Pharmaceutical compositions comprising activated carbon
11712422 · 2023-08-01
Assignee
Inventors
Cpc classification
A61K9/5026
HUMAN NECESSITIES
A61P1/04
HUMAN NECESSITIES
A61P1/00
HUMAN NECESSITIES
A61K9/2081
HUMAN NECESSITIES
A61K9/5042
HUMAN NECESSITIES
A61K9/5073
HUMAN NECESSITIES
A61K9/5047
HUMAN NECESSITIES
International classification
A61K9/50
HUMAN NECESSITIES
A61K9/00
HUMAN NECESSITIES
Abstract
The invention provides a pharmaceutical composition comprising activated carbon particles, for oral administration. The pharmaceutical composition may be for (use in) the treatment of gastrointestinal fistula.
Claims
1. An oral pharmaceutical composition comprising coated activated carbon, comprising: (a) a core consisting of activated carbon; (b) a first layer around the core, wherein the first layer forms an insoluble semipermeable membrane around the core, and comprises a material which is insoluble in water and, optionally, a water soluble material in an amount of from 0.1 to 30% by weight of the amount of the insoluble material; and (c) a second layer around the first layer which dissolves at a pH of from 5 to 7, wherein, upon dissolution of the second layer, the first layer allows gradual diffusion of molecules through the semipermeable membrane towards the core into contact with the activated carbon of the core and retains substantially all of the activated carbon within the semipermeable membrane.
2. The pharmaceutical composition according to claim 1, wherein the activated carbon has a particle size of from 0.02 to 5.0 mm.
3. The pharmaceutical composition according to claim 1, wherein the insoluble material comprises one or more selected from the group consisting of ethyl cellulose, glycerylmonostearate, cellulose acetate butyrate, dipolylactic acid, polyvinyl chloride, and poly(meth)acrylate polymers.
4. The pharmaceutical composition according to claim 1, wherein the first layer further comprises the water soluble material.
5. The pharmaceutical composition according to claim 4, wherein the water soluble material comprises hydroxypropylmethyl cellulose (HPMC).
6. The pharmaceutical composition according to claim 5, wherein the water soluble material is mixed with the insoluble material.
7. The pharmaceutical composition according to claim 5, wherein the water soluble material is present in an amount of from 5 to 15% by weight of the amount of the insoluble material.
8. The pharmaceutical composition according to claim 1, wherein the second layer is an enteric layer comprising a material which remains substantially intact at pH 1 to 4.9, and breaks down rapidly at a pH of from 5 to 7.
9. The pharmaceutical composition according to claim 1, wherein the second layer comprises a pH sensitive polymer.
10. The pharmaceutical composition according to claim 1, wherein the second layer comprises a polymer selected from the group consisting of hypromellose acetate succinate, cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), copolymers of methacrylic acid and ethyl acrylate, copolymers of methacrylic acid and methyl methacrylate copolymers (1:1 ratio), copolymers of methacrylic acid and methyl methacrylate (1:2 ratio), polyvinyl acetate phthalate (PVAP), and shellac resins.
11. The pharmaceutical composition according to claim 1, wherein the activated carbon is the sole active pharmaceutical ingredient present in the composition.
12. The pharmaceutical composition according to claim 1, wherein the first layer comprises ethyl cellulose, and optionally further comprises hydroxypropylmethylcellulose (HPMC); and the second layer comprises hydroxypropylmethylcellulose acetate succinate (HPMC AS).
13. The pharmaceutical composition according to claim 1, wherein the activated carbon has a particle size of from 0.6 to 1.2 mm.
14. The pharmaceutical composition according to claim 5, wherein the water soluble material is present in an amount of 2 to 25% by weight of the amount of the insoluble material.
15. A method of administering activated carbon to a subject in need thereof, comprising orally administering a pharmaceutical composition according to claim 1 to the subject, wherein the subject is suffering from a condition selected from the group consisting of gastrointestinal (GI) dysfunction, GI diseases, malfunction of the GI tract, fistula, Irritable Bowel Disease (IBD), ulcerative colitis, Crohn's disease, Irritable Bowel Syndrome (IBS), poisoning, or wherein the subject has been or is being treated with another pharmaceutical composition associated with a presence or build-up of the other pharmaceutical composition and/or its metabolite(s) in the lower ileum, colon or caecum, and the method reduces the presence of the other pharmaceutical composition and/or its metabolite(s) in the lower ileum, colon or caecum of the subject.
16. The method according to claim 15, wherein the other pharmaceutical composition and/or its metabolites are selected from the group consisting of antibiotics, irinotecan, and the metabolite SN38.
17. An oral pharmaceutical composition comprising coated activated carbon comprising: (a) a core consisting of activated carbon; (b) a first layer around the core, wherein the first layer forms an insoluble semipermeable membrane around the core, and comprises a material which is insoluble in water and, optionally, a water soluble material in an amount of from 0.1 to 30% by weight of the amount of the insoluble material; and (c) a second layer around the first layer which dissolves at a predetermined location in the gastrointestinal tract, wherein, upon dissolution of the second layer, the first layer allows gradual diffusion of molecules through the semipermeable membrane towards the core into contact with the activated carbon of the core and retains substantially all of the activated carbon within the semipermeable membrane.
18. The pharmaceutical composition according to claim 17, wherein the second layer comprises a material which dissolves at a pH of from 5 to 7.
Description
DETAILED DESCRIPTION OF THE INVENTION
(1) The present invention will now be illustrated with reference to the following examples and attached drawings in which:
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A. THE COMPONENTS OF THE COMPOSITION
(12) The composition (e.g. pharmaceutical composition) of the invention comprises:
(13) (a) a core comprising activated carbon (e.g. activated carbon as the sole active pharmaceutical ingredient);
(14) (b) a first (e.g. an inner) layer around (e.g. surrounding) the core, the first layer comprising an insoluble semipermeable material; and
(15) (c) a second (e.g. outer) layer around (e.g. surrounding) the first layer which breaks down rapidly (dissolves) at a predetermined pH (e.g. a layer which breaks down rapidly (dissolves) at pH 5 to pH 7) or which dissolves at a predetermined location in the gastrointestinal tract.
(16) The following deals with each layer in turn.
(17) (a) A Core Comprising Activated Carbon
(18) Activated Carbon and its Production
(19) To assure the suitability of the activated carbon starting material for processing into a final uniform and reproducible product, the activated carbon starting material is subjected to a pre-treatment process. The objective of this pre-treatment is to reduce the number of burrs, tips and sharp edges because these will negatively impact the quality of the first (and second) layers which are applied to the surface of the activated carbon. A burr, tip or sharp edge is more difficult to cover with a uniform layer of coating material, hence particles are subjected to mechanical erosion to form a more uniform surface.
(20) In this example the process involves the equipment shown in
(21) The starting material activated carbon is made from coconut shells (Chemviron Carbon, Lockett Road, Ashton-ln-Makerfield, Lancashire WN4 8DE UK product name AQUACARB 607C 14×40 having a particle size from 1.40 mm to 0.425 mm). This quality of activated carbon starting material will, when subjected to the below described instrumental set up by the described instrumental parameters, result in a product, having suitable properties for being further processed into the final coated product with the desired properties.
(22) The mechanically erosion of the carbon particle is done in the equipment shown in
(23) On the instrument, a high pressure (in this case 8 bar) is applied to a small inner-tubing 100. This inner-tubing is inserted in a larger outer-tubing having a larger diameter. A heavy airstream, in this case approx. 21 m.sup.3/h in the small inner-tube will thus be injected into the outer-tube 102, creating a jet air-flow through this tube. At inlet 104, before the airflow from the inner-tube is led into the outer-tube, a vacuum will arise creating a flow of in this case approx. 35 m.sup.3/h. The first part of the outer-tube serves as a collision tube and is connected to a tube with higher diameter 106. To make the instrument more compact, the tube 106 in this case has a curvature diverting the airstream (180°) and let into a cyclone 108. Active carbon starting material is gradually fed into the tubing at inlet 104, in this case at a rate of 2 kg/min. The carbon particles will in this case gain a velocity of around 70 km/h in the first part of the collision tube and carbon particles will collide with each other resulting in any sharp edges and burrs being eroded. The velocity of the particles will decline as the diameter of the outer-tube is enlarged in this case to around 35 km/h at the inlet to the cyclone. Extract ventilation is applied to the top of the cyclone at 110 and regulated to balance the incoming air, so the net airflow is nearly zero at the bottom outlet 112 of the cyclone at. Small carbon particles and fragments are removed by ventilation from the top of the cyclone 110, while larger particles are collected at the outlet 112 at the bottom of the cyclone. After collection of the larger particles, the process may be repeated several times by introducing the collected particles into the system again at inlet 104 until the carbon particles are sufficiently eroded for further processing. After completing the erosion process, the collected particles are now subjected to a vibration sieve in portions of 200 g and sieved through a 1.0 and subsequently a 0.6 mm sieve. The fraction passing the 1.0 mm sieve and not the 0.6 mm sieve has an acceptable particle size and shape to be used as starting material for coating processes.
(24) In the current example, 2125 g of activated carbon was introduced in the process. 2003 g of carbon was collected after repeating the erosion process for 25 times. A loss of 6% smaller particles and fragments was noticed. Following sieving, the useful product fraction (0.6<p<1.0) yielded 924 g The pre-treatment process had after correcting for sampling, an overall yield of approx 48% in this example.
(25) The useful product fraction is coated as set out below.
(26) Testing the Surface of the Activated Carbon
(27) Macroscopy and digital image analysis may be used to assess the effect of the deburring process. Using digital image analysis it is possible to characterize the shape of the individual particles and small points of roughness or tips can be identified. The technique is based upon being able to detect even very small tips (typically in the range from approximately 20-100 μm). The measurement utilizes a macro scope with a low magnification (approximately 4×) and acquiring images with a digital camera. The images are analyzed using digital image analysis software (Media Cybernetics Image Pro-Plus version 6.1.0.346). The detailed settings are specified in the attached appendix I.
(28) The procedure is that the particles are first converted to a black and white mask. The particles are then measured with regards to area. After this the images are treated with a function to even out small tips called 2×21 square, close, 6 passes. The area of the particle in the treated image is measured. To obtain the tips, the treated image is subtracted from the untreated. The resulting image contains the tips and also some residual noise. The residual noise is removed using a function called 2×2 square open, 1 pass. The resulting particles are the tips.
(29) A number of samples have been analyzed to evaluate if the analytical procedure can differentiate between coal particles having been processed increasingly number of times. Particles having been processed (by the apparatus of
(30) As expected, the number of tips decreases with increasing number of treatments. This correlation is also in good agreement with what has been observed, i.e. that the more times the particles are treated, the more complete the coating.
(31) (b) The First Layer Around the Core, the First Layer Comprising an Insoluble Semipermeable Material:
(32) It was a target to develop film compositions with a minimum of additives (especially for the inner film) to minimise take up of adsorptive capacity by additives. The first (e.g. an inner) layer may therefore consist essentially of the insoluble semipermeable material (e.g. ethyl cellulose) and (optionally) the water soluble material (e.g. HPMC). Avoiding other ingredients/excipients prevents loss of adsorptive capacity of the activated carbon to these excipients. The simplest film would be an ethylcellulose film (insoluble semipermeable material alone) applied from an ethanol solution. It was expected that this film would be very tight, not allowing sufficient/efficient passage of unwanted substances. Thus, to ensure that the adsorption capacity of activated carbon is made available/accessible, different water soluble materials (e.g. water soluble polymers) were mixed into the ethylcellulose to make holes in it or make it dissolve (on exposure to the pH in the lower intestine/colon). Polyvinylpyrrolidone (PVP), Hypromellose (HPMC) and Polyvinyl alcohol (PVA) were used as water soluble polymers. PVP is both soluble in water at ethanol, HPMC only in water. Low viscosity grades of PVP and HPMC were chosen (Kollidon K30 and Pharmacoat 603 respectively) in order not to influence the coating process with highly viscous film solutions.
(33) For the following examples, the film coating was performed by methods well known in the art, in a GEA Aeromatic Fielder Strea 1 fluid-bed installed with a wurster tube. Liquid was pumped with a peristaltic pump. As Hypromellose (HPMC) is not soluble in Ethanol and Ethylcellulose is not soluble in water, the ethanol/water mix at which both polymers can dissolve was found to be between 70:30 and 80:20. The mix 75:25 was chosen as standard in the film (first layer) formulations with Ethylcellulose combined with Hypromellose.
(34) The first layer was added by the above methods, to provide compositions according to the invention as set out in the Tables below.
(35) (c) The Second Layer Around the First Layer which Dissolves at a Predetermined PH and/or which Dissolves at a Predetermined Location in the Gastrointestinal Tract:
(36) For the enteric coating, a polymer with release at higher pH was selected, aiming at having the activated carbon available as close to the colon as possible. On the other hand, choosing an enteric coating with release at a too high pH could mean that the activated carbon would not be available in all patients (because gut pH and transit time can vary considerably from patient to patient and day to day). Based on this, Aqoat HG (HPMC-AS; Hypromellose-Acetate-Succinate; releases at pH 6.5) was chosen for the examples. Alternatives could be e.g. other Aqoat products (which release at other pH values), mixtures of Eudragit S 100/FS 30 D and Eudragit L 100 to reduce the release from pH 7.0 resulting from using Eudragit S 100/FS 30 D alone.
(37) The amount of enteric layer in the following examples is 8 to 16% w/w of the total composition, for example 10 to 14% w/w of the total composition, for example 12% w/w of the total composition.
(38) For the following examples, the film coating was performed by methods well known in the art, in a GEA Aeromatic Fielder Strea 1 fluid-bed installed with a wurster tube. Liquid was pumped with a peristaltic pump.
(39) The second layer was added by the above methods, to provide compositions according to the invention as set out in the Tables below.
EXAMPLES
(40) The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.
(41) Testing Compositions of the Invention
(42) Analytical Methods
(43) Adsorption Capacity
(44) The development and testing of formulations was based on model chemicals. The choice of model chemical adsorbants should reflect different types of chemical structure and preferably they should be relevant to the human digestional tract. The model adsorbants for this work were:
Phenazone: Phenazone is a water soluble (51.9 g/L) analgesic which is used to determine the adsorption capacity of activated carbon as described in Ph.Eur (2005:0313). Phenazone has a molar mass of 188.2 g/mol, pka of 1.5 and a Log P of 0.38. It is therefore a polar chemical which is not ionized in the stomach. Phenazone is not normally found in the GI tract but was used as it is used in the pharmacopeia method for adsorption.
(45) Indole: Indole is an aromatic heterocyclic organic compound which is a precursor for many pharmaceuticals. Indole can be produced by bacteria as a degradation product of the amino acid tryptophan. It occurs naturally in human feces at levels of approximately 100 mg/I and has an intense fecal odor. Indole has a molar mass of 116.14 g/mol, solubility in water is 3.56 mg/mL and the pKa is reported as 16.22. Indole is therefore a more lipid soluble compound compared to Phenazone (Log P=2.14), and not ionized in the GI tract.
(46) Butyric acid: Butyric acid is a short chain fatty acid found in milk, butter and cheese, and as a product of anaerobic fermentation for instance in the colon. The content of fatty acids is generally low in the GI as they normally are rapidly absorbed. However some salts of fatty acids such as calcium salts are known to be excreated in larger amounts. Butyric acid has a molecular weight of 88.11 g/mol, is miscible with water and has pKa of 4.82. At neutral pH it is therefore dissociated making it very soluble.
(47) Cholic acid: Cholic acid is a bile acid, a white crystalline substance slightly soluble in water (175 mg/L). Cholic acid is one of two major bile acids produced by the liver where it is synthesized from cholesterol. Of the two major bile acids, cholate derivatives represent approximately eighty percent of all bile acids. It has a molecular weight of 408.57 g/mol and a pKa of 4.98 which means that it will be inonized at neutral pH. In healthy humans approximately 500 mg is excreted daily in the faeces.
(48) Release Testing
(49) The following setup was used to test the different film coated systems using one or more of the above model chemicals.
(50) The testing of experiments were conducted in in a USP Paddle dissolution apparatus at 37° C. Minimum 500 ml of liquid was required to secure proper stirring so this volume was fixed. At the same time the pH was controlled to either 6.8 for colonic conditions by adding a phosphate buffer system at an isotonic level or by using 0.1 N HCl for simulating gastric conditions.
(51) For Phenazone it was found important to fix the relation between the three parameters being amount of Phenazone, amount of activated carbon and concentration of Phenazone. When using 500 ml of release liquid it was necessary to use 6 g of activated carbon for each test to compare with pharmacopeia test. At specified intervals samples were drawn, diluted and tested at 238 nm in a spectrophotometer.
(52) Also when measuring Butyric acid it was important to fix the relation between amount of Butyric acid, amount of activated carbon and concentration of Butyric acid. As for Phenazone, when using 500 ml of release liquid it was also necessary to use 6 g of activated carbon for each test. Two different concentrations of Butyric acid in the release liquid were used: 0.88 g/L or 10 g/L. Butyric acid was quantified at 220 nm.
(53) Indole could not be dissolved to the same high concentration and therefore 100 mg/L was used. 1 g of activated carbon in 500 ml liquid was used for testing to improve the separation power of the test comparing the use of 6 g activated carbon. Indole was quantified at 215 nm.
(54) Cholic acid was not found to be a strong UV absorbent and even at the highest possible concentration (400 mg/L) it was not possible to measure Cholic acid samples directly on the UV spectrophotometer. The samples were therefore measured by HPLC with UV detection at 220 nm (mobile phase: 15% phosphoric acid 0.05M in water/85% Methanol; Column: Kromasil C18; Column temperature: 30° C.; <injection volume: 100 μL). Again 6 g of activated carbon was used for 500 ml of the test solution.
(55) Loss on Drying
(56) Loss of Drying was determined by measuring the evaporation when stored in an oven at 130° C. until constant weight, typically over night. The value was expressed as percentage evaporated from the original mass.
C RESULTS AND DISCUSSION
(57) Production of Compositions of the Invention
(58) Compositions according to the invention were made according to the following Tables, in 300 g batches (i.e. 300 g activated carbon):
(59) TABLE-US-00001 Batch Core First layer Second layer RD1202-19-C2 Activated carbon 90% ethylcellulose, Aquoat HG Sanded/deburred 10% HPMC Weight increase Weight increase (thickness) 8% (thickness) 4% RD1202-22-C2 Activated carbon 90% ethylcellulose, Aquoat HG Sanded/deburred 10% HPMC Weight increase Weight increase (thickness) 8% (thickness) 6% RD1202-23-C2 Activated carbon 90% ethylcellulose, Aquoat HG Raw (not sanded) 10% HPMC Weight increase Weight increase (thickness) 8% (thickness) 4%
(60) RD1202-19-C2 and RD1202-22-C2 are compositions of the invention and were based on sanded/deburred activated carbon produced by the method described above. The purpose of the sanding process was to round the corner of the activated carbon crystals to allow for the layers/films to cover the corners. Non-sanded activated carbon has very sharp and apex corners which would be considered difficult to cover uniformly during film coating. RD1202-23-C2 used raw and un-sanded activated carbon. The sanded activated carbon for all batches was fractionated by particle size and only the fraction 0.6 mm to 1.2 mm was used. However, it was subsequently decided that the to fraction 0.6 mm to 1.0 mm is preferred.
(61) The first layer for the examples in the Table was 90% ethylycellulose, 10% HPMC, and was applied in ethanol/water by the film coating process described above. The film coating processes all performed well in the STREA fluid-bed without the need for adding plastizicer. Inlet air temperature setpoint for the ethanol:water films was 33° C. Batches were removed after 4% (RD1202-19-C2, RD1202-23-C2) or 6% (RD1202-19-C2) theoretical weight increase.
(62) The second enteric layer was applied to the first layer, also by methods described above. The enteric polymer was Hypromellose-Acetate-Succinate (HPMC-AS; Aqoat HG) dissolving at pH 6.5. Aqoat HG was designed for organic coating (ethanol/water mixture) and can be applied without the addition of plasticizers or lubricants. As the composition was already film coated using organic coatings, organic coating was used. The second layer film was formulated as a 6% solution in ethanol/water 80:20 and applied until 8% weight increase.
(63) More information is given in the following Table:
(64) TABLE-US-00002 Inner Film Batch no RD1202-19 RD1202-22 RD1202-23 — Ethylcellulose (Ethocel 90% 90% 90% — 7) Hypromellose (HPMC; 10% 10% 10% — Pharmacoat 603) Activated charcoal Sainted Sanded Raw Sanded % increase in weight 4% 6% 4% 0% Ethanol 96% 75% 75% 75% — Purified Water 25% 25% 25% — Enteric Film Batch no RD1202-19- RD1202-22- RD 1202-23- RD1202-24 C2 C2 C2 Hypromellose-AS (Aqoat 100% 100% 100% 100% HG) % increase in weight 8% 8% 8% 8% Ethanol 96% 80% 80% 80% 80% Purified Water 20% 20% 20% 20%
(65) Samples from the Tables above were tested in the release systems described hereinbefore in both acidic conditions and at pH 6.8. Activated carbon was used as a control, as was RD1202-24 which included the sanded activated carbon covered with only the Aqoat enteric layer. Results are presented in the following tables and figures. Note that all samples (but not the controls) are enteric coated on top of the first layer.
(66) Data from Phenazone adsorption tests are given in
(67) In both conditions, uncoated activated carbon adsorbs more than 42% within 5 hours and thereby meets the limit in Ph.Eur.
(68) Samples with only an enteric coating and the batch with non-sanded activated carbon were found to adsorb 5-10% of the Phenazone present within 1 hour in 0.1 M HCl and from that time point not to adsorb further. The adsorption capacity of the activated carbon in compositions of the invention RD1202-19-C2 and RD1202-22-C2 was not released (
(69) When tested in pH 6.8 the control with the enteric coat only [no ethylcellulose HPMC layer (RD1202-24)] was quickly dissolved and was not found to reduce the adsorption capacity of the activated carbon.
(70) The compositions of the invention [RD1202-19-C2, RD1202-22-C2, RD1202-23-C2] all reduce the release rate of adsorption capacity in phosphate buffer pH 6.8 compared to batch RD1202-24 (see
(71) Release of adsorption capacity was also found to be influenced by film thickness: the 6% weight increase samples released adsorption capacity a little more slowly than the 4% weight increase samples. The sanded samples did not release 100% of the capacity within 24 hours when tested with Phenazone (about 62% for the 4% samples and 44% for the 6% samples), indicating constant adsorption over a long time (e.g. on a timescale indicative of the time it would take to pass through the gut).
(72) The above results indicate that the compositions of the invention are suitable for use to release the adsorptive capacity of active carbon in the colon following oral administration. As can be seen, the activated carbon is protected at stomach pH (
(73) Data from Indole adsorption tests are given in
(74) As the amount of Indole was limited by the solubility of Indole, all added Indole was adsorped within 3 hours in both acid and neutral conditions as if no coating was present (
(75) Changing the pH to 6.8 the enteric coat (RD1202-24) was quickly dissolved and did not reduce the capacity of the activated carbon. Comparing the products of the invention with HPMC containing inner films, the samples containing sanded activated carbon, RD1202-19-C2 and RD1202-22-C2, reduce the release of the adsorptive capacity at pH 6.8, compared to batch RD1202-24; whereas the non-sanded batch release the adsorptive capacity as if no inner coating was present. The two repetitions of the sanded samples from the same test date demonstrated good reproducibility in the test for both formulations, which both released at the same rate in acid.
(76) Thus, the release of adsorptive capacity was again found to be quicker for the non-sanded batch (RD1202-23-C2) compared to the sanded batch (RD1202-19-C2) indicating problems with thinner coating on the apexes of the non-sanded material.
(77) Release rate was again found to be influenced by film thickness as the 6% weight increase samples released a little slower than the 4% weight increase samples.
(78) All tested samples released 100% of the adsorption capacity within 24 hours.
(79) The above results indicate that the compositions of the invention are are suitable for use to release the adsorptive capacity of active carbon in the colon following oral administration. As can be seen, the activated carbon is protected at stomach pH (
(80) Data from butyric acid adsorption tests are given in
(81) In acid conditions the HPMC containing films let the activated carbon adsorb 10-15% of the Butyric acid in two hours, which corresponded to 50% of the capacity (
(82) Changing the pH to 6.8 (
(83) In general, release of adsorption capacity was faster in acid conditions compared to neutral conditions which was surprising because the products were enteric coated and were supposed to hold tight in acid condition. However, it must be concluded that the dissociated Butyric acid molecule penetrates the films better than the ionic form at neutral pH. Comparing the products of the invention with HPMC containing inner films, all of them again reduced the release of adsorption capacity at pH 6.8 compared to batch RD1202-24. Again two of the samples were tested twice, and for one of them good reproducibility in the test was demonstrated. Some variation was found for the other sample.
(84) The release rate was again found to be quicker for the non-sanded batch (RD1202-23-C2) compared to the sanded batch (RD1202-19-C2) indicating problems with thinner coating on the apexes of the non-sanded material.
(85) Also, the release rate was again found to be influenced by film thickness as the 6% weight increase samples released a little slower than the 4% weight increase samples.
(86) The above results indicate that the compositions of the invention are are suitable for use to release the adsorptive capacity of active carbon in the colon following oral administration. As can be seen, for compositions of the invention, the adsorption capacity is slowly released at pH values in the lower intestine and colon (
(87) Data from Cholic acid adsorption tests are given in
(88) In acid conditions only a small part of the capacity was released in two hours (˜7%) and there is almost no difference between the samples.
(89) Changing the pH to 6.8 reduced the adsorption rate on the uncoated activated carbon but not the capacity. The enteric film (batch RD1202-24) was dissolved with time and the capacity released, but it took several hours.
(90) Comparing with the test of samples without enteric coating (not shown) data, were found very similar; and the enteric coat was not found to reduce or delay the adsorption. Only for the 6% film coated sample (RD1202-22-C2) a small delay in release of adsorptive capacity was observed, differentiating this sample form the 4% film coated sample (RD1202-19-C2).
(91) The above results indicate that the compositions of the invention are suitable for use to release the adsorptive capacity of active carbon in the colon following oral administration. As can be seen, the adsorption capacity is slowly released at pH values in the lower intestine and colon (
CONCLUSION
(92) The above results indicate that compositions of the invention would provide prolonged adsorption of various components by activated carbon at pH values found in the colon, following removal of the enteric layer. Further, the compositions of the invention are protected at stomach pH by the enteric layer so will not adsorb of nutrients etc. higher up the GI tract. This is indicative that compositions of the invention will provide effective adsorption by activated carbon (e.g. to treat fistula or other medical condition) in vivo, without the problems of the known oral formulations. It further indicates that compositions of the invention may retain some adsorptive capacity (that is have some residual adsorptive power) all the way through the G I tract and into the rectum and anus. The retention of adsorptive capacity of activated carbon throughout the lower intestine and colon is important because the exact location of the fistula may not be known and/or because it may be difficult to target the exact site of the fistula. Other medical conditions may be more effectively treated using the formulations of the invention, which may effectively and steadily release the adsorptive capacity of activated carbon throughout the lower intestine, colon etc.
(93) The results also indicate that the performance of the compositions of the invention (e.g. where the adsorptive capacity is released, how long adsorptive capacity is maintained etc.) may be varied by adjusting the compositions, thicknesses etc of the first and second layers. Variations of this nature, which are within the scope of the invention, would be readily understood by the skilled person.
(94) The compositions described above (e.g. RD1202-19-C2 and RD1202-22-C2) are suitable for oral administration e.g. as a powder, granules or suspension to treat gastrointestinal fistula (e.g. fistula of the small intestine, fistula of the large intestine, anorectal fistula). In another example the coated particles (granules) may be formulated as a tablet or in a capsule, or as granules (e.g. in a container such as a sachet) for the patient to swallow (e.g. with water).
Example A—Adsorption of Indole and Indole Related Compounds
(95) Indole is an aromatic heterocyclic organic compound. Indole can be produced by bacteria as a degradation product of the amino acid tryptophan, and this takes place mainly in the colon. Indole therefore occurs naturally in human feces, and is present at levels of approximately 100 mg/I. Indole has an intense fecal odor.
(96) A male human subject took two doses (each of 3 to 4 g) of the following formulation A, a composition according to the invention, per day for 5 days.
(97) TABLE-US-00003 Batch Core First layer Second layer Formulation A Activated carbon 90% ethylcellulose, Aquoat HG Sanded/deburred 10% HPMC Weight increase Weight increase (thickness) 8% (thickness) 4%
(98) The formulation was exactly as described for batch RD1202-19-C2 above.
(99) It was found that the smell of the patient's stool was greatly reduced or even completely removed following administration of the formulation of the invention. This is indicative of removal of indole and indole related compounds from the stool. As indicated above, indole is produced mainly in the colon. The results of this test indicate that the activated carbon had removed (adsorbed) the indole (and related compounds) from the stool, which is indicative that in vivo the formulation of the invention retained adsorptive capacity at least until the colon.
Example
(100) Oral Formulation
(101) Activated carbon particles made from coconut shells are milled down to granules of particle size 0.2 mm to 2.0 mm). These individual particles (granules) are each coated with an inner coating (insoluble semipermeable membrane) comprising a mixture of Eudragit RS 30 D and Eudragit RL 30 D, which is applied by methods well known in the art (e.g. the methods of U.S. Pat. No. 6,632,454 B2). The individual coated activated carbon particles (granules) are then each coated with an outer enteric coating comprising Eudragit FS 30 D, again by methods well known in the art (e.g. the methods of U.S. Pat. No. 6,632,454 B2), provide an oral formulation.
(102) The oral formulation is suitable for oral administration e.g. as a powder or suspension to treat gastrointestinal fistula (e.g. fistula of the small intestine, fistula of the large intestine, anorectal fistula). In another example the coated particles (granules) may be formulated as a tablet or in a capsule.
APPENDIX I—THE DETAILED SETTINGS FOR THE DIGITAL IMAGE ANALYSIS SOFTWARE (MEDIA CYBERNETICS IMAGE PRO-PLUS VERSION 6.1.0.346)
(103) TABLE-US-00004 Sub Corners1( ) '<c>J Dim m As Integer Dim num As Integer Dim fil As String * 255 ret = IpDocGet(GETNUMDOC, 0, num) For m = 0 To num-1 ret = IpAppSelectDoc(m) ret = IpBlbShow(1) ret = IpSegSetRange(1, 0, 70) ret = IpSegPreview(CURRENT_C_T) ret = IpBibSetRange(0, 70) ret = IpBlbEnableMeas(BLBM_AREA,1) ret = IpBlbSetFilterRange(BLBM_AREA, 75, 10000000) ret = IpSegShow(0) ret = IpBlbCount( ) ret = IpBlbUpdate(0) ret = IpDcSet(DC_AUTO, 0) ret = IpDcUpdate(DC_FETCH) Next End Sub Sub Corners2( ) Dim fil As String * 255 Dim m As Integer Dim num As Integer Dim mask1 As Integer Dim mask2 As Integer Dim mask3 As Integer ret = IpDocGet(GETNUMDOC, 0, num) For m = 0 To num-1 ret = IpAppSelectDoc(m) ret = IpDocGetStr(INF_FILENAME, DOCSEL_ACTIVE, fil) ret = IpBlbShow(1) ret = IpBlbSetAttr(BLOB__AUTORANGE, 0) ret = IpSegSetRange(l, 0, 70) ret = IpSegPreview(CURRENT_C_T) ret = IpBlbSetRange(0, 70) ret = IpBlbEnableMeas(BLBM_AREA,1) ret = IpBlbSetFilterRange(BLBM_AREA, 75, 1000000) ret = IpSegShow(O) ret = IpBlbCount( ) ret = IpBlbUpdate(0) ret = IpBlbCreateMask( ) ret = IpDocGet(GETACTDOC, 0, mask1) ret = IpAppSelectDoc(m) ret = IpFltClose(MORPHO_2x2SQUARE, 6) ret = IpBlbCount( ) ret = IpBlbUpdate(0) ret = IpBIbCreateMask( ) ret = IpDocGet(GETACTDOC, 0, mask2) ret = IpOpImageLogic(mask1, OPL_XOR, 1) ret = IpDocGet(GETACTDOC, 0, mask3) ret = IpFltOpen(MORPHO_2x2SQUARE, 1) fil = Replace$(fil,″.bmp″, ″ corners.bmp″) ret = IpWsSaveAs(fil, ″bmp″) ret = IpBlbSetAttr(BLOB_AUTORANGE, 1) ret = IpBlbSetAttr(BLOB_BRIGHTOBJ, 1) ret = IpBibEnableMeas(BLBM_AREA,1) ret = IpBlbSetFilterRange(BLBM_AREA, 2,250) ret = IpBlbCount( ) ret = IpBlbUpdate(0) ret = IpDcSet(DC_AUTO, 0) ret = IpDcUpdate(DC_FETCH) ret = IpDocClose( ) ret = IpAppSelectDoc(mask1) ret = IpDocClose( ) ret = IpAppSelectDoc(mask2) ret = IpDocClose( ) ret = IpAppSelectDoc(m) ret = IpDocClose( ) ret = IpAnShow(0) ret = IpCMMShow(CMM_W_CONVERT,0) ret = IpBlbShow(0) ret = IpFltShow(0) ret = IpOpShow(0) Next End Sub
Numbered Statements
(104) There have been disclosed hereinbefore the compositions, uses and methods defined by the following numbered paragraphs:
(105) 1. A composition comprising: (a) a core comprising activated carbon; (b) a first layer around the core, the first layer comprising an insoluble semipermeable material; and (c) a second layer around the first layer which dissolves at a predetermined pH.
(106) 2. A composition according to paragraph 1 wherein the core is activated carbon.
(107) 3. A composition according to paragraph 1 or 2 wherein the first layer allows gradual diffusion of molecules through the semipermeable membrane towards the core into contact with the activated carbon.
(108) 4. A composition according to paragraph 1, 2 or 3 wherein the first layer comprises a mixture of copolymers composed of 85 to 98% by weight free-radical polymerized C.sub.1- to C.sub.4-alkyl esters of acrylic or methacrylic acid and 15 to 2% by weight (methy) acrylate monomers with a quaternary ammonium group in the alkyl radical.
(109) 5. A composition according to any preceding paragraph wherein the first layer comprises a copolymer comprising 65% by weight methyl methacrylate, 30% by weight ethyl acrylate and 5% by weight 2-trimethylammoniummethyl methacrylate chloride.
(110) 6. A composition according to paragraph 1, 2 or 3 wherein the first layer comprises a mixture of copolymers composed of 85 to less than 93% by weight free-radical polymerized C.sub.1- to C.sub.4-alkyl esters of acrylic or methacrylic acid and 15 to more than 7% by weight 2-trimethylammoniummethyl methacrylate chloride.
(111) 7. A composition according to any of paragraphs 1, 2 or 6 wherein the first layer comprises a copolymer comprising 60% by weight methyl methacrylate, 30% by weight ethyl acrylate and 10% by weight 2-trimethylammoniummethyl methacrylate chloride.
(112) 8. A composition according to any preceding paragraph wherein the first layer comprises a mixture of a first copolymer comprising 65% by weight methyl methacrylate, 30% by weight ethyl acrylate and 5% by weight 2-trimethylammoniummethyl methacrylate chloride and a second copolymer comprising 60% by weight methyl methacrylate, 30% by weight ethyl acrylate and 10% by weight 2-trimethylammoniummethyl methacrylate chloride.
(113) 9. A composition according to any preceding paragraph wherein the second layer comprises a material which dissolves at pH 5 to pH 7.
(114) 10. A composition according to any preceding paragraph wherein the second layer is an enteric layer comprising a material which remains substantially intact at pH 1 to 4.9, but which breaks down rapidly at pH 5 to 7.
(115) 11. A composition according to any preceding paragraph wherein the second layer is a pH sensitive polymer.
(116) 12. A composition according to any preceding paragraph wherein the second layer comprises a copolymer composed of 80 to 95% by weight free-radical polymerized C.sub.1- to C.sub.4-alkyl esters of acrylic or methacrylic acid and 5 to 25% by weight (meth)acrylate monomers with an anionic group in the alkyl radical.
(117) 13. A composition according to any preceding paragraph wherein the second layer comprises a (meth)acrylate copolymer comprising 10 to 30% by weight methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weight methacrylic acid.
(118) 14. A composition according to any preceding paragraph wherein the activated carbon is of particle size 0.05 to 2.1 mm.
(119) 15. A composition according to any preceding paragraph wherein the activated carbon is the sole active pharmaceutical ingredient.
(120) 16. A composition according to any preceding paragraph for use in the treatment of fistula, or for use in the manufacture of a medicament for the treatment of fistula.
(121) 17. A method of treatment of fistula, comprising a step of administering (e.g. orally) to a patient in need thereof a composition comprising: (a) a core comprising (e.g. which is) activated carbon; (b) a first layer around the core, the first layer comprising an insoluble semipermeable material; and (c) a second layer around the first layer which dissolves at a predetermined pH.
Other Embodiments
(122) It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.