Delivery of drugs to the lower gi tract

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DESCRIPTION

Administration of drugs to the lower gastrointestinal tract.

Technique field

This invention relates to pharmaceutical compositions for oral administration, to preferentially deliver drugs to the lower gastrointestinal (GI) tract, particularly the colon.

Background

At present, there are no good orally deliverable drug compositions which are aimed at treating various diseases of the colon, such as inflammatory diseases of the colon or those requiring treatment with drugs that are better absorbed through from the colon than through the stomach or upper GI tract. Similarly, there are no orally deliverable drug compositions available for peptides that release peptides in a colon environment, in which the peptides are not degraded to the same extent as they are in the acidic environment of the GI tract. superior, particularly in the stomach.

It is also known that peptides and proteins are large molecules that are labile and polar in an acid medium, which causes them to be poorly absorbed in the upper gastrointestinal tract. These molecules are degraded by brush border and luminal peptidases and generally have very short half-lives. As a result, they have an excessively low and variable bioavailability. Certain researchers have concluded that these molecules can be absorbed regionally in the colon. See, for example, Moore, et al., Inst. J. Pharm 34:35 (1986), commenting on HGH and Yoshikawa, et al., J. Pharmacobiodyn. 8: 291 (1985), commenting on interferon. There is also evidence that there is much lower peptidase activity in the colon, relative to the upper gastrointestinal tract (Woodley, Proc. Int. Syn. Control. Rel. Bioact. Mat. 18: 337 (1991).

Diseases of the colon include such conditions as Crohn's disease, colitis (particularly ulcerative colitis), irritable bowel syndrome, and the like. These diseases include a spectrum of inflammatory bowel disorders with clinical overlap, epidemiological and pathological findings, but without a defined etiology. Both Crohn's disease (CD) and ulcerative colitis (UC) are characterized by chronic inflammation at various points in the GI tract, usually the colon (that is, the part of the intestine that runs from the cecum to the rectum. treating these diseases it is difficult to target drugs that are specifically anti-inflammatory in nature and that act topically at a point of interest. For example, DC seems to affect mainly the terminal ileum and the cecum, while UC seems to have no incidence in the second round of the colon and affect the splenic flexure.

One of the families of compounds used in the treatment of this family of diseases are glucocorticoids. They are believed to be useful as a consequence of the fact that glucocorticoids have the ability to prevent or suppress the development of the manifestations of this inflammation. The belief is that if drugs can be delivered to the inflamed area, the inflammation will recede and the body will ultimately be able to recover. Unfortunately, there are certain side effects that glucoroticoids show if they are administered in a generalized way and these side effects can be quite significant when treating any state of the disease. Another problem with these side effects is that there is no way to deliver the drugs directly to the damaged part of the colon. Most of the formulations that are currently available disintegrate as soon as they pass through the upper tract and, consequently, steroids are absorbed in the body in a generalized way and the subject being treated will experience some of undesirable adverse effects.

General approaches to delivering drugs to the lower GI tract (for example, the colon) include: 1) enteric coating designed to release the drug in the more alkaline environment of the gastrointestinal tract, 2) bioerodible coatings and matrices, 3) prodrugs, 4) temporary release systems, and 5) release systems based on enteric polymeric material that release the drug after transit through the small intestine and into the large intestine. A general discussion of these approaches and others can be found in PCT application WO 91/16881, by Sintov and Rubinstein.

It is known that certain hydrocolloids have a chemical structure that is subject to attack by enzymes that are present in the colon and that cause the structure of hydrocolloids to degrade and decompose. Thus, it has been considered that if a composition could be prepared in such a way that it was composed of a drug useful for the treatment of a colon ailment, which could pass through the upper GI tract without releasing the drug, but preferentially releasing it in the colon, the problem could be solved. Various attempts have been made to use a composition based on galactomannan (such as guar gum), to prepare compositions that are orally administrable but do not release the drug in the upper GI tract but instead do so through from the tract to the colon. None of these attempts has been fully successful and some are more complex than might be desired. An article by Rubinstein and Gilko-Kabir describes a guar gum modified by borax for the purposes of delivery in the colon. However, this

The procedure requires that the guar gum be chemically modified using borax (which is toxic at certain concentrations) in various concentrations, to achieve the desired results. Other attempts have been made using glassy amylose to prepare compositions. These were also minimally successful. Still another approach requires that a galactomannan (locust bean gum) be mixed with an acrylate resin and coated onto a core containing a drug (see US Patent 5,422,121).

It is also known that hydrocolloids that are obtainable from higher plants, such as guar gum, are used to increase gastric residence time and provide sustained release of a drug that has the same bioavailability as the drug formulation. A wide variety of hydrocolloid gums obtained from higher plants could be used to achieve these ends. The type of drug that could be used in the composition of the invention generally included categories of non-peptidic drugs that show a preferential absorption window in the upper GI tract and / or that are generally capable of sustained release. These drugs are generally present in high concentrations in the compositions.

It has now been discovered that drugs with high therapeutic activity (ie, drugs requiring less than about 10% by weight of an orally deliverable composition) can be delivered to the lower GI tract, particularly the colon. By carefully controlling the amount of a hydrocolloid obtainable from upper plants, such as guar gum, a composition for the aforementioned drugs is prepared, which is particularly useful for the treatment of ailments of the lower intestinal tract, in particular of chronic inflammatory diseases of the colon (and other colon disorders, such as irritable bowel syndrome, constipation, diarrhea, etc.) and for the supply of compounds (namely, peptides) to the colon for greater absorption). Families of compounds for which this is particularly valuable include glucocorticoids, local anesthetics, anticholinergics, 5-ASA, stimulant laxatives, peptides, certain antibodies, and certain vaccines. While the amount of hydrocolloid is a factor to consider in preparing the compositions of this invention, other important factors include the particle size of the hydrocolloid, the amount and type of other ingredients, the design of the tablet, and other factors described in This document.

The patent FR 2143059 (see also the patent GB 1318169) (Merck Patent GmbH), belongs to dosage forms based on galactomannans (molded, tablets), which are based on the hydration of the surface of the molded, so that the active material has to diffuse through this gelatin-type hydrate coating and, as a result, there is a delayed release of the active material from this molding (see page 1, lines 37-60; page 3, GB lines 86-94). Nowhere is it described or suggested that galactomannans (GMs) would be useful for delivery to the lower GI tract (eg, colon), as opposed to general delayed delivery, to the stomach and intestines. This document specifically describes that the principle of the delayed release of the active material from a mold containing GM is based on the hydration of the colloid in the presence of water or gastric or intestinal juice and that the release of the active material does not depend on the pH and it is largely dependent on the enzymatic conditions of the digestive juices (see page 3, GB lines 86-98).

GB 1327938 (Sucrest Corp.) pertains to compression vehicles used to facilitate tabletting by compression. Nowhere is there a mention of controlled or delayed release. On the contrary, this document shows that compression vehicles have good fluidity, good stability under normal ambient conditions and do not generate any adverse effect on the disintegration time of the tablet (see page 1, lines 49-54).

WO 96/16638 (Cibus Pharmaceutical, Inc) pertains to pharmaceutical compositions suitable for oral delivery in unit dose form, which show sustained release throughout the gastrointestinal tract (see page 3, lines 30-32).

WO 96/16639 (Cibus Pharmaceutical, Inc) pertains to pharmaceutical compositions containing an NSAID, which show reduced gastric irritation when administered to a subject orally. The composition disperses in the stomach and upper GI tract rapidly, to ensure the release of the NSAID and, at the same time, provide protection to the mucosa (see page 3, line 29 to page 4, line 10).

Objectives of the invention

It is an object of the present invention to provide a unit dose composition comprising a drug useful for the treatment of lower gastrointestinal disorders, in particular colon disorders, which is administered orally and delivers the largest amount of drug, for example, to the colon of a human subject in need.

Another object of the invention is to provide an orally administered unit dose composition comprising: (a) a drug useful for the treatment of disorders of the lower gastrointestinal tract, such as colon disorders, or (b) a drug that degrades in the upper GI tract, the said composition passing through the upper GI tract without releasing significant amounts of the drug, to a human subject being treated and releasing the majority of the drug in the lower GI tract, for example the colon.

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Another objective of the invention is to provide a unit dose composition comprising a drug that is useful for the treatment of disorders of the lower gastrointestinal tract, in particular for the treatment of colon disorders, which is administered orally and minimizes generalized effects to a human subject being treated.

Another object of the invention is to provide an orally administered unit dose composition that delivers the largest amount of the drug for the topical treatment of colon disorders, so that the drug is released for topical treatment, by time that the generalized effects of said drug are minimized.

It is another object of this invention to provide an orally administered unit dose composition which generally releases drugs, such as drugs, by absorption throughout the lower GI tract or colon.

Another objective of this invention is to provide a method for the treatment of a human subject through oral administration of a unit dose composition that achieves the above objectives of this invention.

Still another object of this invention is to provide a process for the preparation of a unit dose tablet composition suitable for oral administration which achieves the above objectives of this invention.

Other objectives of this invention will become apparent to a person skilled in the art upon reading the following specification and claims.

Summary of the invention

The present invention is related to the use of a powder mixture for the preparation of a medicament administered orally in tablet form, for the treatment of a disorder of the lower GI tract of a human subject, in which said mixture comprises :

- between 0.01% by weight and 10.0% by weight of said drug;

- between 40% by weight and 98% by weight of a hydrocolloid gum obtainable from higher plants; Y

- between 2.0% by weight and 50% by weight of a pharmaceutically acceptable excipient,

- in which said mixture is free of any enteric polymeric material and excipients that give rise to the formation of gases.

Description of specific realizations

Described herein is a powder mixture useful for the preparation of a tablet for orally delivering a therapeutically effective amount of a drug to the lower GI tract, particularly the colon, without significant release of the drug to the upper GI tract after administration. of the tablet, comprising the aforementioned composition:

- between approximately 0.01% by weight and approximately 10.0% by weight of said drug;

- between about 40% by weight and about 98% by weight of a hydrocolloid gum obtainable from higher plants; Y

- between about 2.0% by weight and about 50% by weight of a pharmaceutically acceptable excipient, wherein said mixture is free of any enteric polymeric material and excipients that give rise to gas formation.

Also described herein is a pharmaceutical tablet having an internal composition optionally coated by a pharmaceutically acceptable coating (preferably an enteric coating), said tablet being designed for oral delivery of a therapeutically effective amount in the lower GI tract. , particularly in the colon, without significant release of the drug in the upper GI tract after oral administration of the tablet, said tablet composition comprising:

- between about 0.01% by weight and about 10.0% by weight of a drug that is useful for the treatment of a disorder of the lower GI tract,

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- between about 40% by weight and 98% by weight of a hydrocolloid gum obtainable from higher plants;

- between about 2% by weight and about 50% by weight of a pharmaceutically acceptable excipient; Y

- no enteric polymeric material or gas-forming excipients.

Also described herein is a method for treating a disorder of the lower GI tract, particularly the colon, in a human subject, said method comprising orally administration to a subject in need of a tablet described above.

Also described herein is a method for preferentially delivering a drug in the lower GI tract, particularly in the colon, wherein said drug is susceptible to enzymatic degradation in the upper GI tract, said method comprising oral administration to a human subject in need of a compromise described above.

Also described herein is a process for the preparation of a composition in the form of a tablet suitable for oral administration to a human subject, in which the tablet composition preferentially delivers a therapeutically effective amount of said drug in the lower GI tract. , particularly in the colon, without significant release of the drug from the upper GI tract, the aforementioned procedure comprising:

(a) mixing between about 0.5% by weight and about 10.0% by weight of said drug with between about 40% by weight and about 98% by weight of a hydrocolloid gum from higher plants and between about 2% by weight and about 50% by weight of a pharmaceutically acceptable excipient, to form a uniform mixture (b) form a tablet; and (c) optionally coating the tablet.

The compositions of this invention are based on the observation that, by carefully controlling the percentage of a hydrocolloid obtainable from a higher plant, at a very high level in an orally administered dosage form and combining it with a suitable excipient and a particular family of drugs at low concentrations (i.e., less than about 10% by weight), A composition can be obtained which traverses the lower GI tract without releasing any significant amount of drug, but when it reaches the lower GI tract, for example the colon, the drug is preferentially released due, at least in part, to the action from the enzymatic environment in the lower GI tract, which attacks the hydrocolloid to release the drug. The compositions and methods of this invention are of the delayed release type (as compared to sustained or extended release) and are particularly useful for the delivery of glucocorticoids to the colon, as are other drugs (eg, peptides) that they could be inactivated (eg enzymatically degraded) if released in the upper gastrointestinal tract. Thus, for the purposes of this application, a delayed-release composition allows the release of most of the active ingredient in the lower GI tract, particularly in the colon, without releasing any significant amount of drug in the upper GI tract as that the composition traverses the entire GI tract. This composition differs from a sustained release composition that releases the active ingredient on a regular (ie constant) basis through the GI. Generally, a relatively high percentage of the hydrocolloid gum obtainable from higher plants is present, namely, at least between 50 and 98% (depending, in part, on the purity of the commercially available gum), with a lower amount of a pharmaceutically acceptable excipient that provides lubrication, binding and / or disintegration capacity for the composition, as well as providing minimal hardness for the tablet, so that it can be prepared pharmaceutically. This amount is less than about 50% but not more than about 2% by weight of the composition. The remainder is a drug that is present at a level that is therapeutically effective and is dependent on the relative activity of the drug and its interaction with the composition. The drug may be useful for treating lower GI tract conditions, particularly the colon (eg, inflammatory diseases) or other conditions requiring drugs that are better absorbed from the colon.

The compositions

One aspect of this invention is an orally administrable tablet having an internal composition optionally surrounded by a pharmaceutically acceptable coating. The tablet preferentially delivers a therapeutically effective amount of a drug suitable for the lower GI tract, eg, the colon, without significant release of the drug in the upper GI tract after oral administration of the composition to a subject in need thereof. The internal composition of the tablet comprises between about 0.01% by weight and about 10.0% by weight of a suitable drug (eg, for the treatment of inflammatory colon disorders); between about 50% by weight and about 98% by weight of a hydrocolloid gum obtainable from higher plants; and between about 2% by weight and about

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50% by weight of a pharmaceutically acceptable excipient, such as a binder. Other optional materials may be present which will help establish the desired characteristics of the pharmaceutical composition. These include materials that can enhance absorption of the drug in the lower GI tract, protect the drug from degradation, prevent dissolution, and the like. Optionally surrounding the internal composition of the tablet may be a coating which is preferably an internal polymeric material.

The solid tablet of this invention is designed to take advantage of (1) the protective characteristics of hydrocolloid obtainable from higher plants, in the upper GI tract and (2) the disintegrating characteristics of hydrocolloid in the lower GI tract. Thus, the internal composition of the tablet can consist of one of several possible designs: (a) it can be a matrix of a therapeutically effective amount of an active ingredient dispersed uniformly, in combination with a high percentage of the hydrocolloid and a slightly less than other excipients; (b) it can have a core, in which the active ingredient is concentrated, surrounded by a layer of material that is free of the active ingredient and has a high percentage of the hydrocolloid and a generally lower amount of other ingredients; (c) it can have a concentration gradient of the active ingredient, such that there is a higher amount in the core of the tablet with lower amounts in the multiple layers surrounding the core and with little or no active ingredient in the outer layer . Whether the adopted design of the tablet of the type (a), (b) or (c) indicated above, the specificity for regional delivery towards the lower GI treatment, especially towards the colon, is enhanced by coating the tablet with a material that suitable as an enteric coating.

The hydrocolloid used in the present invention is a hydrocolloid that is obtainable from higher plants. By "higher plant", in the present invention we mean an organism of the plant kingdom that lacks the power of locomotion, has cellulose alveoli walls, grows through the synthesis of inorganic substances and includes vascular plants (or tracheophytes) of the division Spennatophyta, in particular those of the class Angiospermae. Gums can be extracted from roots, legumes, legume pods, berries, bark, etc. Thus, higher plants do not include algae, flagella, bacteria, mud molds, fungi, mosses, ferns, horsetails, and the like. Representative hydrocolloid gums, which can be obtained from higher plants, include guar gum, gum tragacanth, karaya gum (also identified as kadaya gum), and locust bean gum (also identified as carob ). Other rubbers will be readily apparent to one of ordinary skill in the art. See, for example, "The Chemistry of Plant Gums and Mucilages," by Smith and Montgomey, from the ACS Monograph Series, no. 141, 1959, Reinhold Publishing Company and the 18^toedition of the Merck Index. Guar gum is a particularly useful and convenient hydrocolloid, since it is a neutral polysaccharide that comprises long galactomannan molecules with some side chain linkages. The hydrocolloids used in the present invention generally have a high viscosity shown after hydration, are normally linear (at least about 50% by weight of the compound is made up of the hydrocarbon skeleton) and will usually have a high molecular weight, usually about 3 x 10⁵ daltons, more usually greater than about 1 x 10⁶ daltons. Hydrocolloid generally occurs as a powdered hydrocolloid gum and exhibits a viscosity at 1% concentration in neutral aqueous solution of at least 75 centipoise per second (cps) at 25 ° C, after 24 hours, using a Brookfield viscometer. (LDF model), with a number 3 spindle at 90 rpm, preferably at least 1 x 10³ cps and most preferably at least about 2 x 10³ cps. Generally, the viscosity increases with increasing molecular weight. See Meer Corporation, "An Introduction to Polyhydrocolloids." The most useful hydrocolloid gums are those in which the hydrocolloid is a polysaccharide hydrocolloid that has been chemically designated as a galactomannan. Galactomannans are polysaccharides that comprise long chains of units (1 ^ 4) - 6-D-mannopyranosyl, to which single units of α-D-galactopyranosyl side chains are attached, through linkages (1 ^ 6) . Galactomannans are found in a wide variety of plants, but differ in molecular size and in the number of D-galactosyl side chains. Galactomannans useful in the present invention are commonly found in legume endosperms. Table 1 shows examples of the legume family, indicating the family and the percentage of endosperm content of the legume seeds.

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TABLE 1

Estimated endosperm content of legume seeds

<td>Family</td><td>% Endosperms</td><td>Family</td><td>% Endosperms</td>

<td>Acacia</td><td> 1-15</td><td>Glottidium</td><td> 2</td>

<td>Suck them</td><td> 2-3</td><td>Glymnocladus</td><td> 15</td>

<td>Baryxylum</td><td> 30</td><td>Indigofera</td><td> 20</td>

<td>Caesalpina</td><td> 8-40</td><td>Lespedeza</td><td> 1-4</td>

<td>Cassia</td><td> 10-60</td><td>Leucaena</td><td> 15</td>

<td>Cercidium</td><td> 20</td><td>Lotus</td><td> 2-4</td>

<td>Ceratonia</td><td> 50</td><td>Lysiloma</td><td> 4</td>

<td>(carob)</td><td></td><td></td><td></td>

<td>Chamaecrista</td><td> 8-15</td><td>Melilotus</td><td> 8-12</td>

<td>Colvillea</td><td> 30</td><td>Mimosa</td><td> 3-30</td>

<td>Crotalaria</td><td> 8-25</td><td>Onomis</td><td> 25</td>

<td>Cyamopsis</td><td> 50</td><td>Parkinsonia</td><td> 25</td>

<td>(guar)</td><td></td><td></td><td></td>

<td>Cytisus</td><td> 15</td><td>Parryella</td><td> 20</td>

<td>Give to</td><td> 20</td><td>Prosopis</td><td> 15</td>

<td>Daubentonia</td><td> 10-15</td><td>Schrankia</td><td> 12</td>

<td>Delonix</td><td> 15</td><td>Sesbania</td><td> 20</td>

<td>Desmanthus</td><td> 15</td><td>Sophora</td><td> 20-25</td>

<td>Desmodium</td><td> 2</td><td>Trifolium</td><td> 3-10</td>

<td>Gleditsia</td><td> 30</td><td>Virgilia</td><td> 20</td>

Table 2 shows the approximate composition of some galactomannans from legume seeds and the percentage of anhydromannose residues versus anhydrogalactose residues. As can be seen in Table 2, the percentage of anhydromannose can vary between approximately 50% and approximately 90% (for example 86%) of the galactomannan composition, with the percentage of anhydrogalactose varying between approximately 10% ( for example 14) and approximately 50%.

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TABLE 2

Approximate composition of some galactomannans from legume seeds

<td>Seed name</td><td>% from Anhydromannose</td><td>% from Anhydrogalac-tose</td>

<td>Caesalpinia spinosa (tara)</td><td> 71</td><td> 26</td>

<td>Caesalpinia cacalaco (huizache)</td><td> 69</td><td> 28</td>

<td>Ceratonia siliqua (carob, bean</td><td> 80-86</td><td> 20-14</td>

<td>carob tree)</td><td></td><td></td>

<td>Cercidium torregyanum (greenwood)</td><td> 73</td><td> 22</td>

<td>Delonix regia (Flamboyan)</td><td> 79</td><td> 19</td>

<td>Cyamopsis tetragonolobus (guar)</td><td> 64</td><td> 36</td>

<td>Gleditsia triacanthos (acacia three</td><td> 71</td><td> 26</td>

<td>thorns)</td><td></td><td></td>

<td>Gymnocladus dioica (coffee grower of</td><td> 71</td><td> 26</td>

<td>Kentucky)</td><td></td><td></td>

<td>Sophora japonica</td><td> 81</td><td> 16</td>

<td>Desmanthus illinoensis (Ayahuasca)</td><td> 70</td><td> 26</td>

<td>Indogofera hirsuta (indigo)</td><td> 72</td><td> 23</td>

<td>Cassia leptocarpa (senna)</td><td> 65</td><td> 21</td>

<td>Crotalaria intermedia (crotalaria)</td><td> 64</td><td> 28</td>

<td>Crotalaria júncea (Crotalaria)</td><td> 60</td><td> 40</td>

<td>Crotalia striata (crotalaria)</td><td> 60</td><td> 40</td>

<td>Trigonella foenum graecum</td><td> 52</td><td> 48</td>

<td>(Fenugreek)</td><td></td><td></td>

<td>Medicago sativa (alfalfa)</td><td> 66</td><td> 33</td>

Preferably, the galactomannan most useful in this invention is obtained from cyamopsis tetragonolobus, commonly identified as guar. It shows a percentage of mannose residues of approximately 64%, with a percentage of galactose residues of approximately 36%. Commercially available guar gum has approximately 66-82% galactomannan polysaccharide, with impurities totaling the remainder of the composition. According to National Formulary (NF) standards, guar gum can contain up to 15% by weight of water, up to 10% by weight of protein, up to 7% by weight of acid-insoluble material, and up to about 1, 5% ash. Guar gum is commercially available from Aquoalin Company, Wilmington, Delaware; Meer Corporation, Cincinnati, Ohio; Stein Hall &amp; Company; and TIC Gums, Inc, Belcamp, Maryland.

Other hydrocolloids will quickly become apparent to those skilled in the art. See, for example, Smith and Montgomery's "The Chemistry of Plant Gums and Mucilages," from the ACS Monograph series, # 141, 1959, Reinhold Publishing Co. and 18^to edition of The Merck Index.

In general, the amount of hydrocolloid to be used is an amount that allows the composition to pass through the upper GI tract without significant disintegration taking place and without significant amounts of drug being released into the upper GI tract, namely to provide a delayed release profile. A significant amount in this case represents more than about 20%, thus, more than about 80% of the drug will be released in the lower GI tract. As a general rule, the amount of hydrocolloid will be greater than approximately

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50%, but less than about 98%. More preferably, the amount will be from about 60% to about 95% by weight of hydrocolloid gum. Depending on individual variability, whether a subject has eaten or fasted, and other factors, it will take 3 to 6 hours for a tablet to pass through the stomach and upper GI tract. During this interval, a small amount of drug (less than 20%, preferably less than 10%) is released from the tablet of the invention. Once the tablet has reached the lower GI tract, particularly the colon, drug release is triggered by enzymatic degradation of galactomannan gum. Once release is triggered, the release rate is relatively fast for certain drugs, for example, between about 80-90% of drug release occurs over a period of between about 2-4 hours or the like, whereas other types of drugs, such as steroids, can be released over a longer period of time, for example, between about 6 and 10 hours.

The invention provides a vehicle for drug delivery preferentially in the lower GI tract, especially the colon. Drugs for which this vehicle will be useful include drugs indicated for the treatment of chronic diseases of the intestine, including inflammatory diseases. These drugs are generally highly active and require no more than about 10% by weight of the total composition. These drugs may include certain glucocorticoids, local anesthetics, stimulant laxatives, peptides (both small and large), antibodies, vaccines, ACE inhibitors, anticholinergics, and other drugs such as diphenoxylate, loperamide, codeine, metronidazole, 5-aminosalicylic acid (5 -ASA), misoprostyl and sulfasalazine. Of these compounds, glucocorticoids (also known as corticosteroids) are particularly valuable, and therefore preferred, particularly for the treatment of inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis. These include hydrocortisone (and pharmaceutically acceptable salts or esters, such as acetate, cypionate, sodium phosphate, sodium succinate, butyrate, valerate, etc.), beclomethasone, becometasone dipropionate, betamethasone (and their pharmaceutically acceptable salts or esters, such such as benzoate, dipropionate, sodium phosphate, acetate, valerate, etc), cortisone, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, flunisolide, Methylprednisone, Methylprednisone Acetate, Methylprednisone Sodium Succinate, Paramethasone Acetate, Prednisolone, Prednisolone Acetate, Prednisolone Sodium Phosphate, Prednisolone Tebutate, Prednisone, Triamcinolone, Triamcinomethyl Acetonide, Triamcinolone Acetonide Diacetonide Triamcinolone Diacetonide Triamcinolone Diacetonide amcinonide, clobetasol propionate, clocortilone pivalate, desonide, deoxymethasone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrisone, mometasone furoate, budesonide, fluticasone, tixicortol pivalate, prednisolone metasulfobenzoate, and the like. Other steroids will be apparent to one of ordinary skill in the art. Their chemical names can be found on page 1451 of Goodman and Gillman's "The Pharmacological Basis of Therapeutics", 8^to edition ("Goodman and Gillman") or the 11th edition of the Merck Index ("Merck"). Among these, dexamethasone, budesonide, and fluticasone are preferred. In general, for glucocorticoids that are relatively insoluble in water, it is preferred that the particle size of the compound used can be reduced to a very small one, particularly micronized. The particle size for the micronized material is generally in the range 1 to 10 microns and can be obtained commercially from compounding suppliers. Alternatively, the compound can be micronixed using procedures available in the art, such as the techniques found in Remington's Chapter 88.

Local anesthetics useful in this invention include certain compounds that are discussed in Chapter 15 of Goodman and Gillman, at pages 311-331. These include procaine, cocaine, lidocaine, tetracaine, mepivacaine, etidocaine, and the like.

Stimulant laxatives useful in this invention include, for example, docusate sodium, senna concentrates [sennosides], bisacodyl, potassium bitartrate, and the like.

Peptides useful in this invention include small peptides having a molecular weight of about 2,000 or less, as well as larger peptides having a molecular weight of more than 2,000 and up to 50,000 or more. Small peptides include LHRH or its derivatives (eg, leuprolide, naferelin, goserelin, deslorelin, historelin, buserelin, and the like and the corresponding acceptable acid addition salts such as acetate, hydrochloride, etc.). Larger peptides useful in the composition of this invention include growth hormone, vasopressin and its analogs, calcitonin, insulin, glucagon, growth hormone releasing hormone (GHRH), relaxin , somatostatin, and cytokines or lymphokines such as tumor necrosis factor, erythropoietin, atrial natriuretic factor, cell growth stimulating factor (GCSF), a, β, and γ interferon, interleukins, granulocyte colony stimulating factor, and the like.

Antibiotics that can be delivered to the colon include IgG antibodies against toxins produced by C. Difficile.

The particle size of the drug used in the preparation of the compositions of this invention can range from about one tenth of a micron to greater than 300 microns. The preparation of microspheres (for example, nanospheres or nanocapsules) of peptides can also provide certain advantages, to help stabilize and manipulate said compounds. For example, polyalkylcyanoacrylate nanocapsules with an average size of 220 nanometers (NM) can be prepared according to the procedure of Al Kouri, et al., Int. J. Pharm. 28: 125432, 1986.

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The percentage of active drug to be included in the composition can vary depending on the activity of the drug in relation to the condition being treated. In general, the composition will contain no more than about 10%, preferably less than 5% of active compound, with a minimum amount of about 0.01% by weight. Preferably, the amount will range from about 1 to about 4% by weight for glucocorticoids. For the highly active LHRH or its derivatives, or for larger peptide molecules, the amount will generally be less than 1%. The amount of drug will depend on its activity, stability, and other factors. For LHRH or its derivatives, such as leuprolide, a significantly greater amount of drug is generally needed than would have been needed for a parenteral injection. For example, a daily dose of leuprolide is 1 mg. Due to the instability of leuprolide, even in the lower GI tract, 10 mg is needed to provide similar bioavailability.

An important aspect of this invention is the weight ratio between the drug in the composition and the hydrocolloid gum. As discussed above, there is significantly more hydrocolloid gum than drug. Generally, the weight ratio of hydrocolloid gum to drug will range from about 9800: 1 to about 4: 1, depending on the potency of the drug and the amount of hydrocolloid gum. For steroid drugs, the ratio will range from about 65: 1 to about 14: 1. For drugs present in the composition at concentrations below 1%, the ratio will be higher, eg, between 1,000: 1 or more and 100: 1 or more.

As a consequence of their size and polarity, peptides such as LHRH derivatives and larger proteins such as interferons and human growth hormones are not completely stable or well absorbed, even in the lower intestinal tract, such as in the colon. To help maintain stability and increase absorption of these compounds, a stabilizer and / or penetration enhancer may optionally be included in the composition of this invention, at a level that enhances the stability and / or rate of absorption in the lower GI tract. Serum albumin (HSA) is a stability enhancer that is particularly valuable for larger molecules. Penetration enhancers (namely, absorption) include compounds such as bile acids (in the form of sodium salt, eg, sodium glycocholate, sodium dehydrocholate, sodium taurocholate), anionic detergents (eg, docusate sodium and sodium lauryl sulfate), non-ionic detergents (medium chain triglycerides, propylene glycol, fatty acid esters of polyoxyethylene sorbitan and the like, salicylates, acyl amino acids, acyl carnitines, lysolectin, and particle-shaped supports. Other enhancers may be apparent to one of ordinary skill in the art. Generally, said enhancers have to be compatible with other components of the composition and should not present adverse toxicological effects, that is, they cannot irreversibly damage the mucosa of the intestine. It is preferred that the enhancer is selected from those that are generally regarded as safe (GRAS) by the US Food and Drug Administration (FDA).

In addition to the materials listed above as penetration enhancers, LHRH compounds and larger compounds may also use certain enzyme inhibitors to further protect peptide molecules from degradation in the lower gastrointestinal tract and in the colon. Although the enzymatic environment in the lower intestinal tract and colon is less pronounced than in the upper intestinal tract, particularly in the stomach, there are still enzymes in the lower intestinal tract that will rapidly degrade peptide molecules. Thus, the addition of enzyme inhibitors in the composition helps to protect the peptide molecules from degradation. Representative enzyme inhibitors include materials such as polyacrylic acid (namely, carboxypolymethylene, identified as CARBOPOL, for example CARBOPOL 934P) and CARBOMER (a cross-linked acrylic acid polymer having a high molecular weight and containing between 56 and 68% carboxylic acid groups), alginic acid (a hydrophilic colloidal carbohydrate extracted from various species of algae, brown marine ones), ethylenediaminetetraacetic acid (EDTA), cationic surfactants (eg, cetylpyridinium chloride), oleic acid, and the like. Other inhibitors may be apparent to one of ordinary skill in the art. Again it is preferable that the enhancer is selected from those that are generally regarded as safe (GRAS) by the US FDA.

In preparing the compositions of this invention, the solubilities and stabilities of the drugs are taken into account. If the composition consists of a matrix tablet that has the drug dispersed evenly throughout the composition and the drug is less soluble in water (for example, a steroid), a lower percentage of hydrocolloid is used, for example, between about 50 and 75%. On the other hand, if the drug is highly soluble in water, a higher percentage of hydrocolloid is used, for example, between about 75 and 95% by weight. If an unstable, water-soluble drug is used (eg, a small peptide or a large protein), a composition of this invention, having an active core redefined from inactive material or having a concentration gradient, may be desirable, such as and as discussed later.

Although practically all drugs have a certain solubility in water, some are more soluble than others. In determining this relative solubility, it is helpful to refer to some descriptive terms for solubility, such as those provided in Remington's Chapter 16. These terms are set out below:

ES 2 231 815 T3

<td colspan="2">Descriptive terms for solubility</td>

<td>Descriptive terms</td><td>Parts of solvent to 1 part of solute</td>

<td>Very soluble .......................... Easily soluble ..................... Soluble .............................. Poorly soluble .................... Slightly soluble ................... Very slightly soluble ................ Practically insoluble or insoluble .......</td><td>............ Less than 1 ............ Between 1 and 30 ............ Between 10 and 30 ............ Between 30 and 100 ............ Between 100 and 1000 ............ Between 1000 and 10000 ............ More than 10,000</td>

For the purposes of providing guidelines to enable one skilled in the art to know how to prepare and use the compositions of this invention, drugs that are generally poorly soluble to highly soluble should be considered as "more soluble in water" or "relatively soluble. in water ”, whereas the drugs that would be considered between slightly soluble in water and insoluble must be considered as "less soluble in water" or "relatively insoluble in water". These are not to be considered rigid and highly restrictive rules, but simply guidance for a person with normal experience.

One or more additional excipients may be included in the composition of this invention, with a view to (1) imparting satisfactory processing and compression characteristics to the composition (e.g., adjusting fluidity, cohesion, and other characteristics of the composition) and ( 2) provide additional desirable physical characteristics to tablets (eg, color, stability, hardness, and disintegration). Most of the excipients contribute to the delayed release of the drug from the composition, with a view to achieving regional delivery to the lower GI tract. As used herein, the term "excipient" can include all excipients present in the dosage form, including all components other than the drug entity and hydrocolloid gum derived from higher plants. A variety of excipient substances may be present in any dosage form, and these may include multiple substances that have a similar pharmaceutical function (eg, lubricants, binders, diluents) or a similar structure (eg, a mixture of monosaccharides. ). Preferably, the fewer excipients present the better. The aforementioned excipients are present in an amount sufficient to provide the composition with the desired delayed release / regional delivery characteristics, hardness rate, and workability characteristics and will preferably be present at a level between about 2% and about 100%. 50% by weight, preferably between about 2% and about 40% by weight, and more preferably, between about 2% and about 10% by weight. The excipients used can be chosen to achieve the desired object of the invention, keeping in mind the activity of the drug being used, as well as its physical and chemical characteristics, such as its solubility in water and the possible interactions with the excipients that are being used. they have to be used. For example, with drugs that are more soluble in water, a lower percentage by weight of excipients will generally be used, namely, less than about 20% or between about 2% and about 15% by weight, preferably not more. of about 10% by weight, while for drugs that are less soluble in water, a higher percentage can be used, for example, between about 20% and up to about 40% by weight. These levels can be adjusted to achieve the desired hardness and porosity for the final tablet composition, with a view to achieving the delayed release profile.

Some of the excipients used in the composition of this invention can play different roles, namely, an excipient can act as a binder to contribute to the regional delivery / delayed release profile, while increasing the hardness characteristics of the composition (for a better handling). Excipients that are useful for adjusting the hardness and porosity of the tablet compositions of this invention include cellulose derivatives, polyoxyethylene polymers of molecular weight (MW) from about 600,000 to about 8,000,000, colloidal silica, other natural hydrocolloid type materials (eg pectin), non-gas forming mineral salts, such as alkaline earth phosphates and sulfates (eg Ca +², Mg +²) and polyvinylpyrrolidone (PVP). Representative polyoxyethylene polymers are available under the Polyox® trademark from Union Carbide Corporation. Examples include a Polyox polymer with a MW of about 600,000 and a viscosity, at 5% aqueous concentration, of between about 4500 and 8800 cps; a Polyox polymer with an approximate MW of 4 x 10⁶, with a viscosity, at a 1% aqueous concentration, of between approximately 1500 and 4500 cps; and a Polyox polymer of MW 8 x 10⁶, with a viscosity, at 1% aqueous concentration, of between approximately 10-15 x 10³ cps. Colloidal silica is available from WR Grace and Co. under the trademark Syloid.^® 244FP. A useful mineral salt is the Emcompress brand^® calcium phosphate. PVP (also identified as Povidone) is available under the brand names Plasdone^® or Polyplasdone^® (a cross-linked PVP) from ISP Technologies, Wayne, NJ. Representative cellulosic derivatives include hydroxypropylmethyl cellulose [HPMC], microcrystalline cellulose [MC], hydroxypropyl cellulose [HPC], and ethyl cellulose [EC]. Spectrum Chemical Mfg. Co., Gardena, CA is a representative commercial source for EC; Dow Chemical Co., Midland, Mich. (under the Methocel® trademark) a source

ES 2 231 815 T3 commercial for HPMC; Hercules Chemical Co., Wilmington, Del. (Under the trademark KLUCEL^®), for HPC; and the FMC Corporation, Philadelphia, PA (under the trademark Avicel^®) for MC. Of these, HPMC is preferred, with Methocel premium, Methocel E3 and Methocel 50LV being particularly useful.

To adjust the hydration rate of the solid hydration formula, the combination of excipients such as cellulosic derivatives, polyoxyethylene, colloidal silica and the like can be used, as well as to allow a lower level of the powdered hydrocolloid gum to be used, obtainable from higher plants, resulting, as a consequence, in less bulky tablets. In addition, combinations of the hydrocolloid gum with excipients can provide greater degrees of control over drug delivery, but care must be taken in preparing combinations to avoid adverse effects. Adverse effects may include incomplete disintegration in the colon, emptying of doses, and the like. The amount and choice of the remaining excipients will also be affected by the remaining ingredients present in the formulation, so that the effects of the other hydrocolloids can be modulated through the other components.

To achieve the desired delayed release profile, an important consideration is the combination of a small amount of an active agent with a particle size distribution of the hydrocolloid that is used in the composition of the invention. In general, the particle size distribution of the hydrocolloid, particularly guar gum, will be sufficient to provide a delayed release profile and will be of an average particle size of less than about 150 µ. Preferably, the size will be less than the mean diameter size of about 125 microns (μ) in diameter (standard sieve size 120), namely, about 50% by weight of the particle mass will be below 125 μ and about 50% by weight of the particle mass will be over 125 µ in diameter. In general, the band will range from about 10 µ to about 125 µ, preferably 20 to 125 µ. Smaller particles can be used, but they are more difficult to handle. Preferably, at least about 90% of the mass of particles in the composition will have a particle size of less than 125 µ. Hydrocolloid supply sources from higher plants are readily available, but it has been found that, if the particle size is appropriately reduced, guar gum identified as SUPERCOL® G3, with a particle size between about 75 and about 300 microns (where a little less than about 50% of the particle mass is smaller than about 150 µ). The SUPERCOL brand is particularly valuable^® U, with a particle size between about 20 and about 100 microns. SUPERCOL brand guar gum is available from the Aqualon Division, Hercules Corp. Wilmington, Delaware. Other sources of supply include Henkel, a division of the Emery Group, Cincinnati, OH, the Meer Corporation, or TIC Gums, Inc. Under certain conditions, guar gum TICO-LV is also useful (with a molecular weight of approximately 300,000, a particle size distribution such that more than 99% of the particles are below 150μ in diameter, and a 1% viscosity in water of about 75-100 cps), from TIC Gums, Inc. Smaller particle sizes can be obtained by grinding either SUPERSOL G3 or SUPERSOL U and sieving to obtain particles of the desired size. Generally, the smaller the particle size within the band, the better the cohesiveness and the less drug is released in the upper GI tract. This is surprising in view of the existence of certain articles suggesting that a smaller particle size results in faster disintegration. (See, for example, an article entitled "Effect of Particle Size Distribution of the Disintegrating Efficiency of Guar Gum", by Sakr and Elsabbagh, Pharm. Ind. 38, NR8, (1976), pp. 732-734). In contrast, the larger the particle size (or coarser), the less cohesive the composition becomes and the faster the drug is released. The type and amount of other excipients will also be affected by the characteristics of the compositions of this invention. A more detailed comment on the particular percentages is provided below. Without wishing to be bound by any particular theory, it is believed that the smaller particle size allows for faster hydration of the surface of the dosage form, which further retards the penetration of water into the interior of the dosage form. This, in combination with the small amount of drug, brilliantly provides a better delayed release profile.

The particle size distribution can be determined through standard sieving procedures, namely, by passing the guar particles through sieves having known mesh sizes (and known openings) and collecting the retained or unretained fractions. . The same procedures are useful for obtaining guar particles of desired sizes, for use in the preparation of the composition of the invention.

From the aforementioned discussion, it is seen that one aspect of this invention resides in a particle mass of a solid dosage form from which a solid tablet containing a certain amount of drug in unit dose form. As a general rule, this unit dose will consist of an amount that can be swallowed by a human subject and that can range from about 100 milligrams to about 1500 mg, preferably not more than 1200 mg and, particularly, not more than about 800 mg. In the case of children, the size of the tablet can be significantly smaller than that of adults and for elderly patients who have difficulty swallowing, the total amount may be less than what would be considered a normal amount for adults. It should be understood that the tablets of this invention can be designed as single tablets having a unit dose amount or various smaller tablets, for example between 2 and 5, can be combined into a capsule for oral administration, such as it is discussed from now on.

ES 2 231 815 T3

To be certain that the tablet composition of the present invention exhibits the desired delayed release characteristics, it is important that certain materials are not present in the composition.

For example, previously, salts that form carbon dioxide in the gut, such as carbonates and bicarbonates, have been shown to be useful for dispersing guar gum dosage forms. Such mineral salts, such as alkaline earth bicarbonates (eg, sodium bicarbonate) may be excluded from the compositions of this invention because it has been found that they tend to be difficult to process and store and tend to cause the compositions to disintegrate too much quickly. Consequently, gas-forming mineral salts in gastric juices are not present in the composition, namely, the composition is free of these materials.

The internal composition that makes up the tablet matrix is ​​also free of any type of enteric polymeric material. An enteric polymeric material is one that is used to apply a film coating to a pharmaceutical product (for example, a tablet), to protect the product from the effects of drug release, or to prevent the release of the drug into the environment. gastric. Said coating material is identified as an "enteric coating". Enteric coatings are those that remain intact in the stomach, but dissolve and release the contents once they reach the small intestine. The purpose of an enteric coating is to delay the release of drugs that are inactivated by stomach contents or that can cause nausea or bleeding by irritating the gastric mucosa.

The action of enteric coatings arises as a consequence of a difference in the composition of the respective gastric and intestinal environments in relation to pH and enzymatic properties. While repeated attempts have been made to produce coatings that are subject to intestinal enzymatic breakdown, this approach is not popular since enzymatic breakdown of the film is quite slow. Thus, the most commonly used enteric coatings are those that remain undissociated in the low pH environment of the stomach, but ionize rapidly when the pH is increased to about 4 or 5. The most effective enteric polymers are polyacids that have a pK between 3 and 5. Although the pharmaceutical literature contains references to many potentially suitable polymers (eg, lacquers), only three or four remain in use.

The most widely used polymer is cellulose acetate phthalate (CAP), which is able to function effectively as an enteric coating. However, a pH greater than 6 is usually required for solubility and, consequently, a delay in drug release may occur. It is also permeable to moisture and gastric fluid, compared to most enteric polymers. Thus, it is susceptible to hydrolytic decomposition when phthalic and acetic acids are separated, resulting in a modification in polymeric properties and, consequently, in enteric properties. Another useful polymer is polyvinyl acetate phthalate (PVAP), which is less permeable to moisture and gastric fluid, more stable to hydrolysis, and capable of ionizing at a lower pH, resulting in release early active ingredient in the duodenum. A more recently available polymer is hydroxypropylmethylcellulose phthalate. It presents a stability similar to that of PVAP and dissociates in the same pH band. A final example of commonly used polymers are those that are based on methacrylic acid-methacrylic acid ester copolymers, with ionizable acid groups. They are represented by polymers identified with the Eudragit brand, available from Rohm Pharma. They have been reported to have the disadvantage of having a delayed breakdown, even at relatively high pH.

Several systems have been introduced that allow each of these enteric polymers to be applied as an aqueous dispersion, thereby facilitating the use of aqueous film coating technology for enteric coating of pharmaceutical dosage forms. As a general rule, the enteric coating will not represent more than about 0.5% by weight to about 10% by weight of the tablet having the composition of this invention.

As a general rule, the composition of this invention having the hydrocolloid obtainable from higher plants will be free of any material that could be considered an enteric coating material, for example, the internal composition will not have any enteric coating type material mixed with the hydrocolloid material, whether the composition is a tablet having a uniform matrix, an active nucleus, or a concentration gradient. This is because the enteric coating material would completely dissolve in the upper GI tract, allowing channeling and drug release before reaching the lower GI tract or colon. However, the tablets, once formed in two, can be coated with an enteric coating material, as indicated below.

As briefly discussed above, the compositions of this invention can have one or more designs:

(a) A tablet that is a uniform matrix (the "uniform matrix tablet").

(b) A tablet having an active core surrounded by an inactive layer (the "active core tablet" or "reservoir tablet").

ES 2 231 815 T3 (c) A tablet having a concentration gradient (the "concentration gradient tablet").

Procedures for the preparation of each of these aspects of the invention, in conjunction with other compositional factors, will be discussed below. Whatever design is used, the overall composition of the ingredients will be within the approximate numerical limits set forth herein. Preparation procedure

Pharmaceutical compression or molding techniques, preferably the former, can be used in preparing the tablet compositions of this invention due to their adaptability to large-scale production processes. Using techniques known in the state of the art, the tablets of the invention can adopt any type of shape that is suitable, such as a discoid, round, oval, oblong, cylindrical, triangular, hexagonal and the like. The tablets can be coated or uncoated. If coated, they may be sugar-coated (to hide objectionable flavors or odors and to provide protection against oxidation), film-coated (a thin film of a water-soluble material for similar purposes), or enteric-coated (to resist dissolving in gastric fluid, but allowing the disintegration of the lining in the small intestine, as discussed above). Depending on whether the tablet is a uniform matrix tablet, an active core tablet, or a concentration gradient tablet, the manufacturing process will vary slightly.

In order to ensure the hardness of the tablets and the uniformity of weight, content and other characteristics, it is preferable to prepare tablets having the composition of this invention by using a pre-granulation technique. Generally, granulation techniques can include the wet granulation process, the fluid bed granulation process, the dry granulation process, or direct compression. Each of these procedures has certain disadvantages and advantages, which are well known in the state of the art. For example, wet granulation has a greater likelihood that the granulation will satisfy all physical requirements for successful tablet compression. However, its main disadvantages lie in the number of separate steps involved and the time and labor required to carry out the procedure, particularly on a large scale. The fluid bed granulation process utilizes the concept of spraying a granulating solution onto suspended particles, which are then rapidly dried in suspended air. However, when the contents of the composition may be particularly sensitive to moisture, or unable to withstand high temperatures during drying, it may be preferable to use the dry granulation process and, in this process, the continuous tapping technique is used to form the granules. In each of these processes, granules of the desired size are formed from the composition using the active ingredient and the hydrocolloid obtainable from higher plants having the desired particle size. Once the granules having the desired flow characteristics have been obtained, a lubricant is added and thoroughly mixed with the resulting granules to form a composition from which tablets are obtained by direct compression. The lubricant is necessary to ensure that the tablets are released from the compressor, tableting machine or extrusion die. Remington's Chapter 89 provides comments on granulation techniques, as well as direct compression and other aspects of tabletting.

Once the tablets have been formed in a suitable manner, they can be coated through any of the necessary coating techniques, as discussed in Remington's Chapter 90. For example, tablets can be sugar coated according to the procedure discussed there, or film coated or, preferably, enteric coated. Enteric coating is preferred in the tablets of this invention to minimize the release of any type of drug in the upper GI tract and ensure release in the lower GI tract, particularly the colon. The sections of Remington's Chapters 88 and 90 are relevant.

In general, a uniform matrix tablet is prepared using standard tableting techniques known to one of ordinary skill in the art, such as those discussed in "Remington's Pharmaceutical Sciences" 18th edition, Chapter 89, pp. 1633-1658 (Mach Publishing Company, 1990). In the simplest procedure, the ingredients (with the exception of the lubricant), are simply mixed together to provide a uniform mixture having the active ingredient fully dispersed, the lubricant is then added and mixing is performed and the tablets are compressed. on a suitable tablet machine.

Another aspect of this invention is the powder mixture that is useful for the preparation of the internal composition of the tablet of this invention. The powder mix will vary slightly depending on how it is used in the preparation of the tablet. If the design of the tablet is a uniform matrix or a concentration gradient, the composition will generally fall within the following parameters:

- approximately between 0.01% by weight and approximately 10.0% by weight of drug;

- approximately between 40% by weight and approximately 98% by weight of hydrocolloid gum; Y

- approximately between 2% by weight and approximately 50% by weight of the pharmaceutically acceptable excipient.

ES 2 231 815 T3

Naturally, the powder mixture is free of any type of gas-forming salt or enteric polymeric material. If, on the one hand, the design of the tablet is that of an active core surrounded by a mixture of the gum and excipients, the composition will have between approximately 40% and approximately 98% by weight of hydrocolloid gum, the rest corresponding to excipient. The active core can be prepared in any way that is suitable so that the active ingredient is dispersed in a suitable support and is then subjected to compression to form said core. Suitable carriers include materials such as sugars (viz. Lactose) and other pharmaceutically acceptable carriers that do not interact with the drug.

If it is desired to obtain an active core surrounded by a hydrocolloid / excipient mixture, a compression coating process is preferably used to form the tablet.

As a general rule, the active core design is particularly useful for peptides such as LHRH and its derivatives. In this case, the peptide, its stabilizers (such as alginic acid, CARBOPOL934P or EDTA) and the absorption enhancers are mixed with a suitable substance, for example lactose. The active core is then surrounded by the hydrocolloid gum and other excipients using compression coating or other coating techniques generally known to those skilled in the art.

Compression coating consists of compressing a dry coating around a tablet core, which involves the use of a modified tablet machine. The finished product is a tablet within a tablet. The main advantage of compression coating is that it eliminates the use of any solvent, whether aqueous or organic. Another advantage resides in the fact that it provides a process for the preparation of active cores of water-sensitive active agents. In compression coating, the internal tablet usually undergoes a slight compression as each of the components is formulated, with the final compression being the most important. This technique can also be used to obtain a tablet that has a concentration gradient in which a higher percentage of the active ingredient is in the core and a lower percentage of the active ingredient is in the outer layer.

The process includes first preparing a core tablet by mixing the active ingredient in combination with appropriate excipients, such as lactose, Avicel PH-200, and a lubricant such as magnesium stearate and compressing the resulting mixture in a press to manufacture. Tablets, for example, using flat faced punches (diameter between 2 and 10 mm) in a Stokes B2 rotary tablet press. The weight and hardness of the tablets are adjusted to the required needs. The resulting tablet is then compression coated using the appropriate sized concave punch, eg, between about 5mm and about 15mm. Approximately one third of the inactive coating is then placed on the extrusion die, the active core is placed on top of the one to be coated, the remaining two-thirds of the coating material is added along and over the part. upper part of the active nucleus. The tablet is then compressed.

Another aspect of this invention is constituted by a process for the preparation of a composition, in the form of a tablet suitable for oral administration, to a human subject. As discussed above, the tablet composition preferentially delivers a therapeutically effective amount of a drug to the lower GI tract, particularly the colon, without significant release of the drug to the upper GI tract. One aspect of the process of this invention comprises mixing between about 0.01% by weight and about 10.0% by weight of a drug that is useful in the treatment of colon or lower GI tract disorders. or (b) from a drug that is better absorbed from the lower GI tract or from the colon than from the upper GI tract, with between about 40% by weight and about 98% by weight of a hydrocolloid gum obtainable from a higher plant; and between about 2% by weight and about 50% by weight of a pharmaceutically acceptable excipient, to form a uniform mixture. The uniform mixture is then tabletted and optionally coated with a suitable coating material. In the process, it is preferred that the mean particle size of the hydrocolloid gum is about 150 microns or less. It is also preferred that prior to tabletting, the mixture is granulated via either a dry granulation process or a wet granulation process. These two dry granulation or wet granulation processes are mentioned in Remington's chapter 88. In general, in the wet granulation process, the hydrocolloid of the suitable particle size is mixed with a solution of an excipient and the active ingredient. This procedure is particularly suitable for corticosteroids such as dexamethasone or budesonide. Solvents for the excipient active ingredient can be of any type but ethanol has been found to be particularly suitable. The active ingredient and excipient solution is added to the hydrocolloid very slowly over a period of time to form a uniform mixture of wet granules, which are passed through a screen of suitable mesh size and dried. As a general rule, the size of the screen used is a fairly large mesh, such as a number 18 size, to provide large wet particles.

After the large wet particles have dried, the dry granules are passed through a sieve with a mesh size resulting in smaller sizes. These resulting granules are then mixed with a suitable lubricant, such as magnesium stearate, and with another excipient, preferably HPMC, and a

ES 2 231 815 T3, once thoroughly mixed, are subjected to compression to form tablets. By varying the amount of solvent, the time to equilibrate with the ambient humidity and the size of the grain, etc., tablets can be designed so that the release occurs at different rates and in different parts of the colon. As a general rule, it is preferable that the solvent used to form the granules initially is a non-solvent for guar gum. For this reason ethanol is preferred.

As a general rule, when a larger amount of solvent is used relative to guar gum, the size of the resulting granules usually increases. In general, the hardness of tablets prepared through the wet granulation process is improved by decreasing the particle sizes of the granules. This is considered to be due to the fact that more particle bonds are formed with the smaller particles, as a consequence of the larger total surface area. Hardness can also be improved by the presence of moisture due to the plasticizing effect of water on the polymer.

A non-solvent such as ethanol in the process can then result in softer tablets. Softer tablets would lead to faster disintegration in the upper GI tract. In general, for the treatment of ascending colon ulcer, compressing tablets with smaller granules is preferred over using less ethanol in the wet granulation process. On the other hand, for diseases localized to the descending colon, more of a non-solvent, such as ethanol, would generally be used in the wet granulation procedure and compression would be applied to the tablets with larger granules, to retard the onset of action of rapid drug release.

Administration

In general, the tablets of this invention will be administered orally to a mammalian subject in need thereof, using a level of drug that is sufficient to provide the desired physiological effect. The mammalian subject can be a domestic animal or a pet, but is preferably a human subject. The level of drug that is required to provide the desired physiological result is readily determined by one of ordinary skill in the art, referring to standard texts such as Goodman and Gillman and the Physician's Desk Reference. In the case of steroids administered orally, the amount administered using a composition of this invention will be significantly lower than that used for a standard formulation, because the drug will be preferentially released in the lower GI tract (for example, in the colon ) and will not be released, in significant amounts, into the upper GI tract. On the other hand, in the case of large or small peptides or for protein molecules, a greater quantity will be needed than is necessary for a composition of this invention that had to be administered on a daily basis, through the intramuscular, subcutaneous route, prolonged or similar. For example, the daily amount delivered would be up to about ten times the amount delivered through other known, non-oral means of delivery.

The following examples are provided to better explain the invention and to provide specific examples regarding how to prepare and use the invention. However, they should be considered as an example only and not as limiting when interpreting the field of protection of the claims. Examples

Example 1

This example shows certain compositions of this invention in which the active ingredient is dexamethasone. The example provides guidance to show whether a composition meets certain objectives of the invention.

A series of guar-based tablets were prepared to achieve different profiles for dexamethasone release in the gastrointestinal tract. The formulations were formulated based on preliminary studies regarding the effects of excipients on the hardness of the tablets and the integrity in the dissolution medium. Four dosage forms were chosen and tested in a three-part in vitro dissolution system. Three of these dosage forms represent compositions of this invention and preferentially direct drug delivery to the colon. The fourth, fast-release dosage form was found to release almost the entire drug loading integrity into the gastric fluid of the stomach, for comparison purposes.

Tablet ingredients

Avicel PH200 (microcrystalline cellulose) was purchased from FMC Corporation. Methocel E50LV and E3 (HPMC) were obtained from Dow Corporation. Micronized dexamethasone, USP grade, was purchased from Upjhon Company. Encompress (dicalcium phosphate) was purchased from Mendell. Magnesium stearate was obtained from Whittaker, Clark &amp; ​​Daniels. Coarse grade (G3) and fine grade (U) guar gum were purchased from Aqualon. Mixing the powder and preparing the tablet

For the initial small batches (viz. 20 grams), the powders were generally simply mixed by spatulation prior to tabletting. When larger batches were required (at

ES 2 231 815 T3 viz. 150 grams), the powdered ingredients (with the exception of magnesium stearate) were first sieved (# 40 mesh) and mixed with the spatulation procedure, then with a V-mixer for space of 10 minutes. Magnesium stearate was added, as a tabletting lubricant, and the final powder blend was mixed for another 10 minute period.

All of the powders (with the exception of dexamethasone) for the dosage forms used in this Example 1 were passed through a 40 mesh size sieve. The dexamethasone was then pre-mixed with approximately one sixth of the total guar gum powder by spatulation, to obtain uniformity of drug content.

The tablets were manually compressed with a rotary tablet machine [Dual Pressure Press Model, FJ Strokes Machine Company, Philadelphia, PA, with punches (Cups: concave, shallow, monoradial, 13/32 ”diameter). )]. The tablets weighed approximately 300-350 mg each and contained approximately 9-13 mg of drug, to provide a final concentration of 3% by weight. The formulations of the four selected formulations were:

A. 60.5% G3 grade guar, 36% HPMC E3, 3% Dex, 0.5% magnesium stearate.

B. 60.5% G3 grade guar, 36% HPMC E50LV, 3% Dex, 0.5% magnesium stearate.

C. 24.5% G3 grade guar, 72% Avicel, 3% Dex, 0.5% magnesium stearate.

D. 60.5% Grade U Guar, 36% Emcompress, 3% Dex, 0.5% Magnesium Stearate.

Formulations A, B and D are representative of the invention.

Measurement of physical characteristics

1. Tablet hardness

The tablet hardness test was carried out using a Vanderkamp VK 200 Tablet Hardness Tester (Vankel Industries, Inc., Edison, NH). A tablet was placed on the strain gauge. As the movable jaw pressed against the tablet, the force corresponding to the moment the initial fracture was detected was recorded.

two. Loss of material

The tablets were weighed before (a) and after (b) dissolution. Subsequently, they were dried at 60 ° C. They were weighed again (c). To determine the amount of material loss, the following calculations were made:

1. The weight of the tablets was measured before (a) and after (b) dissolution.

two. The tablets were dried and weighed (c).

3. The amount of material loss = ac; the amount of water absorbed, in percentage by weight = (ba) / c * 100%.

3. Friability

The friability test for tablets was carried out using a Tablet Friabilater (VanKel Industries, Inc. Edison, NH). Approximately 4 g (w₀) of dedusted tablets were subjected to 100 6-inch free drops on a rotating drum at 25 rpm and then weighed again (w). Friability, f, was calculated using the following formula:

f = 100 * (1-wo / w)

Values ​​of f between 0.8 and 1.0% were considered as the upper limit of acceptability. Dissolution test

1. Simulated Gastric Fluid (SGF) Preparation

Sodium chloride (7g) and pepsin (11.2g) were co-dissolved in 24.5 ml of hydrochloric acid. Deionized water was added to make a final volume equal to 3,500 ml.

ES 2 231 815 T3

two. Simulated intestinal fluid preparation (SIF)

Monobasic potassium phosphate (23.8 g) was dissolved in 875 ml of water. Sodium hydroxide (665 ml, 0.2N) and 1400 ml of water were then added. Pancreatin (35g) was added and the resulting solution was adjusted with 0.2N sodium hydroxide to a pH of 7.5 ± 0.5. The solution was then diluted with water to a final volume of 3500 ml.

3. Simulated Colon Fluid (SCF) Preparation

The SCF comprised homogenized stool samples from healthy volunteers or colitis patients (homogenized samples in case they were not fluid enough). The preparations were used undiluted.

Four. Dissolution test

The tablets were weighed and placed in 500 ml of simulated gastric fluid (SGF) for a period of 2 hours, with a stirring speed set at 50 rpm (2 USP procedure; paddle). Samples (5 ml) were taken at specified intervals for drug content analysis and replaced with fresh medium. To check for drug release in SIF, the tablets were subsequently transferred using an aluminum plate into beakers containing 500 ml of SIF (method 2 USP, paddle). During the transfer, the fluid was carefully removed by tilting the plate. The tablets were immersed in SIF for a period of 4 hours and stirred at a speed of 50 rpm. During this period, 5 ml samples were collected at specific time points and replaced with fresh medium. To carry out a new dissolution in colon fluids, the tablets were then transferred to 10 g of SCF. The medium was mixed by dipping a piston up and down between 8 and 9 times per minute inside the tube. Samples (0.5 g) were taken, at specified intervals, over a period of 18 hours, without replacement of the colon medium. The temperature was maintained at 37 ° C throughout the experiment.

Quantitative analysis

Calibration was performed by averaged single point internal standard calibration. A standard solution was prepared containing 50 jug / ml of dexamethasone (Dex) and 50 jug / ml of triamcinolone acetonide (TrAce). The standard mixture was injected before and after the 20 sample injections. The internal standard peak areas and the respective standard areas were then averaged in order to be used as a single point calibration factor. Calibration curves were previously generated for both Dex and TrAce. The respective curves were determined to be linear and passed through zero. The standards were therefore considered adequate for single point calibration.

All sample quantities were carefully measured (by mass or volume) and then fortified with 30 µl of a Dex / TrAce mixture at a rate of 1 mg / ml. The boost equals 30 pg of Dex and TrA. Once the samples were prepared (according to the descriptions in the following sections), they were injected onto an HPLC column. The resulting concentrations of Dex and TrAce were calculated from the respective standards as follows:

smp

Cstd (A smp • ^TOstd)

In which:

C_smp = concentration of sample C_std = concentration of the standard Asmp = area of ​​the sample Astd = area of ​​the standard

The original concentration of Dex in the sample was then calculated as follows:

X = [(M * t / T) -d] / Z (2)

In which:

X = Dex concentration

M = measured concentration of Dex from Equation 1

T = measured concentration of TrAce from Equation 2 t = mass (in pg) of reinforced TrAce in the sample

ES 2 231 815 T3 d = mass (in pg) of reinforced Dex in the sample

Z = amount of sample (mg or ml)

The samples were analyzed by means of HPLC, in order to quantify the released dexamethasone. The results were expressed as a percentage of drug released in relation to the amount of intact tablet.

Analytical sample preparation

1. Gastric fluid samples

For the analysis of the samples from the SGF, 0.5 ml of sample was placed in a test tube, to which 30 µl of a Dex / Triamcinolone mixture was added at a rate of 1 mg / ml mixture (TrAce) ( internal standard for calibration). Two ml of 100% ethanol were added followed by 150 µl of 0.2N NaOH solution, to bring the pH to 5.0. The sample was mixed by means of repeated inversion before being injected onto an HPLC column for drug content analysis.

two. Intestinal fluid samples

To carry out the analysis of the samples from SIF, 0.5 ml of sample was transferred to a test tube and 30 µl of a Dex / TrAce mixture was added at a rate of 1mg / ml. Two ml of 100% ethanol were then added and the sample was mixed by means of repeated inversion before injection on the HPLC column to carry out the analysis of the drug content.

3. Colon fluid samples

To carry out the analysis of samples from SCF, between 150 and 500 mg of sample was added to a test tube and the mass was recorded. Thirty µl of a standard mixture of Dex and TrAce (1 mg / ml) was then added together with 2 ml of water and 2 ml of 100% ethanol. The mixture was then sonicated for 5 minutes and coarse solids were removed by centrifugation. The resulting supernatants were transferred to a syringe and filtered through a 0.45 micron filter. Samples were mixed by repeated inversion prior to injection onto the HPLC column for analysis.

Testing for hardness and friability was performed on the four dosage forms examined in drug release studies (prepared by premixing Dex). The results are shown in Table 3.

TABLE 3

<td>Formulation</td><td>Hardness (kp) (n = 7)</td><td>Friability (%) (n = 1)</td>

<td>C.</td><td> 14±1</td><td> 0,04</td>

<td>D.</td><td> 2,2±0,8</td><td> 0,89</td>

<td>TO.</td><td> 4,5±0,6</td><td> 0,28</td>

<td>B.</td><td> 3,6±0,6</td><td> 0,19</td>

Drug release

Results obtained from three-part dissolution check systems are discussed below.

The profile for drug release varied depending on the formulation. A tablet from formulation C demonstrated a "fast" release of the drug with approximately 90% of the Dex originally contained in the tablet being released into the SGF, at the 2 hour time point. This tablet disintegrated rapidly in the presence of SGF. In contrast, the tablet prepared from formulations A, B and D showed very little drug release until placed in the SCF, the drug release profiles for tablets prepared from formulation A showing a Substantial drug release in SCF, with most drug release from tablets A, B, and D occurring preferentially in the presence of SCF. The complete disintegration of these tablets took place in the presence of SCF, whereas when immersed in SIF for the same period of time a very weak disintegration was observed.

ES 2 231 815 T3

Based on the results obtained, formulations A, B and D are capable of releasing a small amount, if any, of any type of drug in the stomach and small intestine, while preferentially releasing drug from in a sustained manner once the tablets reach the colon. Although total disintegration of the tablets was observed at 24 hours, no total release of Dex was detected in these experiments. Agitation conditions in the SCF system were relatively mild; A likely explanation for these results lies in the fact that all of the Dex was released from these dosage forms but was not evenly distributed throughout the viscous dissolution medium. The rapid-release tablet first releases drug in the stomach and / or small intestine. This dosage form C provides a relatively rapid entry of the drug into the body, compared to the other three dosage forms. In addition to rapid drug release, C was observed to fully disintegrate in SGF within 1 to 2 hours.

Example 2

This example provides a pharmacoscintigraphic evaluation of the four formulations of Example 1 and shows the preferential release of the active ingredient, dexamethasone, in the colon from the three formulations of this invention. A study was designed to investigate the gastrointestinal transit and disintegration of the four formulations of Example 1 and to evaluate the subsequent absorption of dexamethasone released from the preparations. The study was a double-blind, parallel group design, in which blocks of eight healthy subjects received one of four different formulations. Thirty-two healthy volunteers (18 males, 14 females) received tablets each weighing approximately 333 mg and containing approximately 2.7% dexamethasone (i.e. no more than 9 mg dexamethasone per tablet). , prepared as indicated in Example 1. Each of the subjects received a single radius tablet marked with ¹⁵³Ye.

Clinical supplies

To radioactively label the dosage forms, neutron activation procedures were used. These techniques require the addition of a stable isotope into a formulation; subsequent irradiation at a neutron source converts the isotope to a radionuclide that emits gamma radiation. By utilizing these neutron activation procedures, radiation exposure of workers can be minimized and complicated delivery systems can be easily and efficiently marked. In order to validate this technique, it has to be demonstrated that the irradiation procedure has no effect on the formulation, namely, the preparation has to behave similarly both before and after the irradiation procedure. Dosage forms were irradiated for a period of 6 minutes, at a neutron flux of 10¹²n cm²s¹48 hours before dosing and in vitro checks showed that neither the addition of samarium oxide nor the neutron activation procedure affected the behavior of the dosage forms or the stability of the drug.

Dosage details

Volunteers reported to the trial site on an empty stomach (from midnight). Anterior and lateral anatomical markers containing 0.1 MBq were attached to the skin over the right lobe of the liver.⁹⁹Tc^m. Each of the volunteers was administered a single radioactively labeled dose, at approximately 8:00 am, with 240 ml of water.

Previous scintigraphic images were recorded at frequent intervals over a period of up to 16 hours, using a gamma camera (General Electric Maxicamera) with a 40 cm field of view and equipped with a low energy parallel hole collimator. Images were recorded at intervals of approximately 10 minutes, for a period of up to 12 hours after ingestion of the dose, and then at intervals of approximately 30 minutes until 16 hours after ingestion of the dose. New visits were made to the clinical unit 24 and 36 hours after ingestion of the dose, with a view to allowing new images to be taken. The images had a duration of 50 seconds during the first 9 hours after the application of the dose, but the uptake time was prolonged up to 80 seconds until 16 hours had elapsed after the ingestion of the dose. The images obtained 24 and 36 hours after ingestion of the dose were taken for 120 seconds. The volunteer remained moderately active during the study period and all the images were taken with the subjects positioned in front of the gamma camera. The images were recorded using a Bartec computer system and stored on an optical disk for subsequent analysis.

A light lunch, snack, and dinner were provided at 4, 9, and 14 hours after ingestion of the dose, respectively. Each of the subjects drank 200 ml of water within two hours of ingesting the dose and fluids were allowed ad libitum after lunch. At the completion of study day 1, subjects were instructed to fast until they returned to the clinical unit the following morning. Food was allowed ad libitum only after 24 hours after obtaining the image and the blood sample.

Blood sampling

Venous blood samples (10 ml) were extracted through an intravenous cannula or by venipuncture, according to the following time schedule:

ES 2 231 815 T3 pre-dose), 1.0; 2.0; 4.0; 6.0; 8.0; 10.0; 12.0; 14.0; 16.0; 24.0 and 36.0, hours after ingestion of the dose.

The first 2 ml of blood drawn through the cannula were discarded and the next 10 ml applied to serum separation manovettes. The cannulas were frequently flushed with saline during the course of day 1 of the study. The total amount of blood drawn from each of the volunteers for the study, including the pre and post-medical studies, was 190 ml.

The samples were left at room temperature for approximately 30 minutes until a clot formed. The samples were then subjected to centrifugation at approximately 3,000 rpm (or 1800g) for a period of 7 minutes at 4 ° C. The resulting serum fraction was divided into two aliquots by applying it by pipetting to the pre-labeled polypropylene screw-cap tubes. The samples were flash frozen and then immediately stored at 20 ° C. One of the samples was subsequently shipped on dry ice to a test center trial.

Scintigraphic data analysis

The data obtained from the study were analyzed in line with the pharmaceutical profiles of the standard operating procedure for the quality control of the gamma camera data analysis, to obtain the following parameters:

I. Time to empty the stomach:

II. Transit time through the small intestine; (a) time for complete disintegration of the tablet and (b) anatomical location.

III. Arrival time to the colon; (a) Initial tablet disintegration time and (b) anatomical location

IV. Transit histograms

The recorded time of movement of the tablet from the stomach to the small intestine was taken as the middle term between the recorded times for the two images close to the transition. The times recorded for arrival in the colon and for the initial and complete disintegration of the tablet were determined in the same way. The transit time through the small intestine was calculated by deducting the gastric emptying time from the time in which the initial arrival to the colon took place. The initial disintegration of the tablet was defined as the time taken to detect radioactive marker release signals from the tablet in consecutive images, while the complete release was defined as the time in which all the radioactive label had dispersed within the tract. gastrointestinal and there was no sign of a different "core"

Gastrointestinal transit

The average gastric emptying time (I), the average transit time through the small intestine (II), and the average arrival time to the colon (III), all of them in minutes, are summarized in Table 4. As It can be seen, all of the formulations A, B and D remained intact for long enough to reach the colon.

TABLE 4

Summary formulation of gastrointestinal transit

<td>Formulation</td><td>I</td><td>II</td><td>III</td>

<td>TO</td><td> 56+42</td><td> 258+96</td><td> 313+89</td>

<td>B</td><td> 33+23</td><td> 218+33</td><td> 251+21</td>

<td>C</td><td> (1)</td><td> (1)</td><td> (1)</td>

<td>D</td><td> 52+43</td><td> 243+85</td><td> 295+73</td>

(1) determination of the rapid disintegration avoided Tablet disintegration

Average tablet initial disintegration time in minutes (IV (a)) and anatomical location (IV (b)) and average total tablet disintegration time in minutes (V (a)) and anatomical location (V (b)) are summarized in Table 5.

ES 2 231 815 T3

TABLE 5

Summary of tablet disintegration

<td>Formulation</td><td>IV (a)</td><td>IV (b)</td><td>He)</td><td>V (b)</td>

<td>TO</td><td> 104+60</td><td>UI</td><td> 472±161</td><td>c</td>

<td>B</td><td> 345±138</td><td>c</td><td> 741±194</td><td>c</td>

<td>C</td><td> 10±17</td><td>s</td><td> 125±310</td><td>s</td>

<td>D</td><td> 213±97</td><td>I</td><td> 734±228</td><td>c</td>

S = stomach; c = colon; I = intestine; UI = upper intestine

After the administration of formulations A, B, C and D, the initial disintegration time of the tablet took place, on average, at 104 ± 60 minutes (range 40 to 227 minutes) after dosing; at 345 ± 138 minutes (band 174 to 630 minutes) after dosing; at 10 ± 17 (band 1 to 48 minutes) post-dose and 213 ± 97 minutes (band 138 to 442 minutes) post-dose. The initial disintegration took place in the stomach for each of the subjects who had received Regimen C and also in the upper intestines for the volunteers who had received Regimen A. In seven of the eight subjects who received Regimen D, the tablets they began to disintegrate in the small intestine, while in subject 005, the onset of disintegration was only observed once the tablet had reached the ascending colon. In six of the eight subjects who received Regimen B, initial disintegration of the tablets was also observed after arrival in the colon. However, a small amount of radioactive material was observed to "leak" from each of the four formulations shortly after administration of the preparations. This material was found to initially disperse throughout the gastrointestinal tract, however, it often could not be detected on subsequent images. This material was considered to originate from progressive erosion of the surface of the tablets as a consequence of the continuous peristaltic action of the intestine. Due to this reason, the initial decay was recorded as the midpoint between the two images, after which radioactive marker was observed in consecutive images.

Complete disintegration of the tablet was defined as the time by which all of the radioactive label had dispersed in the gastrointestinal tract and no signs of a distinct "core" remained. Complete disintegration of the tablet took place at an average of 472 ± 161 minutes (band between 305 and 769 minutes, n = 8) from the administration of the dose, at 741 ± 194 minutes (between 399 and 934 minutes, n = 8) from the administration of the dose, at 125 ± 310 minutes (range between 1 and 829 minutes, n = 7) from the administration of the dose and at 734 ± 228 minutes, n = 5) a from the administration of the dose, for Regimens A, B, C and D, respectively. Complete disintegration of the tablet did not occur during the first 16 hours after dosing in three of the eight subjects who received Regimen D and, in the remaining five subjects who received this formulation, disintegration occurred distally. Complete disintegration was observed closer to the colon in those subjects who received Regimes A and B, the disintegration of Formulation B usually taking place more distally than that of Formulation A. The distribution of radioactive labeling within the colon at 24 and 36 hours after dosing was the usual for all four formulations and was in line with previous scintigraphic studies.

Complete disintegration occurred in the stomach in six of the eight subjects who had received the Regimen.

C. However, in subject 032, complete disintegration occurred in the ascending colon and disintegration had to have occurred in the large intestine in subject 017, since the radioactive marker was still evident in the colon after 24 hours from dose administration. The reason for this dichotomy in the results for these two subjects who had received Regimen C is not clear, but it may be that the rate of hydration of the hydrophilic polymers is critical for the formation of a gel layer, which, in turn. Instead, determine the integrity properties of the actual tablet. It is possible that in six of the 8 subjects, the gel layer did not form rapidly, leading to rapid disintegration of the tablet, while in subjects 017 and 032, the hydration of the polymer had occurred rapidly, improving as a result of significantly the integrity of the tablet.

Scintigraphic data suggests that each of the four formulations behaved in a unique way, thereby making the distinction between them possible. Formulation C showed early rapid release in most cases. In three of the eight subjects who received Regimen D, complete disintegration of the tablets occurred during the initial sixteen-hour imaging period. In these cases, the complete release of the material took place during the course of one night and by virtue of the anatomical location of the marker 24 hours after the administration of the dose, it could be concluded that the release took place in some way in the large intestine. The release from Regime A took place in a closer position

ES 2 231 815 T3 to the large intestine, while the release from Regimen B occurred in the distal colon, in five of the eight subjects who received this formulation.

Thus, formulations A, B and D (representative of the compositions of this invention) all show a preferential disintegration in the colon.

Example 3

Following the procedures of Example 1, but substituting with the following compounds, similar compositions were prepared:

A. Budesonide

B. Fluticasone

C. Predisolone

D. Prednisone

E. Hydrocortisone

Once the invention has been fully described, it will be apparent to one skilled in the art that many changes and modifications can be made therein without departing from the spirit of the appended claims. Example 4

This example explains a wet granulation process for the preparation of tablets containing dexamethasone according to the invention.

In this procedure, dexamethasone and PVP were co-dissolved in ethanol. This mixture was added dropwise to guar gum to form wet granules, which were passed through a sieve having a mesh size of 18, and then dried at 60 ° C. The dried granules were passed through sieves with various mesh sizes and mixed with other ingredients such as HPMC and magnesium stearate. The resulting powder granule mixture was compressed into tablets.

In greater detail, 0.174 grams of dexamethasone and 5.2 grams of PVP were co-dissolved in ethanol (Lot A used 50 ml and Lot B used 25 ml of ethanol). The ethanolic mixture was added to 100 grams of guar gum G3 dropwise and mixed, then sieved through 18 mesh, drying at 60 ° C, until the ethanol evaporated. The dry granules were sieved according to the following table

<td colspan="7">The relationship between # mesh and particle diameter, μm</td>

<td>Mesh#</td><td> 30</td><td> 40</td><td> 60</td><td> 120</td><td> 140</td><td> 200</td>

<td>Diameter</td><td> 600</td><td> 425</td><td> 250</td><td> 125</td><td> 106</td><td> 75</td>

The screened granules were mixed with HPMC E3 and magnesium stearate in a V-frame mixer for a period of 10 minutes. This powder mixture was subjected to manual compression, by means of a rotary press, to form tablets (the weight of the tablets was 500 mg and the diameter of the punches 13/32 "with a concave face). The formulation for each of the sub-lots was as follows:

<td>HPMC E3</td><td> 38,9%</td><td>15.56g</td>

<td>Magnesium stearate</td><td> 0,5%</td><td>0.20g</td>

<td>Dexamethasone</td><td> 0,1%</td><td>0.04g</td>

<td>PVP</td><td> 3,0%</td><td>1.20g</td>

<td>Guar G3 G3</td><td> 57,5%</td><td>23.00g</td>

<td>Total</td><td> 100,0%</td><td>40.00g</td>

These tablets are useful in the process of this invention.

ES 2 231 815 T3

Example 5

This example sets forth a process for compression coating a core tablet with a composition comprising a hydrocolloid gum obtainable from higher plants and other pharmaceutical excipients. The described procedure can be adjusted to include an active ingredient in the core tablet.

A core tablet was prepared by mixing 79.5% lactose (Fast-Flo lactose), 20% Avivel PH-200 and 0.5% magnesium stearate in a V-mixer, over a period of 10 minutes. The mixed formulation was compressed using flat face punches (dia. = 7 mm) on a Stokes B2 rotary tablet press. The tablet weight was adjusted to 75 mg / tablet and the hardness was kept between 6 and 7 kP.

For compression coating, 12.7mm diameter concave punches were used. Approximately one third (208 mg) of the total amount of guar gum composition (625 mg) was initially placed in the nozzle. The core tablet was then centrally placed on top of the guar gum layer. Approximately 208 mg of the guar gum composition was then poured across the core tablet, followed by the remaining 208 mg as the top layer of the tablet. The tablet was then compressed and dropped into deionized water for about a 13 hour period, in a glass beaker, without shaking. After 13 hours a gel layer formed around the tablet, which was swollen compared to its original size. When the tablet was split into equal halves, the core was found to be still dry.