EP2542222A2

EP2542222A2 - Melt-coated pharmaceutical forms

Info

Publication number: EP2542222A2
Application number: EP11705898A
Authority: EP
Inventors: Karl Kolter; Dejan Djuric
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2010-03-05
Filing date: 2011-03-01
Publication date: 2013-01-09
Also published as: JP2013521249A; WO2011107466A3; CN102781429A; WO2011107466A2

Abstract

The invention relates to preparations of active agents not easily soluble in water, consisting of carrier particles having active agent-containing coatings, wherein the active agents not easily soluble in water are embedded in coatings made of amphiphilic copolymers and the coatings are applied in the form of a solvent-free melt.

Description

Melt-coated dosage forms

Description The present invention relates to carrier particles coated with active substance-containing coatings, wherein the sparingly water-soluble active ingredient is embedded in a coating of amphiphilic copolymers which are obtained by polymerization of vinyl acetate and N-vinyl lactams in the presence of a polyether embedded, and the coatings Form of a melt can be applied. Furthermore, the invention relates to processes for the preparation of such coated carrier particles and agglomerates of such particles and their use in pharmaceutical dosage forms.

The coating of particles with active substance-containing coatings is usually carried out by spraying solutions of the coating compositions

A disadvantage of processing from the solution is the difficult handling of organic solvents, which place high demands on the environment and equipment. Furthermore, it is often difficult to find a suitable organic solvent for poorly soluble drugs.

It is known from WO 2005/034908 to apply melts or dispersions containing, as active ingredients, a combination of fibrates and statins, to carrier particles in the fluidized-bed granulator. The active ingredient combinations are present as solid solutions or solid dispersions of the active ingredients in hydrophilic or hydrophobic or pH-dependent soluble polymers. The granules thus obtained can be pressed into tablets.

Amphiphilic copolymers such as graft polymers obtained by radical polymerization of vinyl acetate and N-vinyl lactams in the presence of a polyether are known per se.

WO 2007/051743 discloses the use of water-soluble or water-dispersible copolymers of N-vinyllactam, vinyl acetate and polyethers as solubilizers for pharmaceutical, cosmetic, food-processing, agrotechnical or other technical applications. This generally describes that the corresponding graft polymers can also be processed in the melt with the active ingredients.

From WO 2009/013202 it is known that such graft polymers of N-vinyl lactam, vinyl acetate and polyethers are melted in the extruder and mixed with powdered or liquid active ingredients and can be processed into tablets. The object of the present invention was to find an improved process for coating and agglomerating carrier particles. Accordingly, a process for coating carrier particles with drug-containing coatings has been developed wherein the sparingly water-soluble drug is embedded in a coating of amphiphilic copolymers obtained by polymerizing vinyl acetate and N-vinyl lactams in the presence of a polyether, which characterized in that the coatings are applied in the form of a melt.

The melt is solvent-free. For the purposes of the present invention, "solvent-free" means that less than 5000 ppm of solvent are contained.

Suitable amphiphilic copolymers for embedding water-soluble active ingredients and their processability by melt extrusion are known, for example, from WO 2007/051743.

Corresponding copolymers are obtained by free-radically initiated polymerization of a mixture of i) 30 to 80% by weight of N-vinyllactam,

ii) 10 to 50 wt .-% of vinyl acetate and

iii) 10 to 50% by weight of a polyether, with the proviso that the sum of i), ii) and iii) is equal to 100% by weight.

According to one embodiment of the invention, preferred copolymers obtained from: i) 30 to 70% by weight of N-vinyllactam

ü) 15 to 35 wt .-% vinyl acetate, and

iü) 10 to 35 wt .-% of a polyether used.

Copolymers particularly preferably used are obtainable from: i) 40 to 60% by weight of N-vinyllactam

ü) 15 to 35 wt .-% vinyl acetate

iü) 10 to 30 wt .-% of a polyether Very particularly preferably used copolymers are obtainable from i) 50 to 60 wt .-% N-vinyl lactam

ii) 25 to 35% by weight of vinyl acetate, and

iii) 10 to 20% by weight of a polyether,

The proviso that the sum of the components i), ii), and iii) is equal to 100% by weight also applies to the preferred and particularly preferred compositions. Suitable N-vinyllactam are N-vinylcaprolactam or N-vinylpyrrolidone or mixtures thereof. Preference is given to using N-vinylcaprolactam.

Accordingly, an amphiphilic copolymer of N-vinylcaprolactam, vinyl acetate and a polyether is particularly preferred.

The graft is polyether. Suitable polyethers are preferably polyalkylene glycols. The polyalkylene glycols may have molecular weights of 1000 to 100000 Da [Dalton], preferably 1500 to 35000 Da, more preferably 1500 to 10000 Da. The molecular weights are determined on the basis of the measured according to DIN 53240 OH number.

Particularly preferred polyalkylene glycols are polyethylene glycols. Also suitable are polypropylene glycols, polytetrahydrofurans or polybutylene glycols obtained from 2-ethyloxirane or 2,3-dimethyloxirane.

Suitable polyethers are also random or block copolymers of polyalkylene glycols obtained from ethylene oxide, propylene oxide and butylene oxides, such as, for example, polyethylene glycol-polypropylene glycol block copolymers. The block copolymers may be of the AB or ABA type.

The preferred polyalkylene glycols also include those which are alkylated at one or both OH end groups. Suitable alkyl radicals are branched or unbranched C to C22-alkyl radicals, preferably C 1 -C 6 -alkyl radicals, for example methyl, ethyl, n-butyl, isobutyl, pentyl, hexyl, octyl, nonyl, decyl , Dodecyl, tridecyl or octadecyl radicals.

General processes for the preparation of the copolymers used according to the invention are known per se. The preparation is carried out by free radical-initiated polymerization, preferably in solution, in nonaqueous, organic solvents or in mixed nonaqueous / aqueous solvents. Suitable preparation processes are described, for example, in WO 2007/051743 and WO 2009/013202 the disclosure of which is expressly incorporated by reference to the manufacturing process.

As amphiphilic copolymers are in particular polymers obtained by polymerization of vinyl acetate and N-vinyl lactams in the presence of a polyether used.

In the coating also other polymers or low molecular weight substances can be incorporated.

The inventive method is characterized in that carrier particles are coated with a melt. The melt is composed of sparingly soluble active ingredient, solubilizing polymer and optionally further additives. After cooling and solidification of the melt results in a coating containing the active ingredient in dissolved form.

The coating of the carrier particles with a melt can be carried out in conventional fluidized bed apparatuses. The melt is sprayed onto a fluidized bed of carrier particles.

The melt is advantageously provided even before the actual spraying in a tempered storage vessel. According to one embodiment of the invention, the melt, consisting of polymer, active ingredient and optionally further additives, can then be sprayed by means of nozzles with the aid of a likewise tempered melt pump. Single-fluid nozzles or multi-fluid nozzles can be used as nozzles. In particular, two-component nozzles are suitable as multi-substance nozzles.

In addition to the fluidized bed apparatus, other equipment can be used in which the carrier particles are set in motion by rotation of boilers or by incoming air such. Coating kettle, intensive mixer, horizontal drum coater, ball coater, Innojet tools. Also suitable is the so-called

Beam fluidized bed (Procelltechnologie) for the application of the described formulations.

The supply air temperatures are usually between 30 and 200 ° C, preferably between 40 and 120 ° C. The product temperatures are generally between 20 and 100, preferably between 30 and 80 ° C.

According to a further embodiment of the invention, the melt can also be applied without sputtering, for example by pouring in a thin stream. As already described, the melt is solvent-free. The total content of solvents customarily used for such purposes, such as alkanols, for example ethanol, methanol or isopropanol, furthermore acetone, ethyl acetate, dichloromethane, chloroform, dimethylformamide and / or methyl ethyl ketone, should be less than 5000 ppm. The content of alkanols should preferably be less than 10 ppm.

Particularly suitable as carrier particles are spherical or at least approximately spherical particles, so-called "nonpareils." According to one embodiment of the invention, the nonpareils are pure, ie 100% by weight, of pharmaceutical auxiliaries. Carrageenan, starch or microcrystalline cellulose are available in different sizes (100 - 2000 μηη) .Usually the particle sizes are 700-1000 M. Carrier particles may also be tablets or granules.

Usually, the weight ratio of active ingredient to amphiphilic copolymer in the coating is between 1:99 and 80:20, preferably between 10:90 and 60:40. Thus, in the final solidified polymer coating of the carrier particles, active agent concentrations of from 1 to 80% by weight, based on the total mass, result.

It is also possible to coat granules or fine powders as carrier particles, it also being possible in the latter case for an agglomeration of the carrier particles. According to one embodiment of the invention, such granules or powders may also contain one or more active substances.

The layer thickness of the active substance-containing coatings of amphiphilic copolymer may be 5 to 1000, preferably 10 to 700 μηη. According to the invention, the term "sparingly soluble in water" also encompasses practically insoluble substances and means that a solution of the substance in water requires at least 30 to 100 g of water per g of substance at 20 ° C. In the case of practically insoluble substances, at least 10,000 g of water per For the purposes of the present invention, substances which are sparingly soluble in water are preferably understood to mean biologically active substances such as pharmaceutical active substances for humans and animals, cosmetic or agrochemical active substances or nutritional supplements or dietetic active substances or organic pigments. Suitable biologically active substances according to the invention are in principle all solid active compounds which have a melting point which is below the decomposition point below the melting conditions of the coating mixture. The copolymers can generally be processed at temperatures up to 260 ° C. The lower temperature limit depends on the composition of the mixtures to be melted and the sparingly soluble substances to be processed in each case. The minimum temperature limit can be 30 ° C.

The lower temperature limit depends on the viscosity of the melt, which must be low enough to be sprayed. Furthermore, the nozzle shapes and diameters are of importance for the melt viscosity to be adjusted over the temperature.

The pharmaceutical active ingredients used are water-insoluble to sparingly soluble substances. According to DAB 9 (German Pharmacopoeia), the classification of the solubility of active pharmaceutical ingredients is as follows: sparingly soluble (soluble in 30 to 100 parts of solvent); poorly soluble (soluble in 100 to 1000 parts of solvent); practically insoluble (soluble in more than 10,000 parts solvent). The active ingredients can come from any indication.

Examples include benzodiazepines, antihypertensives, vitamins, cytostatic drugs - especially taxol, anesthetics, neuroleptics, antidepressants, antiviral agents such as anti-HIV agents, antibiotics, antimycotics, anti-dementia, fungicides, chemotherapeutics, urologics, antiplatelet agents, sulfonamides, anticonvulsants, Hormones, immunoglobulins, serums, thyroid therapeutics, psychotropic drugs, Parkinson's and other antihyperkinetics, ophthalmics, neuropathy preparations, calcium metabolism regulators, muscle relaxants, anesthetics, lipid lowering agents, liver therapeutics, coronary agents, cardiakats, immunotherapeutics, regulatory peptides and their inhibitors, hypnotics, sedatives, gynecologics, gout, fibrinolytics , Enzyme preparations and transport proteins, Enzyme inhibitors, Emetics, Medication enhancing agents, Diuretics, Diagnostics, Corticoids, Cholinergics, Ballenwegherapeutika, Antiasthmatika, Broncholytika, Betarezeptorenblocker, Calci antagonists, ACE inhibitors, atherosclerosis agents, antiphlogistics, anticoagulants, anti-hypotensive agents, antihypoglycemic agents, antihypertensives, antifibrinolytics, antiepileptics, antiemetics, antidotes, antidiabetics, antiarrhythmics, antianemics, antiallergic drugs, anthelmintics, analgesics, analeptics, aldosterone antagonists, weight loss agents called.

Even sparingly soluble active ingredients of traditional Chinese medicine can be processed.

The content of solubilizer according to the invention in the pharmaceutical preparation is, depending on the active ingredient, in the range of 20 to 99 wt .-%. Of course, further pharmaceutically customary excipients may be added to the formulation according to the invention, such as further solubilizers, polymers, dyes, inorganic carriers, disintegrants, gelling agents, slow-release agents, antioxidants, flavoring agents, plasticizers, buffer substances. By incorporating enteric polymers or retardation polymers, the release of the active ingredient can be controlled in a targeted manner.

The addition of crystallization-inhibiting substances such as Kollidon 30 can increase the stability of the solid solutions.

Suitable plasticizers are, for example, triacetin, triethyl citrate, glycerol monostearate, polyethylene glycols or poloxamers.

Surfactants having an HLB value (hydrophilic lipophilic balance) greater than 11, for example ethoxylated hydrogenated castor oil (Cremophor® RH 40), ethoxylated castor oil (Cremophor EL) with 35 ethylene oxide units, are suitable as additional solubility promoters. , Polysorbate 80, poloxamers or sodium lauryl sulfate. Dyes are e.g. Iron oxides, titanium dioxide, triphenylmethane dyes, azo dyes, quinoline dyes, indigotine dyes, carotenoids to dye the dosage forms, opacifying agents such as titanium dioxide or talc to increase the light transmission and to save dyes. In addition to the application in cosmetics and pharmacy, the preparations according to the invention are also suitable for use in the food industry, for example for the incorporation of poorly water-soluble or water-insoluble nutrients, auxiliaries or additives, such. fat-soluble vitamins or carotenoids. The application of the preparations according to the invention in agrochemistry can u. a. Formulations include pesticides, herbicides, fungicides or insecticides, especially those preparations of pesticides used as spray or casting broths. The coated carrier particles obtained according to the invention can be used as capsule fillings or in sachets.

The coated carrier particles in the form of pellets or granules can also be pressed into tablets. In this case, other common Tabllettenhilfsstoffe as fillers, binders, disintegrants and flow and release agents are used.

With the aid of the method according to the invention, active substance-containing coatings on carrier particles can be obtained as so-called solid solutions with sparingly soluble substances. Solid solutions according to the invention are systems in which no crystalline components of the sparingly soluble substance are observed. As stated, the preparations obtained by the process according to the invention are amorphous, which means that the crystalline proportions of the biologically active substance are less than 5% by weight. Preferably, the amorphous state is checked by DSC or XRD. Such an amorphous state may also be referred to as an amorphous state.

The process of the invention allows the production of stable preparations with high drug loading and good stability with respect to the amorphous state of the sparingly soluble substance. The peculiarity of this method is that an amphiphilic polymer is used together with sparingly soluble active ingredient in the form of a solvent-free melt. The amphiphilic polymer is able to melt or dissolve the active ingredient below its melting point. The coating is thus not a conventional pellet or tablet coating, but a coating that holds poorly soluble drug in dissolved form. The solid solution formed can also serve as a binder bridge between carrier particles and thus as a granulation aid. The advantage of solid solutions is that sparingly soluble drugs can be made more bioavailable. The active ingredients may be contained in the coating or binder layer in amorphous or molecularly dissolved form.

Due to the amphiphilic polymer structure, the polymer is ideally suited as a basis for solid solutions. As already described, solid solutions can be achieved via a melt extrusion process. An elegant alternative method is the formation of the solid solution as a coating on solid dosage forms such as pellets, granules, powders or even tablets. The use of common fluidized bed systems makes this process all the more interesting. In addition, the freedom of solvent of the melt has a positive effect on the properties of the coatings. These are less porous, but smoother and more homogeneous. Another advantage of this processing method is that solid solutions of sparingly soluble drugs can be made into multiparticulate solid dosage forms. NEN. These multiparticulate dosage forms can be filled, for example, into hard gelatin capsules or even pressed into tablets.

Examples

As the amphiphilic copolymer was a graft polymer of 13 wt .-% polyethylene glycol. MG 6000, 57% by weight of N-vinylcaprolactam and 30% by weight of vinyl acetate having an average molecular weight of 44,000 daltons.

The processing took place in a fluidized-bed granulator from Glatt Glatt (GPCG 3.1). The spraying was carried out with a two-fluid nozzle, diameter 4 mm.

The melt was obtained by heating the coating components to 70 ° C and on the carrier particles of sucrose (pellets with particle sizes of 710-850 μηη (sieve fraction)) or Granulac 200 (lactose, Messrs. Meggle, (d50) = 30 μηη, bulk density 535 g / l) applied.

The process parameters for processing in the fluidized bed granulator are given in the individual examples.

The coatings prepared were examined for crystallinity and morphogenicity using XRD and DSC using the following equipment and conditions:

XRD (X-Ray Diffractogram)

Measuring instrument: Diffractometer D 8 Advance with 9-fold sample changer (Fa.Bruker / AXS)

Type of measurement: θ- Θ Geometry in reflection

Angular range 2 theta: 2-80 °

Increment: 0.02 °

Measuring time per angle step: 4.8s

Divergence Slit: Göbel mirror with 0.4 mm plug

Antiscattering Slit: target gap

Detector: Sol-X detector

Temperature: room temperature

Generator setting: 40kV / 50mA

In the examples below, different carrier particles were provided with active substance-containing coatings. Example 1 :

The XRD analysis showed no crystalline active ingredients.

The release of the active ingredient from 400 mg pellets was carried out in a USP apparatus 2 in 700 ml of 0.1 normal HCL. After 60 minutes, 90% of the drug was released.

Example 2:

The XRD analysis showed no crystalline active ingredients.

The release of the drug from 0.6 g pellets was performed in a USP Apparatus 2 in 700 mL 0.1 normal HCL. After 60 minutes, 70% of the drug was released. Example 3:

¹⁾ Poloxamer 188

The XRD analysis showed no crystalline active ingredients.

The release of the active ingredient from 400 mg pellets was carried out in a USP apparatus 2 in 700 ml of 0.1 normal HCL. After 40 minutes, 100% of the drug was released.

Example 4:

²⁾ Poloxamer 407

The XRD analysis showed no crystalline active ingredients.

Release of the active ingredient from 515 mg pellets was carried out in USP Apparatus 2 in 700 mL 0.1 normal HCL. After 30 minutes, 100% of the drug was released. Example 5:

The XRD analysis showed no crystalline active ingredients.

The release of the active ingredient from 300 mg pellets was carried out in a USP apparatus 2 in 700 ml of 0.1 normal HCL. After 30 minutes, 100% of the drug was released.

Example 6:

The XRD analysis showed no crystalline active ingredients.

The release of the active ingredient from 420 mg pellets was carried out in USP Apparatus 2 in 700 mL 0.1 normal HCL. After 60 minutes, 100% of the drug was released. Example 7:

The XRD analysis showed no crystalline active ingredients.

The release of the active ingredient from 600 mg pellets was carried out in a USP apparatus 2 in 700 ml of 0.1 normal HCL. After 60 minutes, 100% of the drug was released.

Example 8:

The XRD analysis showed no crystalline active ingredients.

The release of the active ingredient from 600 mg of granules was carried out in a USP apparatus 2 in 700 mL 0.1 normal HCL. After 60 minutes, 100% of the drug was released. Example 9:

The XRD analysis showed no crystalline active ingredients.

The release of the active ingredient from 400 mg of granules was carried out in a USP apparatus 2 700 ml of 0.1 normal HCL. After 60 minutes, 85% of the drug was released.

Claims

claims

1 . Preparations of sparingly water-soluble active ingredients consisting of carrier-containing coatings provided carrier particles, wherein the schwerlös- lent active ingredients are embedded in coatings of amphiphilic copolymers, and the coatings are applied in the form of a solvent-free melt.

Preparations according to Claim 1, in which amphiphilic copolymers are used which are prepared by free-radically initiated polymerization of a mixture of i) 30 to 80% by weight of N-vinyllactam,

ii) 10 to 50 wt .-% of vinyl acetate and

iii) from 10 to 50% by weight of a polyether, with the proviso that the sum of i), ii) and iii) is equal to 100% by weight

3. Preparations according to claim 1 and 2, wherein the copolymers are obtained from:

From 30 to 70% by weight of N-vinyllactam

15 to 35% by weight of vinyl acetate, and

10 to 35 wt .-% of a polyether.

Preparations according to any one of claims 1 to 3, wherein the copolymers will be comprised of: i) from 40 to 60% by weight of N-vinyl lactam

ii) 15 to 35% by weight of vinyl acetate

iii) 10 to 30 wt .-% of a polyether.

Preparations according to any one of claims 1 to 4, wherein the copolymers will be comprised of: i) from 50 to 60% by weight of N-vinyl lactam

ii) 25 to 35% by weight of vinyl acetate, and

iii) 10 to 20 wt .-% of a polyether.

Gd / Ya 19.10.2010

6. Preparations according to one of claims 1 to 5, wherein pellets of pharmaceutical excipients are used as carrier particles.

7. Preparations according to one of claims 1 to 6, wherein the carrier particles of sucrose, carrageenan, starch, lactose or microcrystalline cellulose.

8. Preparations according to one of claims 1 to 7, wherein the carrier particles have particle sizes of 100 to 2000 μηη.

Preparations according to one of claims 1 to 5, wherein particles which consist of active ingredient and amphiphilic polymer are used as carrier particles.

10. Preparations according to one of claims 1 to 9, wherein the coatings additionally contain pharmaceutical excipients.

1 1. Preparations according to one of claims 1 to 10, wherein the coatings contain from 20 to 99% by weight of amphiphilic polymer.

12. A process for the preparation of preparations according to any one of claims 1 to 1 1, characterized in that the preparation of the preparations by applying a melt containing one or more

Active ingredients and an amphiphilic copolymer, carried on a fluidized bed of carrier particles.

13. The method according to claim 12, characterized in that the application of the melt takes place by spraying.

14. The method according to claim 12 or 13, characterized in that the

Melt at temperatures of 30 to 260 ° C is obtained.

15. The method according to any one of claims 12 to 14, characterized in that the melt is solvent-free.

16. The method according to any one of claims 12 to 15, characterized in that the solvent content of the melt is less than 5000 ppm.

17. dosage forms containing preparations according to any one of claims 1 to 1 1st

18. Dosage forms according to claim 17 in the form of tablets, capsules or sachets.