Drug-loaded modified-release pellets

Abstract

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 the core, wherein the core comprises 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 a pH-dependent release 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] Pharmaceutical formulations are provided that allow for targeted and modified release of an active ingredient, such as metformin or an acid addition salt of metformin, particularly metformin hydrochloride, from drug-loaded pellets in the colon.

[0002] The pellets are characterized not only by targeted release but also by a high active ingredient content.

[0003] Methods of preparation are also provided. [Background technology]

[0004] Oral administration is the most common form of administration of active pharmaceutical ingredients. Many formulations have been proposed to formulate drugs for oral administration. These formulations have in common that they release the drug in the intestinal tract after ingestion of the formulation.

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

[0006] Targeted drug delivery to the colon is desirable for the local treatment of various colonic pathologies such as ulcerative colitis, Crohn's disease, amebiasis, and colon cancer, but is also desirable for systemic delivery of drugs.

[0007] To reach the colon, a pharmaceutical formulation must pass through the oral cavity, stomach and small intestine before reaching the target site, the colon, which belongs to the large intestine.

[0008] Colon-specific drug delivery systems must be able to protect the drug on its way to the colon. Drug release must not occur in the stomach or small intestine. Once released in the colon, the drug is primarily absorbed through the intestinal mucosa.

[0009] A variety of formulations have been proposed to achieve colonic delivery.

[0010] US Patent No. 5,999,629 describes a formulation for delivery of a drug to the colon, comprising particles having a core and a coating for the core, the core containing the drug and the coating comprising a monolayer of a mixture of a first material susceptible to attack by E. coli and a second material which is a film-forming polymeric material having a pH threshold of about pH 6.5 or higher.

[0011] Patent Document 2 describes a pharmaceutical preparation for the treatment of inflammatory diseases of the large intestine. The preparation is a capsule containing pellets and has multiple coatings: an active substance layer applied directly to the starter pellets; a swelling layer applied directly to the active substance layer; a delay layer applied directly to the swelling layer; and an outermost coating that does not dissolve at pH values ​​< 5.5 but dissolves well at pH values ​​> 6.0 and is applied directly to the delay layer.

[0012] Patent Document 3 describes a formulation for colonic drug delivery, comprising a drug-containing core and a coating for the core. The coating comprises an outer layer and an inner layer. The outer layer comprises a film-forming enteric polymer having a pH threshold of about pH 6 or higher, and the inner layer comprises a film-forming nonionic polymer soluble in intestinal or gastrointestinal fluids and a buffering agent.

[0013] Patent document 4 describes a method for producing a pharmaceutical composition for oral administration and colonic delivery, in particular of mesalazine or 5-aminosalicylic acid, which comprises an active ingredient powder coating technique and the application of a coating containing 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] Patent Document 5 describes a delayed-release formulation comprising a core and a coating for the core. The core contains a drug, and the coating comprises an outer layer comprising a mixture of a first polymeric material susceptible to attack by E. coli and a second polymeric material having a pH threshold of about pH 5 or higher. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] NZ 748404 A [Patent Document 2] U.S. Patent Application Publication No. 2021 / 228487 [Patent Document 3] Canadian Patent Application Publication No. 3122025 [Patent Document 4] Chinese Patent Application Publication No. 112791060 [Patent Document 5] JO 3574 B1 Summary of the Invention [Problem to be solved by the invention]

[0016] Against this background, there is still a need for formulations that allow colonic delivery, especially of water-soluble APIs.For example, there has been recent interest in colonic release of metformin.Metformin is typically used in the form of its hydrochloride, which is highly soluble in water. [Means for solving the problem]

[0017] The present invention provides a delayed release formulation for delivery of an active pharmaceutical ingredient (API) to the colon, which comprises: Pellets having a core and a layered coating on the core Including, The core contains the API, The layered coating is a first layer comprising a first film-forming polymer; and a second layer comprising a second film-forming polymer; Including, the first film-forming polymer is a film-forming polymer that provides a pH-dependent release above pH 7.0; The second film-forming polymer is a film-forming polymer that provides pH-independent release.

[0018] Preferred embodiments of the invention are defined in the dependent claims. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention is based on the discovery that particularly effective control of the release of an active ingredient, such as metformin or an acid addition salt of metformin, particularly metformin hydrochloride, in the colon can be achieved by a pellet formulation, in which release from the pellet is controlled by two different release control mechanisms. According to the present invention, the pellet comprises a layered coating comprising a first layer providing a pH-dependent release and a second layer providing a pH-independent release.

[0020] The first layer that provides pH-dependent release comprises a first film-forming polymer that provides pH-dependent release at a pH above 7.0.

[0021] The second layer comprises a second film-forming polymer that provides pH-independent release.

[0022] The order in which the first and second layers are applied to the core can be selected.

[0023] According to the present invention, release in the colon does not depend only on an increase in pH but is additionally ensured by a retarding polymer.

[0024] Active ingredient Active pharmaceutical ingredients that can be formulated according to the present invention are those for which release in the colon is desired.

[0025] Formulations according to the present invention are particularly suitable for APIs that are soluble in water (10-30 parts water required per part API); freely soluble in water (1-10 parts water required per part API); or very soluble (less than 1 part water required per part API).

[0026] The solubility is measured at a temperature of 37° C. Parts of solvent or solute are parts by weight.

[0027] A particularly interesting API is metformin (1,1-dimethylbiguanide). Metformin can be provided in a water-soluble form. A preferred example is an acid addition salt of metformin, in particular metformin hydrochloride (solubility >300 g / L).

[0028] Pellet Core The core of the pellets contained in the delayed release formulation according to the present invention contains the active pharmaceutical ingredient.

[0029] Typically, at least 90% by weight of the pellets have a core with a size, optionally including a seal coat, in the range of 100 to 2000 μm as determined by sieve analysis, preferably 200 to 1000 μm, more preferably 300 to 700 μm, and especially 315 to 500 μm.

[0030] In a further preferred embodiment of the invention, the core is circular as indicated by a small eccentricity.

[0031] Eccentricity can be measured by optical means, for example, using the Eyecon2® instrument. This instrument is a direct imaging particle size analyzer capable of measuring size and shape information for particles in the 50-5500 μm range. To obtain the image, the particles are illuminated from different angles by red, green, and blue LEDs.

[0032] The resulting images are analyzed by EyePASS software to determine particle size and shape by calculating a best-fit ellipse. Particle size is given as a numerical or volume distribution (e.g., Dn50 or Dv50), and shape is presented as the mean eccentricity.

[0033] 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:

number

[0034] The eccentricity of a circle is zero. The eccentricity of an ellipse, which is not a circle, is greater than 0 and less than 1.

[0035] The smaller the eccentricity, the rounder the pellet.

[0036] In a preferred embodiment of the invention, the core, optionally including a seal coating, has an average eccentricity of 0.45 or less, preferably 0.40 or less, especially 0.35 or less.

[0037] In preferred embodiments of the invention, the core contains a high proportion of API, for example, the core comprises at least 50% by weight of API, preferably at least 70% by weight of API, more preferably at least 90% by weight of API, especially at least 95% by weight of API, based on the weight of all components of the core.

[0038] Matrix pellet as the core The core of the pellets included in the delayed release formulations according to the present invention may be a matrix pellet comprising the API and one or more binders.

[0039] The binder that can be used to prepare the matrix pellets is typically a polymer or polymer composition.

[0040] Suitable polymers include Carbopol 974 PNF (molecular weight >1000 g / mol); chitosan (molecular weight 5000-190000 g / mol) and HPMC (Pharmacoat 603) (molecular weight 10000-150000 g / mol).

[0041] The cores can be prepared by a process using a spouted bed apparatus, as described in German Patent Application Publication No. 10322062. This process involves introducing an aqueous spray solution containing a polymer and an API into the solids stream of the spouted bed apparatus and related equipment. This approach is characterized by the formation of at least one circular solids stream in the axial direction of the reaction space of the spouted bed apparatus. The air intake required to form the solids stream is supplied axially through a gap in the lower region of the reaction space, and fluid is introduced into the solids stream at one or more locations through one or more single- or multi-component nozzles. Thus, flow conditions in the injection zone can be set to allow selective and adjustable introduction of fluid into the solids stream. The resulting final product is characterized by a nearly uniform particle size with equivalent material properties.

[0042] In this way, matrix pellets can be prepared that have a circular shape characterized by low eccentricity and contain only 3-5% by weight of binder.

[0043] Drug layered inactive starter as core The core of the pellets included in the delayed release formulation according to the present invention may be a drug-layered inactive starter, i.e., an active ingredient-free starter pellet with a layer comprising the drug and one or more binders.

[0044] Any pellets suitable for pharmaceutical use that do not contain an API can be used as the inert starter.

[0045] Suitable inactive starters are, for example, glass beads and pellets made of sucrose, mannose or microcrystalline cellulose. Microcrystalline cellulose inactive starters are preferred. Such pellets are commercially available under the name Cellets®.

[0046] The size of the core is not limited. A suitable size is in the range of 10 μm to 2000 μm, for example, 50 μm to 1500 μm, preferably 100 μm to 1000 μm, and the size can be measured by sieve analysis. In particular, pellets from the 500 to 710 μm sieve fraction can be used.

[0047] Inert starter pellets, such as microcrystalline cellulose-based inert starter pellets (Cellets®), are provided with an API-containing coating. To apply the API-containing coating, the API is mixed with one or more excipients. These excipients typically include film-forming polymers. Suitable film-forming polymers are preferably water-soluble.

[0048] A particularly preferred film-forming polymer is HPMC having a molecular weight of 10,000 to 150,000, such as Pharmacoat® 603 (Shin Etsu).

[0049] The API layer formation can be carried out by any suitable technique.A preferred technique is the Wurster coating technique.In this approach, an aqueous liquid containing the API and a film-forming polymer, and optionally an anti-blocking agent such as colloidal silicon dioxide or talc, is sprayed onto the Wurster coating, which comprises a fluidized bed containing starter pellets.

[0050] Seal Coat To avoid incompatibilities between the active ingredient and other ingredients of the core on the one hand and the coating polymer on the other hand, the core can be seal coated, which is typically water-soluble, in particular based on a water-soluble film-forming polymer.

[0051] The seal coat preferably does not retard or otherwise control the release of the API.

[0052] Preferably, the core, optionally with a seal coating, exhibits immediate release properties, in other words, the core, optionally including the seal coat, when subjected to a 45-minute dissolution test in a pH 6.8 buffer solution using a paddle apparatus at 75 rpm, prior to application of the layered coating, releases more than 90% by weight of the API after 15 minutes.

[0053] Water-soluble film-forming polymers that can be used for seal coating are, for example, HPMC, chitosan, or Carbopol.

[0054] A particularly preferred seal coat is based on HPMC having a molecular weight of 10,000 to 150,000, for example Pharmacoat® 603 (Shin Etsu).

[0055] Controlled-Release Coating The pellets contained in the delayed-release formulation according to the present invention comprise a core 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 a pH-dependent release above pH 7.0. The second film-forming polymer is a film-forming polymer that provides a pH-independent release.

[0056] The first film-forming polymer may be a polymer containing 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.

[0057] An example of a molecular weight is 280,000.

[0058] The first film-forming polymer may be applied in the form of an aqueous dispersion.

[0059] A suitable film-forming dispersion is commercially available as Eudragit® FS30D (Evonik).

[0060] The second film-forming polymer is insoluble or has low water solubility.

[0061] The second film-forming polymer may be polyvinyl acetate, particularly polyvinyl acetate having a molecular weight of 200,000.

[0062] It can be used in the form of polyvinyl acetate dispersion 30% Ph.Eur. or polyvinyl acetate dispersion USP.

[0063] A suitable composition is commercially available as Kollicoat® SR30D (BASF). The dispersion contains approximately 27% polyvinyl acetate, 2.7% povidone, and 0.3% sodium lauryl sulfate.

[0064] The controlled release achieved depends on the level of coating achieved.

[0065] In accordance with the present invention, the coating level is preferably adjusted based on the surface area of ​​the core (including any optional seal coating).

[0066] Typically, pH-dependent coatings are 2-5 mg / cm 2 pH-independent coatings are applied at levels of 0.5-2.5 mg / cm 2 As used herein, coating level refers to the total amount of solids applied by the coating process. This amount can be measured as coating weight gain.

[0067] In one embodiment, the pellets included in the formulation according to the invention comprise, from inside to outside, a core, a first layer (which provides a pH-dependent release) and a second layer (which provides a pH-independent sustained release).

[0068] In this embodiment, the first film-forming polymer is preferably 2-3 mg / cm 2 and the second film-forming polymer is preferably applied at a coating level ranging from 0.5 to 2.5 mg / cm 2 It is applied at coating levels ranging from .

[0069] In another embodiment, the pellets included in the formulation according to the present invention comprise, from inside to outside, a core, a second layer (which provides a pH-independent sustained release) and a first layer (which provides a pH-dependent release).

[0070] In this embodiment, the first film-forming polymer is preferably in an amount of 2 to 5 mg / cm 2 and the second film-forming polymer is preferably applied at a coating level ranging from 0.5 to 2.5 mg / cm 2 It is applied at coating levels ranging from .

[0071] Release Profile The API should not be released within the first 180 minutes, respectively, until the pH reaches 7.2. Between 180 and 300 minutes, the API should be released slowly but completely.

[0072] Formulations according to the invention meet at least three of the following criteria for API release: 10% or less by weight release after 120 minutes; 10% or less by weight release after 180 minutes; 10-30% by weight release after 210 minutes; 40-60% by weight release after 225 minutes; 60-80% by weight release after 240 minutes; and >80% by weight after 270 minutes; release is measured under the following conditions: 0.1 M potassium dihydrogen phosphate (2 hours), followed by buffer pH 5.5 (1 hour) and buffer pH 7.2 (2 hours). [Example]

[0073] Examples 1 and 2 Using Pharmacoat 603 as a binder, the pellets were layered using the Wurster technique to an API content of 50%; first coating Eudragit FS 30D (coating level 30%), second coating Kollicoat SR 30D (coating level 10% or 20%).

[0074] Examples 3 and 4 Using Pharmacoat 603 as a binder, the pellets were layered using the Wurster technique to an API content of 50%; first coating Kollicoat SR 30D (coating level 10%), second coating Eudragit FS 30D (coating level 30% or 50%).

[0075] Examples 5, 6 and 7 The pellets were layered using the Wurster technique with Pharmacoat 603 as a binder to an API content of 50%; seal coated with Carbopol 974P NF (5% coating level); first coated with Eudragit FS 30D (30% coating level), and second coated with Kollicoat SR 30D (10%, 15%, or 20% coating level).

[0076] Examples 8, 9 and 10 Matrix pellets were produced by ProCell technology with an API content of 95% using Carbopol 974P NF as a binder; first coating Eudragit FS 30D (coating level 30%), second coating Kollicoat SR 30D (coating levels 10%, 15%, or 20%).

[0077] Examples 11 and 12 Matrix pellets were produced by ProCell technology with an API content of 99% using chitosan as a binder; seal coated with Pharmacoat 603 (coating level 20%); first coated with Eudragit FS 30D (coating level 30%), and second coated with Kollicoat SR 30D (coating level 15% or 20%).

Claims

1. 1. A delayed release formulation for delivery of an active pharmaceutical ingredient (API) to the colon, comprising: Pellets having a core and a layered coating on the core Including, the core includes an API; The layered coating comprises: a first layer comprising a first film-forming polymer; and a second layer comprising a second film-forming polymer; Including, said first film-forming polymer is a film-forming polymer that provides a pH-dependent release above pH 7.0; The second film-forming polymer is a film-forming polymer that provides pH-independent release. A formulation characterized by:

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

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

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

5. 5. A formulation according to any one of claims 1 to 4, characterized in that at least 90% by weight of the pellets have a core with a size, optionally including a seal coat, in the range of 100 to 2000 μm as determined by sieve analysis.

6. The formulation according to any one of claims 1 to 5, characterized in that the core comprises an inert core and an API-containing layer on the core.

7. A formulation according to any one of claims 1 to 5, characterized in that the core comprises matrix pellets.

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

9. Formulation according to any one of claims 1 to 8, characterised in that the core, optionally including a seal coating, has an average eccentricity of less than or equal to 0.45, preferably less than or equal to 0.40, in particular less than or equal to 0.

35.

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

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

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

13. 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. A formulation according to any one of claims 1 to 13, characterized in that the second film-forming polymer is polyvinyl acetate.

15. pH dependent coating is 2-5 mg / cm ２ and pH-independent coatings are applied at levels of 0.5-2.5 mg / cm ２ The formulation according to any one of claims 1 to 13, characterized in that it is applied at a level of

16. 15. The formulation of any one of claims 1 to 14, characterized in that the pellet comprises, from inside to outside, the core, the first layer (providing a pH-dependent release) and the second layer (providing a pH-independent sustained release).

17. The first film-forming polymer is 2 to 3 mg / cm ２ and the second film-forming polymer is applied at a coating level ranging from 0.5 to 2.5 mg / cm ２ 17. The formulation of claim 16, wherein the formulation is applied at a coating level in the range of

18. 15. The formulation of any one of claims 1 to 14, characterized in that the pellet comprises, from inside to outside, the core, the second layer (providing a pH-independent sustained release) and the first layer (providing a pH-dependent release).

19. The first film-forming polymer is 2 to 5 mg / cm ２ and the second film-forming polymer is applied at a coating level ranging from 0.5 to 2.5 mg / cm ２ 19. The formulation of claim 18, wherein the formulation is applied at a coating level in the range of

20. The formulations meet at least three of the following criteria for API release: 10% or less by weight release after 120 minutes; 10% or less by weight release after 180 minutes; 10-30% by weight release after 210 minutes; 40-60% by weight release after 225 minutes; 60-80% by weight release after 240 minutes; and >80% by weight after 270 minutes; release is measured under the following conditions: 0.1 M potassium dihydrogen phosphate (2 hours), followed by buffer pH 5.5 (1 hour) and buffer pH 7.2 (2 hours). The formulation according to any one of claims 1 to 19, characterized in that it satisfies the following:

Images