Solid pharmaceutical compositions containing clay for the treatment of gastrointestinal disorders

Abstract

The present invention relates to a solid pharmaceutical composition, in particular a tablet, comprising a clay, in particular a smectite.

Description

Cross-reference to related applications

[0001] This application claims priority and benefit to French patent application No. FR2504493 filed with the French National Institute of Industrial Property on April 28, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to a solid pharmaceutical composition, particularly a tablet, comprising clay, such as montmorillonite. Background Technology

[0003] Montmorillonite is a type of clay mineral commonly used in the preparation of medicines intended to treat gastrointestinal disorders, such as functional gastrointestinal disorders like diarrhea, which can be chronic or acute. Other clays, such as attapulgite, are also used for medicinal purposes.

[0004] Currently, there are many medications on the market containing montmorillonite for the treatment of gastrointestinal diseases and symptoms caused by various factors. Smecta® is one such example.

[0005] The effectiveness and popularity of these medications stem from the properties of montmorillonite. Montmorillonite is a natural adsorbent that does not disrupt the gut microbiota or affect intestinal motility; it is not absorbed by the gastrointestinal tract but is excreted unchanged; montmorillonite forms a protective barrier on the digestive tract mucosa without causing any adverse side effects; in fact, it has virtually no contraindications. There is no age limit for receiving montmorillonite, so it can be administered to patients of any age, including infants as young as 2 years old.

[0006] Most montmorillonite-based medications currently on the market (such as Smecta®) are formulated as powders or ready-to-use suspensions, packaged in 3-gram montmorillonite sachets; these medications are administered orally either by mixing the clay powder with water to form a suspension or as ready-to-use sticks. However, due to sensory reasons (unpleasant taste in the mouth, pasty texture), taking these medications can sometimes be difficult to accept.

[0007] One way to overcome this drawback should be to develop solid forms of montmorillonite compositions for oral administration, which would provide an alternative route of oral administration to drinking suspensions.

[0008] However, there are many difficulties in developing such a solid dosage form.

[0009] The first difficulty is obtaining a solid form that allows for the administration of a therapeutic dose (3 grams) of montmorillonite in a sufficiently small volume that can be swallowed; in this case, it is clear that encapsulating montmorillonite powder is not satisfactory, as even with large capsules of about 1 ml, it would take 6 capsules to administer 3g of montmorillonite, which is difficult for patients to accept and impractical, since this form would require up to 36 capsules to be administered daily.

[0010] Therefore, a solution of pre-densifying the clay powder before pressing was chosen. However, this presented a challenge: how to obtain tablets with a satisfactory appearance (smooth, non-brittle), good mechanical strength and storage stability (no cracking or breakage), and most importantly, how to achieve the same properties as the powder formulation (measurement, particle size distribution after dispersion, adsorption capacity). Montmorillonite, in particular, is an extremely fine powder with technical characteristics that make it difficult to formulate into tablet form: high abrasiveness, low flowability and compressibility, and almost insoluble in water and alcohol.

[0011] Finally, the requirement to apply a dosage of 3 grams of clay necessitates the use of as few excipients as possible in the production of tablets of acceptable size; limiting the use of these formulation excipients further complicates the development of high-quality tablets. Summary of the Invention

[0012] There are some solid clay formulations, such as Simcere ® or Dimexanol ® Tablets, suspended in water before application; or Diatabs for dogs. ® Chewable tablets; these formulations are not limited in size because they are not swallowed directly, but they do not solve the problem of poor taste and texture during application.

[0013] Therefore, it is surprising that the applicant has successfully developed a tablet with a high clay content, possessing all the properties required to replace existing powder formulations.

[0014] More specifically, the present invention relates to clay tablets comprising: - At least 80% by weight of clay; -0.5% to 1.5% by weight of sodium stearate; - Using 5% to 15% hydroxypropyl cellulose as a binder, preferably 7% to 10% wt%, even more preferably 8% to 10% wt%; - Optionally, 5% to 15% by weight of a diluent, said diluent being selected from microcrystalline cellulose, starch and pregelatinized starch, maltodextrin, mannitol and dicalcium phosphate; and - Optionally, 2% to 10% by weight of a disintegrant, said disintegrant being selected from low-substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, soybean polysaccharide, starch and pregelatinized starch.

[0015] The clay may be selected from montmorillonite and attapulgite, with montmorillonite being preferred.

[0016] The clay content of the tablet is preferably at least 83% by weight, or even more preferably 85% to 95% by weight.

[0017] Specifically, the clay content per tablet can be from 0.4g to 2.4g, preferably from 0.8g to 1.9g. According to one embodiment, the tablet contains 1.5g of clay.

[0018] Sodium stearate is used as a lubricant, preferably in the form of 0.8% to 1.2% by weight.

[0019] In a preferred embodiment, hydroxypropyl cellulose is ultrafine, i.e., its particle size distribution results in a D0.05... 50 (50% of the maximum particle size) ranges from 15µm to 90µm, and its D 90 (50% maximum particle size) ranges from 35µm to 300µm.

[0020] In a specific embodiment, the tablets according to the present invention do not contain disintegrants.

[0021] According to another specific embodiment, the tablets of the present invention do not contain a diluent.

[0022] In another specific embodiment, the tablets according to the invention contain neither disintegrants nor diluents.

[0023] There is no limitation on the weight of the tablets of the present invention; however, for the contemplated applications, tablets weighing 0.5g to 2.5g, preferably 1g to 2g, are preferred.

[0024] The tablets may have any shape commonly used in the production of tablets for oral administration; by way of example, but not limited to, they may be elongated, such as elliptical.

[0025] According to one embodiment of the invention, the tablet is divisible, i.e., the tablet includes a geometry with a fracture line that allows the tablet to be easily cut into several pieces; preferably, it is cut into two pieces.

[0026] Surprisingly, despite the very low content of excipients in the tablets described in this invention (less than 20% by weight), the experimental portion demonstrates that the tablets according to this invention possess all the properties required to induce the therapeutic effect of clay: - Active ingredient dosage compliance: The dosage of clay in the finished tablets must reach 95% to 105% of the target content; - Adsorption capacity: When tested with strychnine hemisulfate or cobalt hexamine (cobalt(III) chloride), this property must result in an adsorption of 307 mg to 575 mg strychnine hemisulfate per gram of clay, or an adsorption of 80 mEq to 150 mEq cobalt hexamine per 100 grams of clay. -Particle size distribution after dispersion: D 90 Less than 200µm; - Disintegration time: It must be less than or equal to 30 minutes (1800 seconds), preferably 15 minutes (900 seconds); the disintegration time is evaluated according to the European Pharmacopoeia 2.9.1; - Mechanical stability: According to the European Pharmacopoeia 2.9.7, the friability test must result in a loss of less than 1% of the tablet weight.

[0027] Therefore, the clay tablet according to the present invention has the following characteristics: - Disintegration time less than or equal to 30 minutes (1800 seconds), preferably less than or equal to 15 minutes (900 seconds); and / or - The clay content in the finished tablets is 95% to 105% of the target content; and / or - This results in an adsorption capacity of 307 mg to 575 mg of strychnine hemisulfate per gram of clay; or an adsorption capacity of 80 mEq to 150 mEq of cobalt hexaphosphate per 100 grams of clay; and / or - The particle size distribution of the dispersed particles makes D 90 Less than 200µm; and / or - Mechanical stability, such that when assessed by the friability test according to European Pharmacopoeia 2.9.7, the weight loss of the tablet is less than 1%.

[0028] The present invention also relates to tablets according to the invention for treating gastrointestinal disorders, such as functional gastrointestinal disorders, like diarrhea, whether chronic or acute.

[0029] Specifically, they allow for symptomatic treatment of acute diarrhea in children over 2 years of age; symptomatic treatment of chronic diarrhea; symptomatic treatment of pain associated with esophageal, gastroduodenal, and dyspepsia (functional dyspepsia, functional heartburn), gastroesophageal reflux, and colic; symptomatic treatment of functional bowel disorders in children and adults (i.e., bloating and abdominal pain, irritable bowel syndrome); or pain in the esophagus, stomach, duodenum, or colon.

[0030] The present invention also relates to a method for preparing tablets according to the present invention. According to a first embodiment, the tablets of the present invention are prepared by compacting (dry granulation) the clay, comprising the following steps: - The clay is compacted alone or together with one or more excipients; this step can be done using a roller compactor; densifying the clay powder is important for producing tablets with the desired properties; The resulting particles are mixed with the remaining excipients; - Add sodium stearate fumarate and stir; - Press and retract the tablet.

[0031] The implementation of these steps is well known to those skilled in the art.

[0032] According to another embodiment, the tablets of the present invention are prepared by a method including wet granulation; said method includes the following steps: - Mix the clay alone or with all or part of the binder (e.g., 3% to 5% by weight of the total weight of the tablets as binder). - If the binder is not added in the dry mixing step, wet granulation is performed using all or part of the binder; Wet granulation of the mixture is achieved by introducing sufficient water under vigorous stirring. If the binder is not added during the dry mixing stage, it is added to the water and dissolved before granulation.

[0033] - Dry the particles to the desired residual moisture using any known method, preferably in a fluidized bed; - Add any additional binders and other excipients and mix; - Add sodium stearate fumarate and mix; - Press and retract the tablet.

[0034] The method can be carried out using any equipment suitable for this purpose; commonly used granulation mixers or granulation dryers are well known to those skilled in the art. The granules are dried, sieved, and mixed with other ingredients. Attached Figure Description

[0035] Figure 1 The chart shows the results of a comparative test on the tensile strength of tablets prepared by compaction. Detailed Implementation

[0036] Example I. Production of clay tablets IA prepares tablets by compaction (dry granulation) and compression.

[0037] The method comprises two main stages: compaction and pressing. Generally speaking, dry granulation is a method of forming particles from powder. The powder is pressed between two rollers to form a strip, which is then milled through a pre-calibrated and calibrated grid to obtain particles.

[0038] Roller compaction is a dry granulation technique used to agglomerate powder mixtures into particles that possess the properties required to obtain tablets that meet industrial and regulatory requirements. The compaction process proceeds as follows: In a die, a lower punch slides to form a volume (measuring chamber) into which a powder mixture containing binder, lubricant, and compacting clay is introduced. An upper punch closes the volume and, together with the lower punch, compresses the mixture into a tablet. The upper punch retracts, and the lower punch rises, ejecting the tablet.

[0039] More specifically, the tablets were manufactured using a STYL'One Evo compression simulator equipped with tools that allow the tablets to be prepared into a specific desired shape; in this case, the shape chosen for the test was an EU-B 19 x 10 mm R34.8 / R4.6 oval with a break line.

[0040] As part of the development of the tablets according to the present invention, the following formulations were prepared: [Table 1]

[0041] [Table 2]

[0042] IB tablets are prepared by wet granulation and compression.

[0043] High-shear wet granulation (HSWG) tests were conducted using a Mi-Pro high-shear granulator (PROCEPT, Belgium). A dual-fluid nozzle (BF) with a 0.4 mm nozzle orifice was used to deliver the liquid at a rate of 3.0 L / min atomized gas. Water was used as the granulation solution in each test. The test duration was set to 10 minutes, with a wetting time of 2 minutes.

[0044] The drying step was then carried out using a laboratory-scale 4M8Trix fluidized bed (PROCEPT, Belgium) with a mesh substrate.

[0045] Finally, the tablets were manufactured using a STYL'One Evo compaction simulator equipped with tools that could prepare the tablets into the desired specific shape; in this case, the shape chosen for testing was an EU-B 19 x 10 mm R34.8 / R4.6 ellipse with a break line.

[0046] [Table 3]

[0047] II. Tablet Characteristic Evaluation II.A. Analytical Methods II.A.1. Determination of Montmorillonite in principle: After all excipients were calcined, the montmorillonite content was determined by gravimetric method.

[0048] Loss on burning refers to the mass loss obtained at 900°C ± 25°C.

[0049] When calculating the montmorillonite content, the mass loss during the calcination of the raw materials used in production must be taken into account.

[0050] Operation method: Weigh out a tablet using a mortar and pestle, then crush it.

[0051] Place the crushed tablets into a pre-weighed crucible (T) and weigh them (Pe, in grams).

[0052] Place the crucible into the furnace. Raise the temperature from room temperature to 900°C over 2 hours, and then maintain it at 900°C for 1 hour.

[0053] After the crucible containing the residue has cooled, the crucible (Tr) containing the residue is weighed.

[0054] calculate: The montmorillonite content, expressed in grams, in each tablet is given by the following formula: [Mathematical Expression 1]

[0055] in, Tr: Tare weight and mass of residue (g) T: Tare weight (g) T+Pe: Tare weight and mass (g) of the test sample A: Loss on ignition of raw materials used in production (g / 100g) M cp : Actual mass (grams) of the tablet used for the determination II.A.2. Determination of Adsorption Capacity Using Hexaamminecobalt(III) Chloride in principle The method of determining the adsorption capacity (also known as cation exchange capacity (CEC) and exchangeable cations (Al, Ca, Fe, K, Mg, Mn, Na)) of hexaamminecobalt(III) chloride solution is a method for quantitatively determining the hexaamminecobalt(III) chloride remaining in the solution after contact with clay (which has not been adsorbed by the sample).

[0056] The amount of hexaamminecobalt(III) chloride not adsorbed by clay samples was determined by visible light absorption spectrophotometry at a wavelength of 475 nm.

[0057] This method is implemented in accordance with the AFNOR 23470 NF ISO standard.

[0058] hardware - Hexaamminecobalt(III) chloride, purity ≥99%, CAS No.: 10534-89-1, reference VWR A15470 or equivalent. - Sodipro Grade 14 ashless filter paper, 125mm in diameter, slow filtration, refer to Sodipro 6050041-06 or equivalent.

[0059] -10mm quartz dish Operating steps: Solution preparation Preparation of reference standard for hexaamminecobalt(III) chloride solution: 20 mL of 0.0166 mol / L hexaamminecobalt(III) chloride.

[0060] Preparation of sample solution: half a tablet and 50.0 mL of 0.0166 mol / L hexaamminecobalt(III) chloride.

[0061] Preparation of reference solution: 0.70 g powdered sample and 50.0 mL of 0.0166 mol / L hexaamminecobalt(III) chloride. Measurement The adsorption of solutions (pure water, control, control montmorillonite, and sample) at 475 nm was measured.

[0062] Calculation of adsorption capacity The adsorption capacity of the sample: the amount of hexaamminecobalt(III) chloride adsorbed, expressed in milliequivalents / 100 g montmorillonite, is given by the following expression: [Mathematical Expression 2]

[0063] in, The concentration of C6 hexaamminecobalt(III) chloride solution was 0.0166 mmol / mL. Absorbance of A1 hexaamminecobalt(III) chloride reference solution Absorbance of sample A2 Pe test plug (g) M cp Theoretical mass (grams) of tablets under powder test sample conditions. In the case of test samples in tablet form, the actual mass (grams) of the tablet. D. Montmorillonite content (grams) of this batch. 3. Number of cations exchanged The adsorption capacity of reference montmorillonite: the amount of hexaamminecobalt(III) chloride adsorbed, expressed in milliequivalents / 100 g reference montmorillonite, is given by the following expression: [Mathematical Expression 3]

[0064] in, Hr refers to the loss during montmorillonite drying II.A.3. Analyzing the size of the clay particles by laser diffraction. equipment: Particle size analyzers equipped with wet measurement systems, such as the Malvern Mastersizer 3000 or equivalent.

[0065] Sample preparation: Disperse one dose of the product (2 tablets) in 100 ml of Milli-Q water. Disperse under magnetic stirring for 1 hour analyze: The resulting suspension was analyzed according to the manufacturer's recommendations.

[0066] II.A.4. Measurement of disintegration time The disintegration test assesses whether the tablets disintegrate within the time specified in the pharmacopoeia by simulating human intestinal peristalsis in water at a constant temperature of 37°C. This test ensures rapid dispersion of the active ingredient in gastrointestinal fluids and guarantees the efficacy of this form.

[0067] The method is performed by standardizing the stirring of the tablets in a liquid medium (typically water) at 37°C in a test tube with a mesh bottom. The test is complete when no tablet residue remains on the basket mesh.

[0068] Each tablet has a set maximum disintegration time. In the case of immediate-release tablets, the disintegration time must be less than 1800 seconds.

[0069] II.A.5. Measurement of Tensile Strength The "pressure-tensile strength" curve is used to characterize the relative hardness of the product. The curve is independent of the characteristics of the tool used (the shape of the punch, the final thickness of the tablet, etc.).

[0070] The average pressing pressure corresponds to the force applied to the punch as a function of the punch's projected area: [Mathematical Expression 4]

[0071] II.A.6. Friability Assessment The friability test ensures that the tablets have sufficient mechanical strength to ensure that their surface will not be damaged or show signs of wear or breakage under any treatment (mechanical impact, friction, abrasion).

[0072] The mass loss of the tablet can be estimated by applying stress to it. This stress is generated by rotating a roller for a certain period of time (according to European Pharmacopoeia 2.9.7, rotating at 25 rpm for 4 minutes).

[0073] Therefore, 6.5g of tablets were weighed before and after stress. The maximum acceptable mass loss in the pharmaceutical industry is 1% of the mass of the tablet being tested.

[0074] II.B. Results II.B.1. Comparative Test of Tensile Strength of Tablets Prepared by Compression Method The tablets tested were consistent with the formulation detailed in Section A of Part I.

[0075] To achieve satisfactory performance, the tensile strength of the tablet must be at least 1.0 MPa, preferably at least 1.5 MPa.

[0076] The results are listed in Table 4 and presented graphically. Figure 1 middle: [Table 4]

[0077] Note: MgSt = magnesium stearate, SSF = sodium stearate fumarate, HPC = hydroxypropyl cellulose.

[0078] These results indicate that the selection of hydroxypropyl cellulose as a binder and sodium stearate fumarate as a lubricant unexpectedly and significantly improved the tensile strength of the tablets.

[0079] II.B.3. Disintegration Time The disintegration time must be less than or equal to 30 minutes (i.e., 1800 seconds).

[0080] The results are listed in Table 5 below.

[0081] II.B.4. Determination of Montmorillonite When the tablet contains 1.43g to 1.57g of montmorillonite per tablet, the montmorillonite content is considered compliant.

[0082] The results are listed in Table 5 below.

[0083] II.B.5. Adsorption capacity The adsorption capacity of the tablet is considered satisfactory when it can adsorb 80 mEq to 150 mEq of cobalt hexahydrate per 100 g of clay.

[0084] The results are listed in Table 5 below.

[0085] II.B.6. Particle size after dispersion in water The particle size of the clay particles dispersed in water must be such that D 90 The value is less than or equal to 200µm.

[0086] The results are listed in Table 5 below.

[0087] [Table 5]

[0088] in conclusion: These results demonstrate that the performance of the montmorillonite tablets according to the present invention fully meets the requirements.

Claims

1. A clay tablet comprising: - At least 80% by weight of clay; -0.5% to 1.5% by weight of sodium stearate; -5% to 15% by weight, preferably 8% to 10% by weight, of hydroxypropyl cellulose as a binder; - Optionally, 5% to 15% by weight of a diluent, said diluent being selected from microcrystalline cellulose, starch and pregelatinized starch, maltodextrin, mannitol and dicalcium phosphate; and - Optionally, 2% to 10% by weight of a disintegrant, said disintegrant being selected from low-substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, soybean polysaccharide, starch and pregelatinized starch.

2. The clay tablet according to claim 1, characterized in that, The clay is selected from montmorillonite and attapulgite, preferably montmorillonite.

3. The clay tablet according to claim 1 or 2, characterized in that, It contains at least 83% by weight of clay, preferably 85% to 95% by weight.

4. The clay tablet according to any one of the preceding claims, characterized in that, It contains 0.8% to 1.2% sodium stearate.

5. The clay tablet according to any one of the preceding claims, characterized in that, It does not contain disintegrants.

6. The clay tablet according to any one of the preceding claims, characterized in that, It does not contain diluent.

7. The clay tablet according to any one of the preceding claims, characterized in that, Its weight is 0.5g to 2.5g, preferably 1g to 2g.

8. The clay tablet according to any one of the preceding claims, characterized in that, It has the following characteristics: - A disintegration time of less than or equal to 30 minutes (1800 seconds), preferably less than or equal to 15 minutes (900 seconds); and / or - Clay content of 95% to 105% of the target content in the finished tablets; and / or - This results in an adsorption capacity of 307 mg to 575 mg of strychnine hemisulfate per gram of clay, or 80 mEq to 150 mEq of cobalt hexaphosphate per 100 grams of clay; and / or -makes D 90 Particle size distribution of dispersed particles smaller than 200 µm; and / or - This ensures that the tablets exhibit mechanical stability, with a weight loss of less than 1% when assessed by the friability test according to European Pharmacopoeia 2.9.

7.

9. The clay tablet according to any of the preceding claims, used to treat gastrointestinal disorders, such as functional gastrointestinal disorders, like diarrhea, which may be chronic or acute.

10. A method for preparing a tablet according to any one of claims 1 to 8, comprising the following steps: - Compact the clay, alone or together with one or more excipients; The compacted clay and the excipient are mixed; - Press and retract the tablet.

11. A method for preparing a tablet according to any one of claims 1 to 8, comprising the following steps: - The clay is dry-mixed alone or with all or part of the binder and one or more excipients other than sodium stearate fumarate; - If the binder is not added in the dry mixing step, then wet granulation is performed using a portion of the binder; - Dry the particles to the desired residual moisture using any known method, preferably in a fluidized bed; - Add any additional adhesive and mix; - Add sodium stearate fumarate and mix; - Press and retract the tablet.

Images