Drug-loaded regulated release pills

Abstract

A delayed release formulation for delivering an active pharmaceutical ingredient (API) to the colon, comprising: a pill having a core and a layered coating on the core, the core comprising the API, and the layered coating comprising: a first layer comprising a first film-forming polymer and a second layer comprising a second film-forming polymer, wherein the first film-forming polymer is a film-forming polymer that provides a pH dependent release at above pH 7.0, and the second film-forming polymer is a film-forming polymer that provides a pH independent release.

Description

Technical Field

[0001] Provided are pharmaceutical formulations that enable targeted and modified release of an active ingredient (e.g., metformin or an acid addition salt of metformin, particularly metformin hydrochloride) from a drug-loaded pellet in the colon.

[0002] Pellets are characterized not only by targeted release but also by a high active ingredient load.

[0003] A preparation method is also provided. Background Art

[0004] Oral administration is the most popular form of administration of active pharmaceutical ingredients. Many formulations have been proposed to prepare drugs for oral administration. What these formulations have in common is that they release the drug in the intestine after ingestion.

[0005] For some active pharmaceutical ingredients, oral dosage forms that deliver the ingredient in the colon are of interest.

[0006] Targeted drug delivery to the colon is ideal for local treatment of various colonic pathologies (eg, ulcerative colitis, Crohn's disease, amebiasis, colon cancer), but also for systemic delivery of drugs.

[0007] To reach the colon, a drug formulation must pass through the mouth, stomach, and small intestine until it reaches its target site, the colon, which is part of the large intestine.

[0008] Colon-specific drug delivery systems should protect the drug en route to the colon. Drug release should not occur in the stomach or small intestine. After release in the colon, the drug is primarily absorbed through the intestinal mucosa.

[0009] To achieve delivery in the colon, various formulations have been proposed.

[0010] NZ 748404A describes a formulation for delivering a drug to the colon comprising particles having a core and a coating for the core, the core comprising the drug and the coating comprising a monolayer of a mixture of a first material susceptible to attack by colonic bacteria and a second material being a film-forming polymeric material having a pH threshold of about pH 6.5 or higher.

[0011] US2021 / 228487 A1 describes a pharmaceutical formulation for treating inflammatory diseases of the colon. The formulation is a capsule containing pellets having multiple coatings, namely, an active substance layer applied directly to the starting pellet; a swelling layer applied directly to the active substance layer; a delay layer applied directly to the swelling layer; and an outermost coating that is insoluble at pH values <5.5 but dissolves well at pH values greater than 6.0 and is applied directly to the delay layer.

[0012] CA 3 122 025A1 describes a formulation for delivering a drug to the colon, comprising a core containing a drug and a coating for the core. The core comprises an outer layer and an inner layer. The outer layer comprises a film-forming enteric polymer having a pH threshold of approximately pH 6 or above, and the inner layer comprises a film-forming nonionic polymer soluble in small intestinal fluid or gastrointestinal fluid and a buffer.

[0013] CN 112791060 A describes a method for producing a pharmaceutical composition for oral administration and colonic delivery, in particular of mesalamine or 5-aminosalicylic acid. The method involves a powder application technique for the active ingredient and the application of a coating comprising at least an anionic (meth)acrylic copolymer soluble at a pH above 6 and an anionic (meth)acrylic copolymer soluble at a pH above 7.

[0014] JO 3574B1 describes a delayed-release formulation comprising a core comprising a drug and a coating for the core comprising an outer layer comprising a mixture of a first polymeric material susceptible to attack by colonic bacteria and a second polymeric material having a pH threshold of about pH 5 or above.

[0015] In this context, there is still a need for formulations that allow colonic delivery, especially of water-soluble APIs. For example, there has been recent interest in the colonic release of metformin. Metformin is usually used in the form of its hydrochloride, which is highly soluble in water. Summary of the Invention

[0016] The present invention provides a delayed-release formulation for delivering an active pharmaceutical ingredient (API) to the colon, comprising:

[0017] A pellet having a core and a layered coating on the core,

[0018] The core contains the API, and

[0019] The layered coating includes:

[0020] a first layer comprising a first film-forming polymer, and

[0021] a second layer comprising a second film-forming polymer,

[0022] wherein the first film-forming polymer is a film-forming polymer that provides pH-dependent release above pH 7.0, and

[0023] The second film-forming polymer is a film-forming polymer that provides pH-independent release.

[0024] Preferred embodiments of the invention are defined in the dependent claims. DETAILED DESCRIPTION

[0025] The present invention is based on the discovery that a particularly effective controlled release of an active ingredient, such as metformin or an acid addition salt of metformin, in particular metformin hydrochloride, in the colon can be achieved by means of a pellet formulation, wherein the release from the pellet is controlled by two different release control mechanisms. According to the invention, the pellet is provided with a layered coating comprising a first layer providing pH-dependent release and a second layer providing pH-independent release.

[0026] The first layer providing pH-dependent release comprises a first film-forming polymer providing pH-dependent release above pH 7.0.

[0027] The second layer comprises a second film-forming polymer that provides pH-independent release.

[0028] The order in which the first and second layers are applied to the core can be selected.

[0029] According to the present invention, release in the colon is not only dependent on an increase in pH, but is also ensured by means of a delay polymer.

[0030] Active ingredient

[0031] Active pharmaceutical ingredients that may be formulated according to the present invention are those that are desired to be released in the colon.

[0032] The formulations according to the present invention are particularly suitable for use with APIs that are soluble in water (requiring 10 to 30 parts of water per part of API); readily soluble in water (requiring 1 to 10 parts of water per part of API); or even very soluble APIs (requiring less than 1 part of water per part of API).

[0033] Solubility is determined at a temperature of 37° C. Parts of solvent or solute are parts by weight.

[0034] An API of particular interest is metformin (1,1-dimethylbiguanide). Metformin can be provided in a water-soluble form. Preferred examples are acid addition salts of metformin, particularly metformin hydrochloride (solubility >300 g / L).

[0035] Pill core

[0036] The core of the pellets comprised in the delayed-release formulation according to the present invention contains the active pharmaceutical ingredient.

[0037] Typically, at least 90% by weight of the pellets have a core including an optional seal coat having a size in the range 100-2000 μm as determined by sieve analysis. Preferably the range is 200-1000 μm, more preferably 300-700 μm, especially 315-500 μm.

[0038] In another preferred aspect of the invention, the core is circular as indicated by a small eccentricity.

[0039] The eccentricity can be determined optically, for example using The device is a direct imaging particle size analyzer that can measure the size and shape of particles in the 50-5500 μm range. To obtain the image, the particles are illuminated from different angles by red, green, and blue LEDs.

[0040] By software The obtained images are analyzed to determine the particle size and shape by calculating the best fit ellipse. The particle size is shown as a numerical distribution or a volume distribution (e.g., Dn50 or Dv50), and the shape is represented by the average eccentricity.

[0041] The eccentricity ε is a measure of how much the fitted ellipse deviates from a circle. It is calculated from the length of the major axis (a) and the length of the minor axis (b) of the ellipse:

[0042]

[0043] The eccentricity of a circle is zero. The eccentricity of an ellipse, which is not a circle, is greater than zero but less than 1.

[0044] The smaller the eccentricity, the rounder the pill.

[0045] In a preferred aspect of the invention the core including the optional seal coat has an average eccentricity of 0.45 or less, preferably 0.40 or less, in particular 0.35 or less.

[0046] In a preferred aspect of the invention, the core contains a high proportion of API. For example, based on the weight of all components of the core, the core comprises at least 50% wt of API, preferably at least 70% wt of API, more preferably at least 90% wt of API, especially at least 95% wt of API.

[0047] Matrix pellets as core

[0048] The core of the pellet contained in the delayed release formulation according to the present invention may be a matrix pellet comprising the API and one or more binders.

[0049] Binders useful in preparing matrix pellets are typically polymers or polymer compositions.

[0050] Suitable polymers include Carbopol 974P NF (molecular weight >1000 g / mol); chitosan (molecular weight 50,000-190,000 g / mol) and HPMC (Pharmacoat 603) (molecular weight 10,000-150,000 g / mol).

[0051] Cores can be produced using a method using a spouted bed apparatus as described in DE 103 22 062 A1. This method involves introducing an aqueous spray solution containing a polymer and an API into a solids stream in a spouted bed apparatus and related devices. This method is characterized in that at least one circular solids stream is formed in the axial direction of the reaction space of the spouted bed apparatus. To this end, the inlet air required to form the solids stream is fed through a gap in the lower region and in the axial direction of the reaction space, and the fluid is introduced into the solids stream at one or more locations using one or more single- or multi-component nozzles. This allows the flow conditions in the spraying region to be adjusted, allowing the fluid to be selectively and adjustably introduced into the solids stream. The resulting end products are distinguished by approximately equal grain size and identical material properties.

[0052] In this way, matrix pellets can be prepared having a spherical shape characterized by low eccentricity and containing only 3-5 wt% binder.

[0053] Inert starting pellets for drug layering as core

[0054] The core of the pellets comprised in the delayed release formulation according to the invention may be a drug-layered inert starter core, ie a starter core pellet containing no active ingredient, which is provided with a layer comprising the drug and one or more binders.

[0055] Any pellet suitable for pharmaceutical use that does not contain API can be used as the inert starting pellet core.

[0056] Suitable inert starting cores are, for example, glass beads and pellets made of sucrose, mannose or microcrystalline cellulose. Inert starting cores made of microcrystalline cellulose are preferred. Such pellets can be prepared in the form of It is commercially available under the name of .

[0057] The size of the core is not limited. Suitable sizes are in the range of 10 μm to 2000 μm, for example in the range of 50 μm to 1500 μm, preferably in the range of 100 μm to 1000 μm, and the size can be determined by sieve analysis. In particular, pellets with a sieve size fraction of 500-710 μm can be used.

[0058] Inert starting core (e.g. based on microcrystalline cellulose The inert starting core pellets (pills) are provided with an API comprising a coating. To apply the API comprising a coating, the API is combined with one or more excipients. These excipients typically comprise a film-forming polymer. Suitable film-forming polymers are preferably water-soluble.

[0059] A particularly preferred film-forming polymer is HPMC having a molecular weight of 10,000 to 150,000, e.g. 603(Shin Etsu).

[0060] The API layering can be performed by any suitable technique. A preferred technique is the Wurster coating technique. In this method, an aqueous liquid containing the API and a film-forming polymer and optionally an anti-adherent agent (e.g., colloidal silicon dioxide or talc) is sprayed onto a coater containing a fluidized bed containing the starting core pellets.

[0061] Seal coating

[0062] In order to avoid any incompatibility between the active ingredient and other components of the core and the coating polymer, the core may be seal-coated. The seal coat is typically water-soluble, in particular based on a water-soluble film-forming polymer.

[0063] The seal coat preferably does not delay or otherwise control the release of the API.

[0064] Preferably, the core optionally provided with a seal coat shows an immediate release profile. In other words, the core optionally comprising a seal coat prior to application of the layered coating releases more than 90% wt of the API after 15 minutes when subjected to a dissolution test in a pH 6.8 buffer using a paddle apparatus at 75 rpm for 45 minutes.

[0065] Water-soluble film-forming polymers that can be used for the seal coat are, for example, HPMC, chitosan or Carbopol.

[0066] Particularly preferred seal coats are based on HPMC with a molecular weight of 10,000 to 150,000, e.g. 603(Shin Etsu).

[0067] Release Control Coating

[0068] The pellets included in the delayed-release formulation according to the present invention comprise a core provided with a layered coating. The layered coating comprises a first layer comprising a first film-forming polymer and a second layer comprising a second film-forming polymer. The first film-forming polymer is a film-forming polymer that provides pH-dependent release at a pH above 7.0. The second film-forming polymer is a film-forming polymer that provides pH-independent release.

[0069] The first film-forming polymer may be a polymer comprising anionic repeating units based on (meth)acrylic acid. For example, it may be a copolymer of methyl acrylate, methyl methacrylate, and methacrylic acid. An example of such a copolymer is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1.

[0070] An example of a molecular weight is 280,000.

[0071] The first film-forming polymer may be applied in the form of an aqueous dispersion.

[0072] Suitable film-forming dispersions are FS30 D (Evonik) is commercially available.

[0073] The second film-forming polymer is insoluble in water or has low water solubility.

[0074] The second film-forming polymer may be polyvinyl acetate, particularly polyvinyl acetate having a molecular weight of 200,000.

[0075] It can be used in the form of a 30% poly(vinyl acetate) dispersion according to the European Pharmacopoeia (Ph. Eur.) or a polyvinyl acetate dispersion according to the United States Pharmacopoeia (USP).

[0076] Suitable compositions can SR30 D (BASF) is commercially available. The dispersion contains approximately 27% polyvinyl acetate, 2.7% povidone, and 0.3% sodium lauryl sulfate.

[0077] The release control achieved depends on the level of coating achieved.

[0078] According to the present invention, the coating level is preferably adjusted based on the surface area of the core (including any optional seal coating).

[0079] Typically, 2-5 mg / cm 2 A pH-dependent coating is applied at a level of 0.5-2.5 mg / cm 2 The pH independent coating is applied at a level of . As used herein, coating level refers to the total amount of solids applied by the coating process. This amount can be determined as coating weight gain.

[0080] In one embodiment, the pellet contained in the formulation according to the present invention comprises, from the inside out, a core, a first layer (which provides pH-dependent release), and a second layer (which provides pH-independent sustained release).

[0081] In this embodiment, the first film-forming polymer is preferably present at 2 to 3 mg / cm 2 The coating level is applied in the range of 0.5 to 2.5 mg / cm2 and the second film-forming polymer is preferably applied at a level of 0.5 to 2.5 mg / cm2. 2 A range of coating levels was applied.

[0082] In another embodiment, the pellet contained in the formulation according to the present invention comprises, from the inside out, a core, a second layer (which provides pH-independent sustained release), and a first layer (which provides pH-dependent release).

[0083] In this embodiment, the first film-forming polymer is preferably present at a concentration of 2 to 5 mg / cm 2 The coating level is applied in the range of 0.5 to 2.5 mg / cm2 and the second film-forming polymer is preferably applied at a level of 0.5 to 2.5 mg / cm2. 2 A range of coating levels was applied.

[0084] Release curve

[0085] The API should not be released significantly during the first 180 minutes until the pH reaches 7.2. Between 180 and 300 minutes, the API should be released slowly but completely.

[0086] The formulation according to the present invention meets at least 3 of the following criteria for API release: no more than 10 wt% released after 120 minutes; no more than 10 wt% released after 180 minutes; 10 to 30 wt% released after 210 minutes; 40 to 60 wt% released after 225 minutes; 60 to 80 wt% released after 240 minutes; more than 80 wt% released after 270 minutes; wherein the release is measured under the following conditions: 0.1 M potassium dihydrogen phosphate (2 hours), followed by a pH 5.5 buffer (1 hour) and a pH 7.2 buffer (2 hours).

[0087] Example

[0088] Examples 1.) and 2.)

[0089] Pellets with an API content of 50% were layered coated using Wurster technology using Pharmacoat 603 as a binder; the first coating was Eudragit FS 30D (coating level 30%) and the second coating was Kollicoat SR 30D (coating level 10% or 20%).

[0090] Examples 3.) and 4.)

[0091] Pellets with an API content of 50% were layered coated using Wurster technology using Pharmacoat 603 as a binder; the first coating was Kollicoat SR 30D (coating level 10%) and the second coating was Eudragit FS 30D (coating level 30% or 50%).

[0092] Examples 5.), 6.), and 7.)

[0093] Pellets with an API content of 50% were layered coated using Wurster technology using Pharmacoat 603 as a binder; a seal coat with Carbopol 974P NF (coating level 5%); a first coat of Eudragit FS 30D (coating level 30%) and a second coat of Kollicoat SR 30D (coating level 10%, 15% or 20%).

[0094] Examples 8.), 9.), and 10.)

[0095] Matrix pellets with an API content of 95% were produced by ProCell technology using Carbopol 974P NF as a binder; the first coating was Eudragit FS 30D (coating level 30%) and the second coating was Kollicoat SR 30D (coating level 10%, 15% or 20%).

[0096] Examples 11.) and 12.)

[0097] Matrix pellets with an API content of 99% were produced by ProCell technology using chitosan as a binder; with a seal coat of Pharmacoat 603 (coating level 20%); a primary coat of Eudragit FS 30D (coating level 30%), and a secondary coat of Kollicoat SR 30D (coating level 15% or 20%).

Claims

1. A delayed-release formulation for delivering an active pharmaceutical ingredient (API) to the colon, comprising: A pellet having a core and a layered coating on said core, The core contains the API, and The layered coating comprises: a first layer comprising a first film-forming polymer, and a second layer comprising a second film-forming polymer, wherein the first film-forming polymer is a film-forming polymer that provides pH-dependent release above pH 7.0, and The second film-forming polymer is a film-forming polymer that provides pH-independent release.

2. The formulation of claim 1, wherein the API is soluble in water such that no more than 10 to 30 parts of water are required per part of API to form a solution, wherein all parts are by weight.

3. The formulation of claim 2, wherein the API is a water-soluble form of metformin.

4. The formulation of claim 2, wherein the API is metformin hydrochloride.

5. A formulation according to any one of claims 1 to 4, at least 90% by weight of the pellets having a core having a size in the range 100-2000 μm as determined by sieve analysis, said core comprising an optional seal coat.

6. The formulation of any one of claims 1 to 5, wherein the core comprises an inert core, and a layer comprising the API on the core.

7. The formulation of any one of claims 1 to 5, wherein the core comprises a matrix pellet.

8. The formulation according to any one of claims 1 to 7, wherein the core comprises at least 50% wt API, preferably at least 70% wt API, more preferably at least 90% wt API, based on the weight of all components of the core.

9. The formulation according to any one of claims 1 to 8, wherein the core including the optional seal coating has a mean eccentricity of 0.45 or less, preferably 0.40 or less, in particular 0.35 or less.

10. The formulation according to any one of claims 1 to 9, wherein the core optionally comprising a seal coat prior to application of the layered coating releases more than 90% wt of the API after 15 minutes when subjected to a dissolution test in a pH 6.8 buffer using a paddle apparatus at 75 rpm for 45 minutes.

11. The formulation of any one of claims 1 to 10, wherein the first film-forming polymer comprises anionic repeating units based on (meth)acrylic acid.

12. The formulation of claim 11, wherein the first film-forming polymer is a copolymer of methyl acrylate, methyl methacrylate, and methacrylic acid.

13. The formulation of claim 12, wherein the first film-forming polymer is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:

1.

14. The formulation of any one of claims 1 to 13, wherein the second film-forming polymer is polyvinyl acetate.

15. The preparation according to any one of claims 1 to 13, wherein the dosage is 2-5 mg / cm 2 A pH-dependent coating is applied at a level of 0.5-2.5 mg / cm 2 A pH independent coating was applied at a level of 100 ng / min.

16. The formulation according to any one of claims 1 to 14, wherein the pellet comprises, from the inside out: The core, the first layer providing pH-dependent release and the second layer providing pH-independent sustained release.

17. The formulation of claim 16, wherein the first film-forming polymer is present at 2 to 3 mg / cm 2 The coating level is applied in the range of 0.5 to 2.5 mg / cm 2 A range of coating levels was applied.

18. The formulation according to any one of claims 1 to 14, wherein the pellet comprises, from the inside out: The core, the second layer providing pH-independent sustained release, and the first layer providing pH-dependent release.

19. The formulation of claim 18, wherein the first film-forming polymer is present at a concentration of 2 to 5 mg / cm 2 The coating level is applied in the range of 0.5 to 2.5 mg / cm 2 A range of coating levels was applied.

20. A formulation according to any one of claims 1 to 19, wherein the formulation meets at least three of the following criteria for API release: no more than 10 wt% released after 120 minutes; no more than 10 wt% released after 180 minutes; 10 to 30 wt% released after 210 minutes; 40 to 60 wt% released after 225 minutes; 60 to 80 wt% released after 240 minutes; more than 80 wt% released after 270 minutes; wherein the release is determined under the following conditions: 0.1 M potassium dihydrogen phosphate (2 hours), followed by pH 5.5 buffer (1 hour) and pH 7.2 buffer (2 hours).

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