WO2020060426A1

WO2020060426A1 - An oral preparation containing sodium butyrate

Info

Publication number: WO2020060426A1
Application number: PCT/PL2019/000079
Authority: WO
Inventors: Agnieszka GAWROŃSKA; Krzysztof Gawroński; Mateusz GAWROŃSKA; Andrzej SIJKA
Original assignee: Nerr Pharma Społka Z Ograniczoną Odpowiedzialnością
Priority date: 2018-09-18
Filing date: 2019-09-13
Publication date: 2020-03-26
Also published as: PL237391B1; PL427115A1

Abstract

An oral preparation in the form of a tablet comprising sodium butyrate consists of i) core composed of: sodium butyrate in an amount of 55-75% by weight, high-viscosity hydroxypropylmethylcellulose in an amount of 15-30% by weight, magnesium stearate in an amount of 0.5-4% by weight, colloidal silica in an amount of 0.1-1% by weight, inorganic calcium salts in an amount of 10-30% by weight; ii) optionally, an inner retarding coating in an amount of 3-10% by weight relative to the core weight, consisting of hydroxypropylmethylcellulose or ethylcellulose and hydroxypropylmethylcellulose in an amount of 60-90% by weight, a plasticizer in an amount of 8-20% by weight, and an anti-caking agent in an amount of 20-45% by weight; iii) enteric coating in an amount of 3-10% by weight relative to the weight of the core made of poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 in an amount of 65-90% by weight, plasticizer in an amount of 1-8% by weight, and an anti-caking agent in an amount of 5-35% by weight, and optionally an emulsifier when using glycerol monostearate. The oral preparation in the form of a capsule comprising sodium butyrate consists of i) granulate composed of: sodium butyrate in an amount of 55-80% by weight, high-viscosity hydroxypropylmethylcellulose in an amount of 15-40% by weight, magnesium stearate in an amount of 0.5-4% by weight, colloidal silica in an amount of 0.1-1% by weight, optionally inorganic calcium salts in an amount of 10-30% by weight; ii) hard capsule, coated with the coating in an amount of 3-10% by weight relative to the weight of the granulate, made of poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 in an amount of 65-90% by weight, plasticizer in an amount 1-8% by weight, anti-caking agent in an amount of 5-35% by weight, and optionally an emulsifier, iii) optionally, an inner retarding coating on the capsule under the enteric coating, in an amount of 3-10% by weight relative to the weight of the granulate, consisting of hydroxypropylmethylcellulose or ethylcellulose and hydroxypropylmethylcellulose in an amount of 60-90% by weight, plasticizer in an amount of 8-20%, and an anti-caking agent in an amount of 20-45% by weight.

Description

An oral preparation containing sodium butyrate

The present invention relates to an oral preparation comprising sodium butyrate in the form of a tablet, and an oral preparation comprising sodium butyrate in the form of a capsule, intended for use as a medicinal product or a food supplement or food for special medical purpose.

Butyric acid is a component of a normal diet, as it is a part of many natural fats. Fats are digested in the small intestine and virtually 100% of them is absorbed there. Butyric acid, as a component of the normal human diet, is therefore completely absorbed in the small intestine. Studies suggest that butyric acid is virtually absent in the final section of the small intestine. The butyric acid which is a component of a normal diet, like any fatty acid, is consumed as energy material by the body's tissues.

The concentration of butyric acid increases in the large intestine, where it is formed as a result of bacterial fermentation of fiber. Butyric acid is the main nutrient for colonocytes - large intestine epithelial cells. At the same time, butyric acid helps maintain normal large intestine flora.

Butyric acid is used to treat large intestine diseases in humans:

a. Functional disorders - including irritable bowel syndrome

b. Non-specific inflammation of the large intestine - including ulcerative colitis and Crohn's disease

c. As an adjuvant for patients after radiotherapy for colon cancer.

The administration of butyric acid preparations shall fulfill several conditions:

a. The appropriate dose of the preparation shall be provided (the concentration of butyric acid in the human large intestine under physiological conditions is about 1 to 10 mmol/kg)

b. Butyric acid should be delivered to the large intestine. The active substance shall be released from the preparation in the large intestine.

i. The release of the active substance in the small intestine results in the absorption of the entire released substance into the bloodstream, and the reduction or the absence of the active substance reaching the large intestine. ii. Administration of butyric acid to the small intestine has a negligible therapeutic significance (even in cases where the disease is located in the small intestine) due to the butyric acid content in most fats.

c. The butyric acid delivered to the large intestine shall be released from the preparation over long time due to the long passage time through the large intestine (physiologically, this time is from 6 to 24 hours)

Available forms of butyric acid administration:

a. Butyric acid is most often administered in the form of sodium butyrate (sometimes in the literature there are studies with calcium butyrate or with tributyrin - a butyric acid glycerol ester)

b. Retention enemas with sodium butyrate. Enemas ensure delivery of the active substance to the large intestine. With this form of administration, however, the substance reaches only the beginning of the descending colon at maximum - i.e. just over lower one third of the large intestine. The cecum, the ascending colon and the transverse colon are not affected by the active substance. Moreover, the use of enemas is cumbersome for patients, especially with longer-lasting therapy.

c. Oral forms:

i. Gelatin capsules containing 150 mg of sodium butyrate in a triglyceride matrix (some capsules have an enteric coating of sodium alginate). The active substance from this form of preparation is released under the influence of lipases contained in the pancreatic juice. Lipases digest the triglyceride matrix, which releases the active ingredient into the lumen of the small intestine. The release of the active substance into the small intestine, with butyric acid being known to become completely absorbed into the bloodstream from it, is a disadvantage and limitation of this preparation form. In this case, it is difficult to determine what part of the active substance has been released in the small intestine and what part of it reaches the large intestine. It should also be noted that if the active substance reaches the large intestine in the unreleased form, i.e. in the triglyceride matrix, the chances of its release are small due to the negligible amount of lipases in the large intestine. A 150 mg sodium butyrate dose is quite low, this results in the need to administer the product at least twice a day. At the same time, it is known that when dosing more than once a day, especially for long-lasting therapy (use of butyric acid preparations should last at least about 3 months), patients leave some doses, which significantly affects the effectiveness of the therapy. It should be concluded that the action and effectiveness of this form of preparation will not be appropriate due to:

1. Release and absorption of the active substance in the small intestine

2. Impossible or difficult to determine amount of active substance that enters the large intestine for a particular patient

3. Limited or no possibility of the active substance release in the large intestine

4. A low dose of the preparation resulting in the need to take the product at least twice a day.

ii. Modified-release enteric-coated tablets containing 200 mg butyrate sodium. The active substance in this form of the preparation is released in the small intestine. The enteric coating used is made of shellac. Shellac is used to protect the active substance from gastric juice and to deliver the active substance to the small intestine. Shellac is insoluble in an acidic environment, whereas in an environment of pH about 5.5-6.5, it becomes absorbent, swells and becomes permeable to the active substance. Some studies, however, indicate that shellac coatings release the active substance at pH 1.2 already. Shellac coatings are also unstable with active substances with alkaline properties. In such cases, it is necessary to use an intermediate coating that insulates the active substance from the shellac. Sodium butyrate is a substance with alkaline properties, therefore it is necessary to use a subcoating. According to the producer of the preparation, the active substance starts releasing in the small intestine and is released for about 6 hours. As is known, butyric acid is perfectly absorbed from the small intestine into the bloodstream. Therefore, it is not possible to determine what part of the active substance will reach the large intestine and be released there. Dose 200 mg of sodium butyrate is a relatively low dose, which results in a necessity to administer the preparation at least twice a day. At the same time, it is known that when dosing more than once a day, especially for long-lasting therapy (use of butyric acid preparations should last at least about 3 months), patients leave some doses, which significantly affects the effectiveness of the therapy. Sodium butyrate is a very fine and fluffy substance, it is very difficult to tablet. This entails the need to use a large amount of excipients that increase the weight and dimensions of the tablet. Large tablets are difficult to swallow, especially for children and the elderly. The weight of the tablet containing 200 mg sodium butyrate is over 1 120 mg.

It should be concluded that the action and effectiveness of this form of preparation will not be appropriate due to:

1. Release and absorption of the active substance in the small intestine

2. The amount of active substance reaching the large intestine is impossible to determine.

3. A low dose of the preparation results in the need to take the product at least twice a day

iii. ln the subject literature, there is also a product described containing 1000 mg of sodium butyrate in an enteric-coated tablet with shellac-based coating. The described product releases the active substance with a delay of 3-hour order compared to the product without shellac coating. According to the study authors, delaying release by about 3 hours should ensure that the active substance reaches the large intestine. However, the study did not measure changes in the concentration of butyric acid in the large intestine, but only changes in the concentration of C13 carbon in exhaled air (sodium butyrate was labeled with C13 carbon). This study did not demonstrate unambiguously that the test preparation ensures active substance delivery to the large intestine. In addition, it should be remembered that the passage time through the small intestine can reach up to 5 hours, which with a release delay of 3 hours results in a much smaller amount of active substance that has a chance to reach the large intestine. The described preparation releases the active substance in a short time, which also does not ensure the butyric acid action along the entire length of the large intestine. In addition, it should be mentioned that shellac coatings are also unstable with active substances with alkaline properties. In such cases it is necessary to use an intermediate coating that insulates the active substance from the shellac coating. Sodium butyrate is a substance with alkaline properties, therefore it is necessary to use a subcoating. Although the preparation contained 1000 mg of sodium butyrate, the total weight of the tablet was approximately 1400 mg. Such large tablet sizes may pose a serious difficulty in swallowing, especially for children and the elderly.

1. A shell made of shellac, which does not guarantee reaching the active substance into the large intestine, but only a release delay of 3 hours, may result in the release and absorption of the active substance in the small intestine.

3. Short time of active substance release, which does not ensure the action of butyric acid along the entire length of the large intestine.

According to review of sodium butyrate preparations known from the literature and market, and their efficiency, it appears that with regard to the butyrate supplied to the distal digestive tract, only in some cases a profile is achieved allowing providing at least 50% of the initial sodium butyrate dose to the large intestine. In case of tests on the artificial intestinal model, it was only possible to obtain such action for the product Debutir, in which the vehicle is a complex lipid-polysaccharide structure.

Thus, it is necessary to develop a form of sodium butyrate administration that would meet the following assumptions:

a. The product should contain at least 500 mg of sodium butyrate;

b. The tablet core weight should not exceed 180% by weight of the active

substance;

c. The release time for 80% of the active substance should be longer than 6

hours;

d. The product should ensure the delivery of the active substance to the large intestine;

e. The product should not release the active substance at pH lower than 7.0; f. The raw materials used for the formulation should give the possibility to

register the product as both a medicinal product and a foodstuff (food supplement or food for special medical purpose).

Hydroxypropylmethylcellulose (HPMC), which is a retarding substance that forms the so-called hydrogels, is used in tablets as a standard. The HPMC content in the tablet core should be from 10% by weight to 30% by weight of the core. Sodium butyrate and HPMC are dusty substances. Their mixture containing from 55 to 75% sodium butyrate is very difficult to tablet using commonly used tableting equipment. Standard binders such as microcrystalline cellulose, lactose, polyvinylpyrrolidone or a combination of silicon dioxide and microcrystalline cellulose do not permit producing tablets with the appropriate active substance content, release time over 6 hours, weight not greater than 180% by weight of the active substance, and adequate hardness and resistance to abrasion.

Choosing the right coating is another problem. Sodium butyrate is a substance with relatively strong alkaline properties, because it is a salt of weak butyric acid and strong sodium hydroxide. When using enteric coatings based on shellac or sodium alginate, available literature data indicate that it is necessary to use an intermediate coating that insulates the alkaline core of the tablet from the enteric coating.

The most important aspect for formulations with a sodium butyrate content higher than 500 mg per tablet and the need to significantly reduce excipients, is to achieve the effect of sustained release of the active substance of more than 6 hours.

The subject of the invention is a preparation that allows to solve all the foregoing problems.

The oral preparation in the form of a tablet comprising sodium butyrate according to the invention consists of:

i) core composed of: sodium butyrate in an amount of 55-75% by weight, high- viscosity hydroxypropylmethylcellulose in an amount of 15-30% by weight, magnesium stearate in an amount of 0.5-4% by weight, colloidal silica in an amount of 0.1-1 % by weight, inorganic calcium salts in an amount of 10-30% by weight, preferably calcium phosphate or sulphate;

ii) optionally an inner retarding coating in an amount of 3-10% by weight based on the core weight, consisting of hydroxypropylmethylcellulose or ethylcellulose and hydroxypropylmethylcellulose in an amount of 60-90% by weight, plasticizer in an amount of 8-20% by weight, preferably polyethylene glycol, most preferably polyethylene glycol 400 or triethyl citrate and anti-caking agent in an amount of 20-45% by weight, preferably talc;

iii) enteric coating in an amount of 3-10% by weight relative to the weight of the core made of poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 in an amount of 65-90% by weight, plasticizer in an amount of 1-8% by weight, preferably triethyl citrate, and an anti-caking agent in an amount of 5-35% by weight, preferably talc or glycerol monostearate, and an emulsifier when using glycerol monostearate, preferably a mixture of sorbitan and oleic acid polyoxyethylene derivatives.

The oral preparation in the form of a capsule containing sodium butyrate according to the invention consists of:

i) granules composed of: sodium butyrate in an amount of 55-80% by weight, high- viscosity hydroxypropylmethylcellulose in an amount of 15-40% by weight, magnesium stearate in an amount of 0.5-4% by weight, colloidal silica in an amount of 0.1-1 % by weight, optionally inorganic calcium salts in an amount of 1- 30% by weight, preferably calcium phosphate or sulphate;

ii) a hard, preferably cellulose or gelatin capsule, coated with an enteric coating in an amount of 3-10% by weight relative to the weight of the granules, made of poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 in an amount of 65-90% by weight, plasticizer in an amount of 1-8% be weight, preferably triethyl citrate and anti-caking agent in an amount of 5-35% by weight, preferably talc or glycerol monostearate and emulsifier in the case of using glycerol monostearate, preferably a mixture of sorbitan and oleic acid polyoxyethylene derivatives;

iii) optionally, an inner retarding coating on the capsule under the enteric coating, in an amount of 3-10% by weight relative to the weight of the granulate, consisting of hydroxypropylmethylcellulose or ethylcellulose and hydroxypropylmethylcellulose in an amount of 60-90% by weight, plasticizer in an amount of 8-20% by weight, preferably polyethylene glycol, most preferably polyethylene glycol 400 or triethyl citrate, and an anti-caking agent in an amount of 20-45% by weight, preferably talc.

The obtained test results have been described in detail and discussed in the examples.

Examples

1) Abbreviations in the coating formulations

Carrageenan is a type of polysaccharides extracted from red seaweed that contains numerous sulphate groups in its structure

Alginate Sodium alginate

Shellac Shellac

GMS Glyceryl monostearate

Polysorbate 80 Polysorbate 80 - a mixture of sorbitan and oleic acid

polyoxyethylene derivatives

TEC Triethyl citrate

Water Water

VivaPharm E5 Hydroxypropylmethylcellulose

Acrylic polymer poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) :3:1

AQUACOAT Aqueous dispersion containing ethylcellulose

2) Abbreviations in formulations for tablet cores or granulate for capsules:

Butyrate Sodium butyrate

Methocel Premium CR Hydroxymethylpropyl cellulose with high viscosity

Lactose Supertab Spray-dried lactose SuperTab 11 SD

Magnesium stearate Magnesium stearate

Colloidal silica Silicon dioxide - Aerosil 200

Calcium phosphate Dicalcium phosphate

Calcium sulphate Calcium sulphate

Methocel Premium DC Hydroxymethylpropyl cellulose with high viscosity

Metolose 90SH 100000SR High viscosity hydroxymethylpropylcellulose Lactose Meggle FlowLac 100 Spray-dried lactose

PVP K30 Polyvinylpyrrolidone

Sodium alginate Sodium alginate

I. The tablets are obtained in the following way:

1) The method of obtaining tablet cores

a. Weighing raw materials: Sodium butyrate, Methocel Premium CR, Inorganic calcium salt, Colloidal silica, Magnesium stearate. Mixing in a mixer.

b. Compacting to obtain granulate.

c. Weighing raw materials: Magnesium stearate. Mixing in a mixer.

d. Tableting.

2) Method of lacquer preparation for coating

a. Weighing raw materials: Distilled water (weigh in two portions of 50% of the required amount each), Acrylic Polymer, TEC, Polysorbate 80, GMS.

b. Heat 50% of distilled water to 80°C.

c. Add TEC, Polysorbate 80 and GMS to hot water. Homogenize the mixture for 10 minutes.

d. Add cold distilled water in an amount of 50% of the weighed water to the “Acrylic Polymer” raw material, mix the mixture.

e. Add the mixture from point "c" to the mixture from point "d". Stir for 30 minutes. Pour through a sieve with a 0.5 mm mesh. 3) Coating of tablet cores

a. Place the tablets to be coated in the drum of the coating machine. Set the minimum drum rotation speed. Heat the tablets to a temperature of 29-33°C. b. Increase the drum rotation speed of the coating machine. Start applying the lacquer.

c. Coat to achieve a weight gain of 3-10% of the initial tablet weight d. After achieving the assumed weight gain of the tablets, stop the application of the lacquer to reduce the rotation speed of the coating machine drum, dry for 2 hours at a temperature of up to 40°C.

Optionally, prior to coating the tablet core, a retarding inner coating made of hydroxypropylmethylcellulose or an aqueous dispersion containing ethylcellulose and hydroxypropylmethylcellulose is applied.

II. Capsules are obtained in the following manner

1) The method of obtaining capsules

a. Weighing raw materials: Sodium butyrate, Methocel Premium CR, optionally Inorganic calcium salt, Colloidal silica, Magnesium stearate. Mixing in a mixer.

b. Compacting to obtain granulate.

c. Weighing raw materials: Magnesium stearate. Mixing in a mixer.

d. Encapsulation for hard capsules.

2) Method of lacquer preparation for coating

b. Heat 50% of distilled water to 80°C.

d. Add cold distilled water in an amount of 50% of the weighed water to the acrylic polymer raw material. Mix the mixture.

e. Add the mixture from point "c" to the mixture from point "d". Stir for 30 minutes. Pour through a sieve with a 0.5 mm mesh.

3) Coating the capsules

a. The capsules filled with granulate ready for coating are placed in the drum of the coating machine. Set the minimum drum rotation speed. Heat the capsules to a temperature of 29-33°C. b. Increase the drum rotation speed of the coating machine. Start applying the lacquer.

c. Coat to achieve a weight gain of 3-10% of the initial capsule weight d. After achieving the assumed weight gain of the capsules, stop the application of the lacquer to reduce the rotation speed of the coating machine drum, dry for 2 hours at a temperature of up to 40°C.

Optionally, before the enteric coating is applied to the hard capsules containing the granulate, a retarding inner coating made of hydroxypropylmethylcellulose or an aqueous dispersion containing ethylcellulose and hydroxypropylmethylcellulose is applied.

Method of preparing the lacquer to make the internal retarding coating for the optional application on the tablet cores or hard capsules containing granulate:

a. Weighing raw materials: hydroxypropylmethylcellulose or ethylcellulose and hydroxypropylmethylcellulose, talc, polyethylene glycol 400 or TEC, distilled water.

b. Mix the raw materials for 30 minutes. Pour through a sieve with a 0.5 mm

mesh.

Negative core comparison formulations are shown below, which did not show satisfactory parameters, namely: they could not be tableted (capping effect), or the tablets were too low in hardness, or the punches wore during tableting, or the core substances could be granulated wet but not tableted.

Tablet core formula·

Exemplary negative enteric coating formulations on core 8A according to the invention

Enteric coatings according to the invention

Inner retarding coating according to the invention

Release results for uncoated tablet cores according to Example "Test 8A.”

Release results after 2 hours at pH 1.2 for tablet cores according to the Example "Test 8A" coated with an enteric coating according to the example "Test OT5".

Release results after 2 and 6 hours at pH 6.8 for tablet cores according to example "Test 8A" coated with an enteric coating according to the example "Test OT5".

Release results at pH 7.2 for tablet cores according to the Example "Test 8A" coated with an enteric coating according to the example "Test OT5".

Release results at pH 7.2 for tablet cores according to the example of "Test 8A" coated with an internal retarding subcoating according to the example "Test OT6" and the enteric coating according to the example "Test OT5".

Release results at pH 7.2 for tablet cores according to the example of "Test 8A" coated with an internal retarding subcoating according to the example "Test OT7" and the enteric coating according to the example "Test OT5".

Release results at pH 7.2 for tablet cores according to the Example "Test 8A" coated with an enteric coating according to the example "Test OT5” after 3 months from the date of production

The release results at pH 7.2 for uncoa :ed size 0 capsules containing 600 mg of granulate, including 350 mg of sodium butyrate, according to the formulation of the example "Test 8A".

The release results at pH 7.2 for size 0 capsules containing 600 mg of granulate, including 350 mg of sodium butyrate, according to the formulation of the example "Test 8A" coated with the enteric coating according to the example "Test OT5".

The release results at pH 7.2 for size 0 capsules containing 600 mg of granulate, including 350 mg of sodium butyrate, according to the formulation of the example "Test 8A" coated with internal retarding coating according to the example“Test OT7”, and then with the enteric coating according to the example "Test OT5".

As a part of developing the tablet core with sodium butyrate, the following works were carried out:

1) The tablet formulation was developed with a total weight of 900 mg and

500 mg sodium butyrate content (1A, 1 B, 1C, 1 D, 1 E) based on the following raw materials for the production of controlled-release tablets: hydroxypropylmethylcellulose (HPMC) - three raw materials - Methocel Premium CR, Methocel Premium DC, Metolose 90SH 100000SR, sodium alginate and carrageenate (carrageenan), two raw materials were used as filler and binder: Supertab lactose and Meggle lactose with slightly different bulk properties, magnesium stearate and colloidal silica were used as anti- caking agents.

2) Technological tests were carried out to manufacture the tablets described in item 1.

a. The initial attempts to obtain tablets containing HPMC (formulations 1A, 1 B, 1 C), in the manual mode of the tablet press, were encouraging, and it was possible to obtain tablets. The tablets, however, had low hardness. Attempts to obtain tablets in the automatic mode of the tablet press operation were unsuccessful

due to very large mass spreads of +/- 20% with simultaneous low hardness. Attempts to increase compression caused the tablet capping phenomenon.

b. Attempts to obtain tablets containing sodium alginate (formulation 1 D) were unsuccessful. The tablet mass was stuck to punches causing their wearing, preventing the tablet machine from operation. The attempts to create them in manual and automatic mode have also been unsuccessful. c. Attempts to obtain tablets containing carrageen (formulations 1E) were unsuccessful. The tablet mass was electrified, which caused uneven powder to be poured into the punches. As a result, the obtained tablets were characterized by large mass spread - over +/- 20% and hardness - even 300% The attempts to produce tablets in manual and automatic mode have also been unsuccessful.

) A formulation 1.1A for wet granulation was developed based on formulation 1A. In terms of quality and quantity, this formulation is the same as the original formulation. The difference consisted in wet granulation of sodium butyrate, HPMC and lactose. Anti-caking agents have been added to the obtained granulate: magnesium stearate and silica and a tableting test was carried out.

a. The attempt at tableting the obtained granulate was unsuccessful.

b. Deterioration of the bulk properties for wet granulate compared to the dry tablet mass was the reason for the failure. The bulk density decreased, the granulate became very fluffy and impossible to tablet, regardless of the tablet press mode and the compression force.

c. After unsuccessful tests with wet granulation, it was decided to continue work using the method of obtaining dry tablet mass using substances with strong binding properties: microcrystalline cellulose and polyvinylpyrrolidone (PVP).

) Modified tablet core formulations with a total weight of 900 mg and 500 mg butyrate sodium content using microcrystalline cellulose and PVP were developed.

a. Tablet formulation using microcrystalline cellulose was carried out using this raw material in an amount of 10% of the tablet weight (formulation 2A). The obtained tablets were characterized by low hardness, and when trying to increase compression, the tablet capping occurred. The attempts to manufacture tablets in both manual and automatic mode have failed. c. Tablet formulation using PVP was carried out using this raw material in an amount of 5% of the tablet weight (formulation 3A). The obtained tablets were characterized by moderate mass spread - below 10% (improvement of bulk properties of the tablet mass), but showed insufficient hardness. Increasing compression again resulted in tablet capping. The attempts to manufacture tablets in both manual and automatic mode have failed.) Further tablet formulations with a total weight of 900 mg containing 500 mg of sodium butyrate were developed. Inorganic calcium salts - calcium phosphate or sulphate (formulations 5A, 5B) were used as a binder. a. Attempts have been made to produce tablets according to new formulations. In the manual mode of tablet press operation, it was possible to obtain tablets of appropriate weight and hardness.

b. In automatic mode, the tablets had excessive mass spread.

f. A decision was made to modify the production process by adding a compacting step to obtain dry granulate.

) The 5A formulation was modified taking into account the additional dry granulation operation. Based on this formulation, the formulation 5.1 A was developed and technological tests of tablet production were carried out according to the new formulation.

a. The obtained tablets were characterized by a higher hardness and a slight mass spread of around 3%

b. The attempt to manufacture tablets in the automatic mode of the tablet press operation has positive result.

c. The release tests of tablets obtained according to 5.1 A were carried out, showing that within 6 hours, less than 70% of sodium butyrate contained in the tablet was released from the tablets. Based on that, the decision was made to develop the following formulas with a lower content of HPMC and/or inorganic calcium salts (formulations 5.2A, 6A, 7A, 8A).

) The formulations 5.2A, 6A, 7A and 8A were developed and tablets were made in accordance with them (taking into account all the changes of the technological process, including compacting).

a. The tablets produced according to the formulation 5.2A were characterized by high hardness and low mass spread, below 3% The release test showed that after about 6 hours, on average, about 95% of the active substance is released.

b. Tablets produced according to formulation 6A were characterized by high hardness, low mass spread at the level of 3%. The release test showed that after about 6 hours, on average, about 89% of the active substance is released.

c. The tablets produced according to formulation 7A were characterized by quite high hardness, low mass spread at the level of 3% The release test showed that after about 6 hours, on average, about 87% of the active substance is released.

d. The tests carried out according to formulations 5.2A, 6A and 7A showed that:

i. All tablets manufactured with inorganic calcium as a binder are characterized by high hardness.

ii. Modification of the technological process by adding dry granulation ensures high repeatability of the process and a low spread of tablet weight. iii. In order to obtain tablets with the assumed release parameters (release of 80% active substance in more than 6 hours), it is necessary to apply an inner retarding layer.

9) Tablets were produced according to formulation 8A. Tablets were characterized by high hardness and low mass spread, below 3% a. The performed release tests showed that, on average, about 77% of the active substance contained in the tablet is released within 6 hours.

10) Tablets manufactured according to formulation 8A were used for subsequent experiments.

As a part of preparing coating of tablets or capsules with sodium butyrate, the following works were carried out:

1) The formulations of the coatings were prepared based on the following raw materials used for the production of enteric coatings: sodium alginate, shellac, ethylcellulose, acrylic polymer. The following was used as binding agents, anti-caking agents and plasticizers: talc, triethyl citrate, polysorbate 80, glyceryl monostearate (formulation Coating 1 , Coating 2, Coating 3, Coating 4, Coating 5).

2) Technological tests were carried out on the production of sodium butyrate tablets encapsulated with the coatings described in item 1 , weighing 5% of the tablet core weight.

a. Attempts to create coatings based on sodium alginate according to Coating

1 formulation had negative result. The coatings were applied quite easily. The coatings were insoluble at pH 1.2 for 2 hours. The coatings were soluble at pH 6.5 - close to the pH limit of 7.0 set in the assumptions. b. Attempts at forming the coatings based on sodium alginate and shellac according to Coating 2 formulation showed that the coatings were applied quite easily, but they dissolved at a pH of about 6.0. The coatings were insoluble at pH 1.2 for 2 hours.

c. Attempts at forming the coatings based on sodium alginate and ethylcellulose according to the Coating 3 formulation were unsuccessful due to the great difficulties with applying the coating associated with clogging of the coating gun nozzle. It was failed to obtain a coating with a weight of 3% of the tablet core weight.

d. Attempts at forming the coatings based on acrylic polymer according to the Coating 4 and Coating 5 formulations were positive. The coatings were insoluble at pH 1.2 for 2 hours. The coatings were dissolved at pH 7.2 above the planned pH limit of 7.0.

4) Due to the necessity of using the retarding subcoating in the case of tablet cores made according to the formulations 5.2A, 6A and 7A, formulations of the subcoatings were developed based on: hydroxypropylmethylcellulose (HPMC) and ethylcellulose and hydroxypropylmethylcellulose (formulations for the subcoatings:

Subcoating 1 , Subcoating 2).

a. The technological tests of applying the Subcoating based on HPMC - Subcoating 1 formulation, were carried out. The tests were successful. The coating was applied quite easily, the resulting film had good mechanical and retarding properties.

b. The technological tests of applying the Subcoating based on HPMC and ethylcellulose - Subcoating 2 formulation, were carried out. The coating was applied quite easily, the film had good mechanical properties and very good retarding properties.

As a part of developing the capsules containing sodium butyrate, the following works were carried out:

1) Size 0 hard capsules were filled with the granulate used to make the tablet cores according to formulation 8A. The content of granulate in one capsule was 600 mg, which is equivalent to 350 mg of sodium butyrate in one capsule.

) The capsules described above were coated with an enteric coating according to the formulation provided in the example "Test OT5".

) The release tests were performed at pH 7.2 for coated capsules and for uncoated capsules. The results of the release tests show that about 83% of the active substance is released from uncoated capsules after 6 hours, while 78% of sodium butyrate is released after 6 hours from capsules coated with an enteric coating.

) The capsules described in item "1" were covered with a retarding inner coating according to the formulation given in the example“Test OT7", with a weight of 5% of the granulate weight, and then an enteric coating was applied according to the formulation given in the example "Test OT5" with a weight of 5% of the granulate.

) Release tests for the capsule described in item "4” were performed at pH

7.2. The results of the release tests indicate that about 28% of the active substance is released after about 6 hours.

Claims

1. An oral preparation in the form of a tablet comprising sodium butyrate, characterized in that it consists of:

i) core composed of: sodium butyrate in an amount of 55-75% by weight, high-viscosity hydroxypropylmethylcellulose in an amount of 15-30% by weight, magnesium stearate in an amount of 0.5-4% by weight, colloidal silica in an amount of 0.1-1 % by weight, inorganic calcium salts in an amount of 10-30% by weight; ii) optionally, an inner retarding coating in an amount of 3-10% by weight relative to the core weight, consisting of hydroxypropylmethylcellulose or ethylcellulose and hydroxypropylmethylcellulose in an amount of 60-90% by weight, a plasticizer in an amount of 8-20% by weight, and an anti-caking agent in an amount of 20-45% by weight;

iii) enteric coating in an amount of 3-10% by weight relative to the weight of the core made of poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 in an amount of 65-90% by weight, plasticizer in an amount of 1-8% by weight, and an anti-caking agent in an amount of 5-35% by weight, and optionally an emulsifier when using glycerol monostearate.

2. The preparation according to claim 1 , characterized in that calcium phosphate or sulphate are used as inorganic calcium salts.

3. The preparation according to claim 1 , characterized in that polyethylene glycol, most preferably polyethylene glycol 400, is used as the inner coating plasticizer.

4. The preparation according to claim 1 , characterized in that triethyl citrate is used as a plasticizer for both coatings.

5. The preparation according to claim 1 , characterized in that talc is used as the anti-caking agent of both coatings.

6. The preparation according to claim 1 , characterized in that glycerol monostearate is used as the anti-caking agent of the enteric coating.

7. The preparation according to claim 1 , characterized in that the emulsifier is used when glycerol monostearate is used as an anti-caking agent for the enteric coating.

8. The preparation according to claim 7, characterized in that the a mixture of polyoxyethylene sorbitan and oleic acid derivatives is used as the emulsifier.

9. The oral preparation in the form of a capsule comprising sodium butyrate, characterized in that it consists of:

i) granulate composed of: sodium butyrate in an amount of 55-80% by weight, high-viscosity hydroxypropylmethylcellulose in an amount of 15-40% by weight, magnesium stearate in an amount of 0.5-4% by weight, colloidal silica in an amount of 0.1-1 % by weight, optionally inorganic calcium salts in an amount of 10- 30% by weight;

ii) hard capsule, coated with the coating in an amount of 3-10% by weight relative to the weight of the granulate, made of poly(methyl acrylate-co- methylmethacrylate-co-methacrylic acid) 7:3:1 in an amount of 65-90% by weight, plasticizer in an amount 1-8% by weight, anti-caking agent in an amount of 5-35% by weight, and optionally an emulsifier,

iii) optionally, an inner retarding coating on the capsule under the enteric coating, in an amount of 3-10% by weight relative to the weight of the granulate, consisting of hydroxypropylmethylcellulose or ethylcellulose and hydroxypropylmethylcellulose in an amount of 60-90% by weight, plasticizer in an amount of 8-20%, and an anti-caking agent in an amount of 20-45% by weight.

10. The preparation according to claim 9, characterized in that calcium phosphate or sulphate are used as inorganic calcium salts.

11. The preparation according to claim 9, characterized in that cellulose capsules or gelatin capsules are used as hard capsules.

12. The preparation according to claim 9, characterized in that polyethylene glycol, most preferably polyethylene glycol 400, is used as the inner coating plasticizer.

13. The preparation according to claim 9, characterized in that triethyl citrate is used as a plasticizer for both coatings.

14. The preparation according to claim 9, characterized in that talc is used as the anti-caking agent for both coatings.

15. The preparation according to claim 9, characterized in that glycerol monostearate is used as the anti-caking agent of the enteric coating.

16. The preparation according to claim 9, characterized in that the emulsifier is used when glycerol monostearate is used as an anti-caking agent.

17. The preparation according to claim 16, characterized in that a mixture of polyoxyethylene sorbitan and oleic acid derivatives is used as the emulsifier.