composition has a spherical morphology, and is preferably present in the form of granules, the average particle size (D50) of said granules being preferably in the range of 50 to 500 μm, more preferably in the range of 80 to 300 μm, and even more preferably in the range of 100 to 250 μm.

[0021] The pigmented compositions have a homogeneous and intense color even when only 0.5% by weight of the colorant is present in the composition (Figure 2).

[0022] During the tabletting process, the compositions of the present invention may be mixed with at least one API at levels ranging from 1-75% API by weight.

[0023] In another embodiment, the composition, preferably the granules, does not comprise any API.

[0024] In a further aspect of the present invention, a method for producing such a composition is provided. The method of the present invention comprises the steps of (i) preparing a solution or suspension comprising at least one polyethylene glycol-polyvinyl alcohol graft copolymer, at least one colorant and at least one lactose, optionally cross-linked insoluble polyvinylpyrrolidone in a liquid medium, and (ii) spraying the solution or suspension obtained in step (i) in an environment of elevated temperature and optionally reduced pressure, thereby removing the liquid medium. In step (i), the at least one polyethylene glycol-polyvinyl alcohol graft copolymer component, at least one colorant and at least one lactose component, and optionally at least one cross-linked insoluble polyvinylpyrrolidone are preferably at least partially dissolved in a liquid medium such as water or an organic solvent such as ethanol, acetic acid and acetone, and mixtures thereof.

[0025] It is particularly advantageous to incorporate the colorant in step (i) as a concentrated liquid (dispersed suspension concentrate or solution concentrate).

[0026] In step (ii), the solution or suspension obtained in step (i) is sprayed, whereby, in contrast to the state of the art, the lubricant is applied to the surface of the spray-dried particles as a solid powder and not as a solution or suspension.

[0027] It is particularly advantageous that this novel process can be integrated into a continuous manufacturing process without additional preparation steps.

[0028] In another aspect, the present invention relates to a composition obtained by the above process. It has been found that the process results in a composition having good flowability, high bulk density and good tabletability as well as uniform color. In a further aspect, the present invention is directed to the use of the above composition as an additive in the preparation of oral dosage forms, in particular as a tableting additive, more particularly as a direct compression additive. Due to its good flowability and high bulk density, the composition is also highly suitable as a diluent for binary mixtures with APIs to be filled into hard shell capsules (e.g. hard gelatin capsules).

[0029] The invention is further illustrated by the following figures and examples. [Brief description of the drawings]

[0030] [Figure 1] Appearance: A physical mixture of a lactose-based tableting aid without coloring agents and increasing amounts of Indigotin 85 (E132) from left (0.5% Indigotin 85) to right (10% Indigotin 85). All samples are white with increasing amounts of colored specks and have a heterogeneous appearance. [Diagram 2] Appearance: Comparison of a direct compression aid composition according to the invention (left) containing 0.5% (w / w) indigotin 85 (E132) as colorant (left sample) with a physical mixture of 0.5% indigotin 85 (E132) and an uncolored tableting aid (right sample). The sample according to the invention (left) has an intense, homogeneously distributed color. EXAMPLES

[0031] method The tap density of the coloured direct compression adjuvant composition was determined according to European Pharmacopoeia 9th Edition, Chapter 2.9.34, Method 2.

[0032] The bulk density of the coloured direct compression adjuvant composition was determined according to Chapter 2.9.34, Method 3 of the European Pharmacopoeia, 9th Edition.

[0033] The Hausner ratio is equal to the ratio of the tamped density to the bulk density.

[0034] The packing factor is equal to the ratio of the bulk density to the true density.

[0035] The flow properties and angle of repose of the coloured direct compression adjuvant composition are determined according to chapters 2.9.16 and 2.9.36 of the European Pharmacopoeia, 9th Edition.

[0036] The particle size distribution (D10, D50, D90) of the direct compression adjuvant composition was determined using a Malvern Mastersizer 2000.

[0037] Tablet hardness was measured according to chapter 2.9.8 of the European Pharmacopoeia 9th edition using a Sotax HT 100 tablet tester. Tablet hardness is determined consecutively on 20 tablets at a test jaw speed of 120 mm / min.

[0038] Example 1: Preparation of a colored direct compression adjuvant composition according to the present invention An aqueous solution of Kollicoat® IR (not containing any colloidal silica), a colorant and a crosslinked insoluble polyvinylpyrrolidone (e.g. Kollidon CL-F) was suspended in water and the suspension was cooled to below 20° C. It is particularly advantageous to incorporate the colorant as a concentrated liquid (dispersed concentrated suspension or concentrated solution). Under stirring, lactose (e.g. GranuLac) was continuously dosed into the suspension. To remove the solvent, the resulting suspension was spray-dried at an inlet air temperature of 155° C.±5° C. and an outlet air temperature of >80° C., whereby magnesium stearate was dosed in dry form into the spray dryer and then cooled, whereby the fine powder was separated from the granules by a cyclone. The direct compression aid had the composition shown in Tables 1 to 5.

[0039] [Table 1]

[0040]

Table 2

[0041]

Table 3

[0042]

Table 4

[0043]

Table 5

[0044]

Table 6

Claims

1. A) 75 to 98.75% by weight of lactose suitable for tableting; B) 0.5 to 10% by weight of a water-soluble polyethylene glycol-polyvinyl alcohol graft copolymer; C) 0 to 15% by weight of crosslinked insoluble polyvinylpyrrolidone; D) 0.25 to 12% by weight of a colorant; E) 0.5 to 10% by weight of a lubricant; A direct compression aid composition in the form of spherical granules comprising: A direct compression aid composition, wherein the total of all components A to E is 100% by weight, and the average particle size (D50) of the spherical granules is in the range of 50 μm to 500 μm.

2. A.) 75 to 98.75% by weight of lactose suitable for tableting B.) 0.5 to 10% by weight of a water-soluble polyethylene glycol-polyvinyl alcohol graft copolymer; C.) 0.25 to 12% by weight of a colorant; D.) 0.5 to 10% by weight of a lubricant; A direct compression aid composition in the form of spherical granules comprising: A direct compression aid composition, wherein the total of all components A to D is 100% by weight, and the average particle size (D50) of the spherical granules is in the range of 50 μm to 500 μm.

3. 3. The direct compression aid composition according to claim 1, having an average particle size of 80 μm to 300 μm.

4. 3. The direct compression aid composition according to claim 1 or 2, having an average particle size of 100 μm to 250 μm.

5. 3. The direct compression aid composition of claim 1 or 2, wherein the lactose is lactose monohydrate.

6. 2. The direct compression aid composition according to claim 1, wherein the insoluble polyvinylpyrrolidone is Kollidon CL-SF and / or Kollidon CL-F and / or Kollidon CL.

7. 3. The direct compression aid composition according to claim 1 or 2, wherein the colorant is an organic dye or a lake thereof.

8. 8. The direct compression aid composition of claim 7, wherein the coloring agent is an FD&C dye or a D&C dye.

9. 3. The direct compression aid composition according to claim 1 or 2, wherein the lubricant is sodium stearyl fumarate, magnesium stearate and / or poloxamer 407 stearate (Kolliphor P407micro).

10. 10. The direct compression aid composition of claim 9, wherein the lubricant is magnesium stearate.

11. 3. The direct compression aid composition of claim 1, wherein the lubricant is located on the surface of the granules.

12. 3. The direct compression aid composition according to claim 1 or 2, having an angle of repose of 25° to 31°.

13. 10. A continuous process for preparing the direct compression aid composition of claim 1, the continuous process comprising spray drying the lactose, polyethylene glycol-polyvinyl alcohol graft copolymer, colorant suspension and optionally cross-linked insoluble polyvinylpyrrolidone suspension, whereby the lubricant is introduced in dry powder form.

14. 3. A continuous process for preparing the direct compression aid composition of claim 2, wherein the continuous process comprises spray drying the lactose, polyethylene glycol-polyvinyl alcohol graft copolymer, and colorant suspension, whereby the lubricant is introduced in dry powder form.

15. 15. The method of claim 13 or 14, wherein the lubricant is added as a dry powder, resulting in a product in which the lubricant adheres to the surface of the spray-dried particles.

16. 3. Use of the direct compression auxiliary composition according to claim 1 or 2 in cosmetic or pharmaceutical preparations, in preparations of agrochemical active agents, in preparations in the field of food, feed and food or feed supplements.

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