Budesonide enteric capsule formulation

Abstract

The present invention relates to budesonide encapsulated in enterically coated hydroxypropyl methylcellulose capsules with a specific range of enteric coating.

Description

[0001] P1825PC00

[0002] BUDESONIDE ENTERIC CAPSULE FORMULATION

[0003] BACKGROUND OF THE PRESENT INVENTION

[0004] Budesonide, a synthetic corticosteroid, is designated chemically as 16a, 17a-

[0005] [(lRS)Butylidenebis(oxy)]-l ip, 21-dihydroxypregna-l,4-diene-3, 20-dione:

[0006] It is marketed as TARPEYO® / KINPEYGO® delayed release capsules 4 mg.

[0007] TARPEYO® / KINPEYGO® is the first approved treatment to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression. The product on the market consists of hydroxypropyl methylcellulose capsules coated with methacrylic acid and methacrylate copolymer as delayed, pH-dependent polymer, talc as anticaking agent and dibutyl sebacate as plasticizer; the capsules carry coated, sustained- release pellets consisting of an inert sugar pellets (sucrose and starch) as carrier, a first coating layer made of budesonide, hydroxypropyl methylcellulose and polyethylene glycol, a second coating layer made of citric acid, hydroxypropyl methylcellulose and polyethylene glycol and a third coating layer made of ethyl cellulose, medium chain triglycerides, oleic acid, hydroxypropyl methylcellulose and polyethylene glycol.

[0008] In this formulation, the coating of the capsules provides the delayed release mechanism to the drug product, preventing the fracture and disintegration of the capsules in the stomach, thereby avoiding the release of the pellets - and consequently the drug substance - until they reach the intended site.

[0009] The coating of the capsules is a critical manufacturing step which must lead to a homogenous defect-free layer, without pores, cracks or poorly coated areas, in order to prevent the premature release of the pellets and the drug substance in the stomach. Achieving an optimal enteric coating in capsules is very challenging as it must comply with the enteric release specification (less than 10% drug release at pH 1.0 after one hour).

[0010] WO2009138716 discloses a formulation comprising a sustained release part made of inert pellets coated with three distinctive layers: one layer should carry the drug substance to be delivered (budesonide); one layer comprising alkali-containing ethylcellulose and pore former should provide the sustained release to control the drug-release rate; an intermediate layer located between the two previous layers to prevent degradation reactions of budesonide. The formulation further comprises a delayed release component in the form of a capsule that has been treated so that the sustained release component is predominately released from the capsule in the intestine.

[0011] WO2023139285 discloses the marketed formulation TARPEYO® / KINPEYGO®. This patent application describes a pharmaceutical composition consisting of capsules with a formulation similar to that described in WO2009138716, namely a capsule comprising a sustained-release component with inert pellets coated with three layers and a delayed-release component. However, this formulation differs from that disclosed in WO2009138716. The main difference resides in the layer that provides sustained release. In particular, the sustained-release layer has a different ratio of ethylcellulose to pore former, and the weight gain of this coating layer is increased. The increase in the amount of sustained-release coating has certain disadvantages, such as increased production costs. There is still need of finding an additional oral formulation of budesonide which is bioequivalent to the commercial budesonide tablet TARPEYO® / KINPEYGO®.

[0012] DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0013] The present invention relates to a budesonide delayed release formulation with enteric coated capsules that is bioequivalent to the commercial TARPEYO® / KINPEYGO®.

[0014] A first aspect of the invention relates to a budesonide delayed release capsule formulation comprising: a) A coated sustained release part in the form of coated sugar pellet comprising three coating layers:

[0015] 1. A first layer comprising budesonide, a swelling polymer and a plasticizer;

[0016] 2. A second layer comprising an organic acid, a swelling polymer and a plasticizer; and

[0017] 3. A third layer comprising 55% to 72% ethylcellulose relative to the weight of the third coating layer, medium-chain triglycerides, oleic acid, and from 12% to 22% of a combination of a swelling polymer and a plasticizer relative to the weight of the third coating layer, wherein the weight gain of the third layer is in the range of 2.5% to 5% by weight, relative to the uncoated sugar pellet; b) A delayed release part in the form of an enterically coated hydroxypropyl methylcellulose capsule wherein the enteric coating is present in an amount from 11 to 16 mg of coating per cm2of capsule surface area.

[0018] The formulation of TARPEYO® / KINPEYGO® is characterised by a very specific release profile, which is a combination of a delayed release to prevent the release of the pellets in the stomach and a sustained release that allows the release of the drug from the pellets over a period of time as it passes through the intestine. This specific profile allows main release of the drug in the ileum which is necessary to treat primary immunoglobulin A nephropathy (IgAN).

[0019] The product on the market TARPEYO® / KINPEYGO® is described in WO2023139285. In the formulation disclosed in this patent the amount of the sustained release coating layer was increased and the ratio ethylcellulose to pore former was changed in respect of the formulation disclosed in WO2009138716 to reach the desired bioavailability.

[0020] However, the addition of a large amount of sustained release coating layer is disadvantageous because it may increase the chance of degradation reactions with the drug substance, which may lead to generation of undesirable impurities. To prevent the degradation, the amount of intermediate protective coating has to also be increased. That results in the increase of the cost of the drug product due to the higher amount of excipients needed and the longer manufacturing process time. Longer coating time also may increase the chance of degradation reaction as the pellets will be under high temperature / humidity for longer period.

[0021] The inventors have surprisingly found that the appropriate drug release profile can be achieved by applying a specific amount of the enteric coating in the delay release capsules while maintaining a low amount of sustained release coating layer in the pellets.

[0022] This solution has the advantage that the intake of excipients by the patients, such as ethylcellulose, oleic acid, medium chain triglycerides, hydroxypropyl methylcellulose, polyethylene glycol, is lower, thereby the safety profile of the drug product is improved. Moreover, lowering the amount of sustained release layer reduces the cost of the formulation as well as the cost of manufacturing as the time required for the coating step is reduced. Furthermore, the stability of the drug product is not compromised as the drug product is under high temperature / humidity for shorter coating process time. Additionally, the residues from this coating (e.g.: ammonium hydroxide if Surelease® is used) are proportionally reduced, so the chance of chemical interaction with the drug substance is also minimized and the stability of the drug product is improved.

[0023] By the term “sustained release” is meant that the drug is released in the body slowly over an extended period of time.

[0024] By the term “delayed release” is meant that the release of the drug is delayed until it passes through the stomach into the small intestine.

[0025] In the present invention, the sustained release part of the capsule formulation comprises a sugar pellet coated with three layers; a first layer of coating with budesonide, a swelling polymer and a plasticizer, a second layer of coating comprising an organic acid, a swelling polymer and a plasticizer, and a third layer comprising ethylcellulose, medium chain triglycerides, oleic acid, a swelling polymer and a plasticizer.

[0026] Sugar pellets predominantly comprise sucrose with smaller amounts of other materials added, such as starch and are commercially available.

[0027] Swelling polymers are polymers that absorb water and increase their volume. Examples of swelling polymers to be used in the above embodiments are hydroxypropyl methylcellulose, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose (CMC), polyethylene oxide, xanthan gum and sodium alginate. A preferred swelling polymer is hydroxypropyl methylcellulose.

[0028] Plasticizers are components that increase the flexibility and plasticity of the coating film by promoting the pliability of the polymer. Examples of plasticizers are polyethylene glycol, triacetin, triethyl citrate, tributyl citrate, and dibutyl sebacate. A preferred plasticizer to be used in the above embodiments is polyethylene glycol. Commercially available coatings comprising a plasticizer and a swelling polymer, for instance Opadry 03B 190009 Clear®, can be used in the formulation according to the present invention.

[0029] Examples of organic acids suitable to be used in the above embodiments are citric acid, glutamic acid, lactic acid, tartaric acid, fumaric acid and malic acid. A preferred acid is citric acid.

[0030] The third layer of coating is the one that determines the sustained release rate. In order to reach a correct delivery in the ileum, a balance between the ethylcellulose component and the combination of plasticizer / swelling polymer components should be reached. Ethylcellulose material is insoluble in water and will start the release of budesonide by diffusion, the plasticizer and swelling polymer will form pores through which the budesonide API will be released.

[0031] The combination of plasticizer and swelling polymer is used in the third layer preferably in a range from 12% to 22%, more preferably from 15% to 20%, relative to the total weight of the third coating layer.

[0032] The ethylcellulose to be used in the above embodiments preferably originates from an alkaline ethyl cellulose aqueous dispersion material which is a derivative ethylcellulose composition comprising a basic component. The preferred alkaline ethylcellulose aqueous dispersion is Surelease®, which comprises ethylcellulose, ammonium hydroxide, medium chain triglycerides and oleic acid.

[0033] The ethylcellulose is preferably used in an amount from 55% to 72%, more preferably from 60% to 68% relative to the weight of the third coating layer.

[0034] As used herein, the term “weight gain” of a coating layer refers to the increase in weight of the sugar pellets resulting from the application of that coating layer, expressed as a percentage relative to the weight of the uncoated sugar pellets. In particular, the weight gain of the third coating layer corresponds to the mass of the sustained-release coating applied to the pellets, relative to the initial weight of the uncoated sugar pellets. This weight gain defines the thickness of the sustained-release layer and contributes to the sustained release characteristics of the formulation. The weight gain of the third coating layer is in the range of 2.5% to 5%, preferably 3% to 4.5% by weight, relative to the uncoated sugar pellets;

[0035] The sustained release part of the capsule of the invention is manufactured by methods known by the skilled person, such as film-coating by bottom spray (e.g.: Wurster setting) using fluid bed technology.

[0036] In one embodiment the budesonide delayed release capsule formulation according to the invention comprises: a) A coated sustained release part in the form of coated sugar pellet comprising three coating layers:

[0037] 1. A first layer comprising budesonide, hydroxypropyl methylcellulose and polyethylene glycol;

[0038] 2. A second layer comprising an organic acid, hydroxypropyl methylcellulose and polyethylene glycol;

[0039] 3. A third layer comprising 55% to 72% ethylcellulose relative to the weight of the third coating layer, medium-chain triglycerides, oleic acid, and from 12% to 22% of a combination of hydroxypropyl methylcellulose and polyethylene glycol relative to the weight of the third coating layer, wherein the weight gain of the third layer is in the range of 2.5% to 5% by weight, relative to the uncoated sugar pellet; and b) A delayed release part in the form of an enterically coated hydroxypropyl methylcellulose capsule wherein the enteric coating is present in an amount from 11 to 16 mg of coating per cm2of capsule surface area.

[0040] Further, the capsule formulation of the present invention may comprise other pharmaceutically acceptable excipients, chosen from, for example, diluents, binders or disintegrants.

[0041] In a preferred embodiment, the sustained release part of the capsule of the present invention is prepared by dissolving hydroxypropyl methylcellulose / polyethylene glycol in an aqueous solvent, preferably purified water. Budesonide is then added to this solution, and the resulting suspension is spray dried onto sugar pellets in a fluid bed. The pellets coated with the first layer are subsequently coated in a fluid bed with a solution comprising an organic acid, preferably citric acid, and hydroxypropyl methylcellulose / polyethylene glycol, thereby resulting in pellets with two coating layers.

[0042] The pellets coated with two layers are then coated in a fluid bed with an alkaline ethylcellulose aqueous dispersion, preferably Surelease®, together with a hydroxypropyl methylcellulose / polyethylene glycol solution, thereby resulting in sugar pellets having three coating layers.

[0043] The sustained release part manufactured according to the above described methods is encapsulated in hydroxypropyl methylcellulose capsules. The filled capsules are banded with an aqueous solution, for example gelatin, in order to remove the uneven surface formed at the between the capsule body and the cap. The banded capsules are then transferred to a perforated pan coater, where the capsules may be pre-coated.

[0044] For the precoating, a combination of plasticizer and a polymer may be used. A preferred pre-coating is an aqueous solution of hydroxypropyl methylcellulose and propylene glycol. The pre-coating is applied to improve the adhesion of the subsequent enteric coating to the capsule and to prevent chipping and cracking of the enteric coating due to external mechanical forces. The capsules are then coated with an enteric coating.

[0045] Examples of enteric coatings are azopolymers, disulphide polymers, cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate tetrahydrophthalate, polyvinyl acetate phthalate, hydroxyethyl ethyl cellulose phthalate, methacrylic acid copolymers, methacrylic acid-acrylic acid copolymers, styrol maleic acid copolymers, hydroxypropyl methylcellulose phthalate.

[0046] Preferred enteric coatings are the combination of methacrylic acid and acrylic acid copolymers, more preferably methacrylic acid-methyl methacrylate copolymers. The combination of methacrylic acid and methyl methacrylate are preferably in a range of molar ratios from 1 : 1 to 1:2.

[0047] Examples of suitable enteric coating include the commercially available Eudragit L- 100® and Eudragit S-100®.

[0048] In a preferred embodiment a combination of methacrylic acid:methyl methacrylate copolymer 1 : 1 (marketed as Eudragit L-100®) and methacrylic acid:methyl methacrylate copolymer 1 : 2 (marketed as Eudragit S-100®) is used.

[0049] In a more preferred embodiment the weight ratio of methacrylic acid:methylmethacrylate copolymer 1 : 1 (marketed as Eudragit L-100®) and methacrylic acid:methyl methacrylate copolymer 1 : 2 (marketed as Eudragit S-100®) is 3: 1

[0050] The skilled person will understand that the enteric coating may further comprise other commonly used materials, such as talc (as plasticiser), dibutyl sebacate (as plasticiser), and a blend of hydroxypropyl methylcellulose (HMPC) and polyethylene glycol (PEG) as a subcoating agent.

[0051] The enteric coating may be applied as a suspension or solution. For instance the capsules of the present invention could be coated with a suspension of methacrylic acid: methyl methacrylate copolymer 1 : 1 (marketed as Eudragit L-100®) and / or methacrylic acid:methyl methacrylate copolymer 1 : 2 (marketed as Eudragit S-100®), talc and dibutyl sebacate.

[0052] In order to get a suspension the methacrylic acid:methyl methacrylate copolymer 1 : 1 and the methacrylic acid:methyl methacrylate copolymer 1 : 2 are dissolved in a solution of organic solvent / water. Preferred organic solvents are alcohols more preferably is isopropanol.

[0053] Preferred ratios of alcohol / water to be used are 70 / 30 to 99 / 1 w / w. Once the two enteric polymers are dissolved, the talc and the dibutyl sebacate are added to the solution until homogenization. The suspension is then applied to the capsule.

[0054] In order to be bioequivalent to the marketed formulation the capsules should have an enteric coating in an amount of 1 Img to 16 mg of coating per cm2of capsule surface area , preferably from 11,5 mg to 14 mg of coating per cm2. This may correspond, for example, to 46 mg to 5 3mg of enteric coating applied to a size 1 capsule.

[0055] The present invention is illustrated by the following Examples.

[0056] Example 1: Preparation coated pellets

[0057] 99.99 grams of Opadry® clear is weighted and added into 1,157 mL of purified water until complete dissolution (1).

[0058] 28.63 grams of budesonide are weighted and added to the previous Opadry® solution (1) under stirring until its complete dispersion, obtaining a homogenous suspension (2).

[0059] 1729 grams of sugar pellets are weighted and placed inside the fluid bed with Wurster settings. The sugar pellets are initially heated up to 45-50°C; then, the suspension (2) is pumped and sprayed into the fluid bed, coating the surface of the sugar pellets. Once the complete suspension (2) is sprayed, a drying step is performed. At the end of this manufacturing step, coated pellets (3) are obtained. 49.86 grams of Opadry® clear is weighted and added into 466 grams of water under stirring until complete dissolution, obtaining a homogenous solution (4). 2.1 grams of anhydrous citric acid are weighted and added to the previous Opadry® solution (4) until its complete dissolution obtaining a homogenous solution (5).

[0060] The previous coated pellets (3) are heated up to 45-50°C; then, the solution (5) is pumped and sprayed into the fluid bed, coating the surface of the coated pellets. Once the complete solution (5) is sprayed, a drying step is performed. At the end of this manufacturing step, coated pellets (6) with two coating layers are obtained.

[0061] 11.14 grams of Opadry® clear is weighted and added into 334 grams of purified water under stirring until complete dissolution, obtaining a homogenous solution (7). 222.8 grams of Surelease® dispersion are weighted and added to the previous Opadry® solution (7)ctill obtaining a homogenous dispersion (8).

[0062] The previous coated pellets (6) are heated up to 45-50°C; then, the dispersion (8) is pumped and sprayed into the fluid bed, coating the surface of the coated pellets. Once the complete dispersion (8) is sprayed, a drying step is performed. Then, a curing step is performed, keeping the coated pellets at a constant temperature of 50°C during 30 minutes At the end of this manufacturing step, coated pellets (9) with three coating layers are obtained.

[0063] 282 mg of the resulting coated pellets (9) are then encapsulated inside hydroxypropyl methylcellulose capsules, leading to the filled capsules (10).

[0064] 600 grams of previous filled capsules were banded , an excess of gelatine solution was prepared by weighing 45 grams of gelatine, which were dissolved in 255 grams of purified water and heated up to 50°C. The heated solution was stirred until complete dissolution of the gelatine and then the resulting solution was applied to the capsule cap-body junction forming a homogenous band around, obtaining the banded capsules (11).

[0065] An excess of enteric coating was prepared. Firstly, 2,007 grams of 2-isopropanol and 69 grams of water were weighed and mixed resulting in a homogenous mixture (12). 120 grams of Eudragit L100 and 40 grams of Eudragit S100 were weighted and added to the solvent mixture (12) previously prepared. The solution was stirred to obtain a homogenous solution (13). 32 grams of dibutyl sebacate and 40 grams of talc were weighed and added to the previous solution (13), resulting in a suspension (14). The previous suspension (14) was homogenized (15).

[0066] 916 grams of the banded capsules (11) were then loaded into a 15” diameter drum of the perforated pan coater and heated up to 35°C. The obtained suspension (15) was then sprayed on the banded capsules until achieving the target capsule weight. The previous suspension (14) was then sprayed on the surface of the capsules (10) until the capsules achieved an increase of weight of about 57.3 mg per capsule, resulting in the final coated capsules.

[0067] Table 1. Composition of formulation of example 1 * percentage upon the total filled capsule weight (358 mg).

[0068] According to WO2023139285, the sustained release third coating layer consists of a pharmaceutically-acceptable polymeric blend comprising a water-insoluble polymer and a pore-forming polymer, wherein the water-insoluble polymer is in an amount from about 47 wt.% to about 56 wt.% of the total sustained release coating and the pore-forming polymer is present in an amount of from about 32 wt.% to about 22 wt.% of the total sustained release coating. Additionally, this application discloses that this third layer is present in an amount of from about 5% wt.% to about 18 wt.% of the total coated core weight.

[0069] In example 1 of this application the third coating layer of the sustained release part contains ethylcellulose in an amount of about 63% wt.% of the weight of the third layer and hydroxypropyl methylcellulose / poly ethylene glycol in an amount of about 17 wt.% of the sustained release pharmaceutically-acceptable of the weight of the third layer. The decrease of the amount of the hydroxypropyl methylcellulose in the third layer of coating leads to further release control with lower amount of the aforementioned blend in the core, shortening the coating step during the manufacturing process. In fact the amount of coating in the third layer of the sustained release part of the formulation was decreased to 3.4 wt.% of the total coated core weight, below the amount needed according to WO2023139285.

[0070] The pharmacokinetics and bioavailability of formulation 1 were tested in a pilot study with healthy volunteers and compared to the reference product Kinpeygo® modified-release hard capsules. The results showed similar pharmacokinetics results under fasting conditions as shown in the table below: It was concluded that the new formulation of example 1 is able to provide similar release profile to the marketed formulation with an improved formulation.

Claims

CLAIMS1. A budesonide delayed release capsule formulation comprising: a) A coated sustained release part in the form of coated sugar pellets comprising three coating layers:

1. A first layer comprising budesonide, a swelling polymer and a plasticizer;2. A second layer comprising an organic acid, a swelling polymer and a plasticizer; and3. A third layer comprising 55% to 72% ethylcellulose relative to the weight of the third coating layer, medium-chain triglycerides, oleic acid, and 12% to 22% of a combination of a swelling polymer and a plasticizer relative to the weight of the third coating layer, wherein the weight gain of the third layer is in the range of 2.5% to 5% by weight, relative to the uncoated sugar pellets; and b) A delayed release part in the form of an enterically coated hydroxypropyl methylcellulose capsule, wherein the enteric coating is present in an amount from 11 to 16 mg of coating per cm2of capsule surface area.

2. A budesonide delayed release capsule formulation according to claim 1, wherein the swelling polymer is hydroxypropyl methylcellulose.

3. A budesonide delayed release capsule formulation according to claim 1 or 2, wherein the plasticizer is polyethylene glycol.

4. A budesonide delayed release capsule formulation according to claim 1 to 3, wherein the enteric coating comprises methacrylic acid- methyl methacrylate copolymer.

5. A budesonide delayed release capsule formulation according to claim 4, wherein the enteric coating comprises a combination of methacrylic acid:methyl methacrylate copolymer 1 :1 and methacrylic acid:methyl methacrylate copolymer 1:2.

6. A budesonide delayed release capsule formulation according to claims 4 and 5, wherein the enteric coating comprises a combination of methacrylic acid:methyl methacrylate copolymer 1 : 1 and methacrylic acid:methyl methacrylate copolymer 1 :2, talc and dibutyl sebacate.

7. A budesonide delayed release capsule formulation according to any one of claims 1 to 6 wherein the organic acid is citric acid.

8. A process for making the delayed release capsule according to claim 1 which comprises: a. Coating sugar pellets with a first layer by spraying a suspension of budesonide, a swelling polymer and a plasticizer; b. Coating the pellets obtained in step (a) with a second layer by spraying a solution comprising an organic acid, a swelling polymer and a plasticizer; c. Coating the pellets obtained in step (b) with a third layer by spraying an alkaline ethylcellulose aqueous dispersion, comprising 55% to 72% ethyl cellulose relative to the weight of the third coating layer, medium chain triglycerides, oleic acid, and ammonia; and 12% to 22% of a combination of a swelling polymer and a plasticizer relative to the weight of the third coating layer, wherein the third coating layer is applied in an amount providing a weight gain of 2.5% to 5% by weight relative to the uncoated sugar pellets; and d. Drying the coated pellets;e. The resulting pellets are then encapsulated in enterically coated hydroxypropyl methylcellulose capsules wherein the enteric coating is in a range from 1 Img to 16 mg coating per cm2of capsule surface.

9. The process according to claim 8 wherein the swelling polymer is hydroxypropyl methylcellulose.

10. The process according to claims 8 or 9, wherein the plasticizer is polyethylene glycol.

11. The process according to claims 8 to 10, wherein the enteric coating comprises a combination of methacrylic acid:methyl methacrylate copolymer 1 : 1 and methacrylic acid:methyl methacrylate copolymer 1 : 2..

12. The process according to claim 11, wherein the weight ratio of methacrylic acid-methyl methacrylate copolymer 1 : 1 (marketed as Eudragit L-100®) and methacrylic acid- methyl methacrylate copolymerl : 2 (marketed as Eudragit S-100®) is 3: 1.

13. The process according to claim 8 to 12, wherein the enteric coating comprises a combination of methacrylic acid:methyl methacrylate copolymer 1 : 1 and methacrylic acid:methyl methacrylate copolymer 1 :2, talc, dibutyl sebacate.

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