MXPA00011974A - Enteric coated pharmaceutical tablet and method of manufacturing - Google Patents

Abstract

A high drug load enteric coated pharmaceutical composition is provided which includes a core in the form of a tablet and which is comprised of a medicament which is sensitive to a low pH environment of less than 3, such as ddl, and having an enteric coating formed of methacrylic acid copolymer and a plasticizer. The tablets may be of varying sized and may be orally ingested individually or a plurality of tablets sufficient to attain a desired dosage may be encapsulated in a dissolvable capsule. The tablets have excellent resistance to disintegration at pH less than 3 but have excellent drug release properties at pH greater than 4.5. A novel method of making said pharmaceutical composition is also disclosed.

Description

PHARMACEUTICAL TABLET WITH ENTÉRICO COATING AND MANUFACTURING METHOD The present invention is directed towards a pharmaceutical composition with enteric coating in the form of a tablet which. comprises a drug with a labile acid drug, such as ddI, which is sensitive to low pH environment of less than 3, and which includes an enteric coating such as Eudragit L-30-D 55 and a plasticizer, but which does not require a sub-layer. The tablets have excellent resistance to disintegration at pH less than 3 but have excellent drug release properties at pH greater than 4.5. A new method of making said pharmaceutical composition is also disclosed.

Background of the Invention The enteric coating has been used for many years to stop the release of the drug from orally ingestible dosage forms. Depending on the composition and / or thickness, the enteric coatings are resistant to stomach acid for periods of time required before they begin to disintegrate and allow release of the drug in the lower part of the stomach or upper Ref.125086 of the small intestine. Examples of enteric coatings are described in US Patent No. 5,225,202 which is hereby incorporated by reference in its entirety. As disclosed in US Patent No. 5,225,202, some examples of previously employed coatings are beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and cetyl alcohol, mastic and shellac, as well as shellac and stearic acid (US Patent No. 2,809,918); polyvinyl acetate and ethyl cellulose (US Patent No. 3,835,221); neutral copolymers of polymethacrylic acid esters (Eudragit L30D) (F. W. Goodhart et al., Pharm. Tech. pp. 64-71, April 1984); copolymers of methacrylic acid and methyl methers of methacrylic acid (Eudragits), or a neutral copolymer of methacrylic acid esters containing metal stearates (Mehta et al., US Pat. Nos. 4,728,512 and 4,794,001).

The polymers of the enteric coatings mostly begin to solubilize at pH 5.5 and above, with maximum solubility ratios at pHs above 6.5.

Numerous enteric coatings and / or sustained release pharmaceutical compositions and methods of making these compositions have been described in the art. Previous similar compositions, however, often comprise numerous extra ingredients in addition to the medicaments, such as fillers, buffering agents, binders and wetting agents, all of which add to the density of the composition and reduce the amount of active medicament that can be used. be contained in the composition. The process of preparing these aforementioned pharmaceutical compositions requires multiple duration steps, including undercoating and external coating steps. Furthermore many of these pharmaceutical compositions are intended for release in the lower tract of the large intestine, for example, in the colon, as opposed to the upper intestines, for example the duodenum of the small intestine.

US Patent No. 5,225,202 discloses enteric coated pharmaceutical compositions using methylcellulose hydroxypropyl phthalate polymer (HPMCO) coatings. The disclosed pharmaceutical compositions comprise a labile acid drug core, a disintegrator, one or more regulatory agents to provide gastric protection in addition to the enteric coating, as well as the enteric coating and plasticizer. The pharmaceutical composition may also include one or more lactose, sugar or starch fillers. According to the invention described in this reference, when the core includes a drug that is incompatible with the enteric coating layer, an additional undercoating layer is employed which acts as a physical barrier between the core and the outer enteric coating layer. to prevent the interaction of labile acid drug and acidic enteric coating. The HPMCP enteric coating starts its dissolution process at pH 5.0. The process of preparing this pharmaceutical composition requires numerous coating steps to apply the sub-layer and then the enteric coating.

US Patent No. 5,026,560 discloses a pharmaceutical composition and a method of manufacturing said pharmaceutical composition, wherein the pharmaceutical composition comprises a seeded Nonpareil core produced by sucrose coated with corn starch, spraying the core with an aqueous binder in a solution of water and ethanol and with a spray powder containing a drug and little replaced hydroxypropylcellulose, followed by the application of an enteric coating. The USA Patent No. 4,524,060 discloses a slow release pharmaceutical composition which provides a constant release composition for the treatment of hypertensive patients, and which comprises a mixture of micronized indoramine or a pharmaceutically acceptable salt thereof, a water channeling agent, a wetting agent, a disintegrant, the mixture being in the form of a compressed tablet and having an enteric coating or constant release coating permeable to intestinal juices.

US Patent No. 5,536,507 is directed toward a pharmaceutical composition having a displaced release coating or enteric coatings in which the active agent of the composition is planned for release of a predominant amount of the drug at a point almost at the entry of or in the large intestine and at a pH of about 6.4-7.0.

Pharmaceutical compositions that include a medicament that is unstable in an acidic medium such as the stomach and that is not adequately regulated will require a protective enteric coating to prevent release of said medicament before reaching the intestines.

DdI, t (also known as didanosine or 2'-3'-dideoxyinosine, and marketed by Bristol-Myers Squibb Co. under the trademark Videx®, is a labile acid drug having the formula and that it has been shown to be effective in the treatment of patients with the HIV virus that causes AIDS. The composition and method of inhibiting replication of HIV with -2 ', 3'-dideoxyinosine has been published. See U.S. Patent Nos. 4,861,759, 5,254,539 and 5,616, 566, which are incorporated herein by reference. More recently Videx® has begun to be widely used as a component of the new therapeutic mixtures used to treat AIDS. It is also a labile acid medicine sensitive to a low pH environment and that will degrade in the stomach.

Videx® is generally available in a variety of oral dosages, including regulated dispersible / chewable tablets in potencies of 25, 50, 100 or 150 mg didanosine. Each tablet is regulated with calcium carbonate and magnesium hydroxide. Videx® tablets also contain aspartame, sorbitol, microcrystalline cellulose, Poliplasdone®, orange-tangerine flavor, and magnesium stearate. The Videx® Regulated Powder for Oral Solution is provided for oral administration in single-dose packages containing 100, 167 and 250 mg of didanosine. The packages of each product potency also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose. A Pediatric Videx® Powder for Oral Solution is also available and is supplied for oral administration in 4 or 8 ounce glass bottles containing 2 or 4 grams of didanosine respectively, and is for mixing with commercial antacids before oral ingestion .

With particular emphasis on tablets, either ingested alone or as part of a therapeutic regimen in combination ("cocktail"), regular regulated chewable / dispersible tablets do not contribute to a patient's relief from a usage point of view. Considering that the other products that are part of the therapeutic mixtures for AIDS are capsules or tablets and easily swallowed the Videx® (mentioned herein as "wddl") the Dispersables / Chewable Regulated Tablets should be chewed, manually crushed, or evenly dispersed perfectly in water before administration. Because ddl is rapidly degraded to acidic pH, ddl in its chewable / dispersible form and its' regulated powder for oral solution contains regulatory agents and is administered with antacids in the form of pediatric powder. However, the presence of large amounts of antacid components in the formulation can cause significant imbalance in the large intestine as seen by severe diarrhea. Many patients also complain about chewing the large ddl tablets (dose = 2 tablets of 2.1 g each), the flavor of the ddl or the time required to disperse the tablet and the volume of fluid (4 ounces) required for the dose. All the factors coupled with the fact that other drugs analogous to the nucleoside are marketed in a more convenient dosing presentation (eg capsule or small tablets), the development of an innovative dosage form of ddl is needed which is easily swallowable and Do not cause side effects of discomfort.

Accordingly, a tablet comprising a drug core and having a coating that prevents release of the drug into the stomach and allows the release of the drug in the small intestine is provided thereby eliminating the need for a stomach antacid that can cause imbalance in the large intestine with chronic use. Accordingly, pharmaceutical compositions that include a medicament that is unstable in an acidic medium such as the stomach will require protection similar to a protective coating to prevent release of said medicament before reaching the intestines.

Description of the invention According to the present invention, there is provided an enteric coating, pharmaceutical composition containing a drug, and a method of manufacturing said pharmaceutical composition which includes a medicament that can degrade in low pH medium but which is protected from this happening by the enteric coating. The pharmaceutical composition of the invention which is advantageously in the form of tablets, includes a core comprising a medicament, such as ddI, which is sensitive to a medium with low pH and optionally a binder or filler, a disintegrating or bulking agent. , and a lubricant. The core further comprises an enteric coating around the core that includes a copolymer of methacrylic acid and a plasticizer.

The novel enteric coating of the invention will be provided for protection of the medicament or therapeutically active agent, such as ddI, at pHs below 3 (such as that found in the stomach) but will allow the release of the drug at a pH of 4.5 or superior (such as that found in the upper intestines).

Accordingly, the pharmaceutical composition of the invention will usually include drugs that are chemically unstable in acidic medium. The pharmaceutical composition of the invention provides excellent protection in highly acidic media (pH < 3) while not displacing rapid release in regions of pH greater than 4, whether in the upper intestine or in the duodenum.

Most of the materials of the known enteric coatings in the medium are acidic in nature and therefore can cause chemical instability when in contact with labile acid ingredients.

This is especially true at high temperatures and wet conditions experienced during the aqueous coating process. To minimize this instability caused by the acid, a protective coating or undercoating is usually applied between the particles, beads, pills, tablets, etc. And the enteric coating. This protective coating physically separates the labile acid drug from the acidic enteric coating and therefore provides stability to the formulation. The process of applying a sublayer, however, is often coupled with multiple heavy and time consuming stages. In addition, the sublayer can cause a delay in the release of the drug.

A process is described so that tablets, beads, lozenges, and / or particles containing labile acidic drugs can be successfully enteric coated with aqueous coatings without the application of the protective layer or sublayer. This process involves increasing the pH of the solution or suspension for the enteric coating by using alkalizing agents. The pH of the suspension for the coating is increased below the point at which the enteric integrity of the polymer can not be lost. The process may also involve the inclusion of binders, such as sodium carboxymethylcellulose, fillers, such as microcrystalline cellulose, disintegrants, such as sodium starch glycolate, and other excipients, such as magnesium oxide, which are relatively alkaline in nature, the formulations of the planned nuclei for enteric coating. Increasing the pH of the coating suspension provides a more stable composition for the labile acid drug of the core. As a result, there is no incompatibility and does not need a protective sublayer between the labile acid drug and the acidic enteric coating. This process not only eliminates the additional cost of the subcoating stage, but it makes it possible to expedite the release of the drug since the layer of the added subcoat retards the release of the drug.

The process of the present invention illustrates the preparation of high potency tablets (up to 99.5%) (uncoated), for labile acid drugs, such as ddl, using an aqueous process. Non-specialized equipment such as mixers, compactors, conventional tableting machines is required, and the coating equipment was found to be suitable for forming and coating tablets.

In the digestive tract, coated tablets pass through the stomach first. The transit time through the stomach is approximately two hours and the pH of this region is approximately 1 to 3. The components of the enteric coating allow the drug core to remain substantially intact and thus prevent the pharmacologically active substance from being released. in this region or the acid to penetrate through the core of the tablet. The tablets then pass through the small intestine where most of the components of the enteric coating will dissolve and release the pharmacologically active substance therein. In a normal flow direction, the small intestine consists of the duodenum, jejunum and ileum. The transit time through the small intestine is about 2-4 hours and the pH of these regions is about 5 to about 7.2.

As used herein, "enteric coating" is a polymeric material or materials that surround the drug core. The enteric coating material of the present invention does not contain any active compound, for example, any therapeutically active agent. Preferably, a substantial amount or all of the polymeric enteric coating material is dissolved before the therapeutically active agent or agent is released from the dosage form, so that delayed dissolution of the drug core is achieved. A suitable pH-sensitive polymer is one that will dissolve in the intestinal juices at high pH levels (pH greater than 4.5) such as in the small intestine and therefore allow the release of the pharmacologically active substance in the regions of the small intestine. and not in the upper portion of the gastrointestinal tract, such as the stomach.

The polymer of the coating material is selected so that the therapeutically active agent will be released when the dosage form reaches the small intestine or a region where the pH is greater than 4.5.

Materials for preferred pH sensitive coatings, which remain intact in the lower pH media of the stomach, but which disintegrate or dissolve at the pH commonly found in the patient's small intestine. The enteric polymer of the coating material begins to dissolve in an aqueous solution at pH between about 4.5 to about 5.5. The solubility-pH behavior of the enteric polymers of the present invention is such that significant dissolution of the enteric polymeric coating will not take place until the dosage form is discharged from the stomach. The pH of the small intestine gradually increases from about 4.5 to about 6.5 in the duodenal bulb to about 7.2 in the distal small bowel projections (ileus). In order to provide predictable dissolution to transit time through the small intestine of about 3 hours and allow reproducible release therein, the coating would begin to dissolve in the pH range of the duodenum and continue to dissolve in the pH range in the small intestine. Accordingly, the amount of enteric polymeric coating will be such that it is substantially dissolved during the transit time, approximately three hours, in the small intestine.

The pharmaceutical drug present in the nucleus will be a labile acid drug such as ddl, pravastatin, erythromycin, digoxin, pancreatin, ddA, ddC, and the like. The present invention is not limited to these drugs and other drugs can also be used. The invention is particularly adapted to pharmaceutical compositions, such as tablets, containing ddl as a medicament. The ddI will be present in an amount of up to about 95% of the composition in the coated tablets.

One or more binders or fillers may be present in the core. Microcrystalline cellulose (pH-101) is the most suitable preferred binder for use herein. Examples of other binders that may be used include sodium carboxymethyl cellulose Avicel ™ RC 591, Avicel ™ CL-611, (FMC Corp), Ceolus ™ (FMC Corp), ProSolv ™ (Ed ard Mendell Co.) Metocel ™ E-5 (Dow Corp .), Starch 1500 (Colorcon, Ltd.), Hydroxypropylmethylcellulose (HPMC) (Shin-Etsu Chemical Co. Ltd.) Polyvinylpyrrolidone, potassium alginate and sodium alginate.

The core of the composition of the invention may also include one or more disintegrating or bulking agents, such as sodium starch glycolate marketed under the trademark EXPLO (Edward Mendell Co.), Ac-Di-Sol (crosslinked sodium carboxymethylcellulose) (FMC Corp). Croscarmellose sodium, corn starch, or crosslinked polyvinylpyrrolidone. A lubricant such as magnesium stearate can also be used in the preparation of the uncoated tablet, specifically as a lubricant for the processes of compaction and rattling.

The core used in the pharmaceutical composition of the invention will be formed of a tablet, preferably a round, biconvex tablet, approximately 3/16 inches. The invention is not, however, in the size of the tablet and tablets of varying sizes can be manufactured. Smaller tablets are advantageous, however, since the passage through the stomach will be easier than that of the larger tablets. Experimentation has shown that the tablet of the present invention having a core comprising ddI as a medicament has the same bioavailability as the pearls described in co-dependent US Application No. 09 / 083,597, which was registered on May 22, 1998. Tablets can be individually ingested, depending on size, or a plurality of tablets sufficient to achieve a particular dose can be encapsulated a soluble capsule.

In an alternative embodiment of the present invention, the core can be prepared from a wet granulation process, using any of the wet granulate binders (if necessary) commonly used in the medium, such as pregelatinized starch, polyvinylpyrrolidone, sodium carboxymethylcellulose HPMC, potassium or sodium alginate. The wet granulation process comprises the steps of preparing the granules suitable for tabletting by mixing a mixture comprising the medicament, a binder, and optionally, a disintegrant and filler; add a predetermined amount of water or granulate solvent to form a wet mass mixture; calibrate the mixture of moist dough in granules to aid drying; dry the wet granules to remove excess moisture; calibrate the dry granules into granules suitable for tableting, and add lubricant, one or more fillers, one or more dry binders, optionally a disintegrant, and other excipients necessary for tabletting the granules.

The enteric coating according to the present invention will include a methacrylic acid copolymer, a plasticizer, and a sufficient amount of NaOH to adjust the pH of the suspension. Other alkalizing agents such as potassium hydroxide, calcium carbonate, sodium carboxymethylcellulose, magnesium oxide and magnesium hydroxide can also be used.

In the shaping of the enteric coated pharmaceutical composition of the invention, a solution of Eudragit L-30-D 55 will be used. Eudragit L-30-D 55 is an aqueous dispersion of an acrylic resin, an anionic copolymer derived from methacrylic acid and ethyl acrylate with a proportion of free carboxyl groups in the ester of about 1: 1, and an average molecular weight of about 250,000, is supplied as an aqueous dispersion containing 30% w / w dry coating substance, is marketed by Rohm-Pharma Co, Germany. As an aqueous, non-hazardous or environmentally damaging coating, organic solvents are used.

Although Eudragit L-30D-55 is the preferred coating polymer, the invention is not limited in this respect and other polymers for enteric coatings known in the art can be employed, such as hydroxypropyl methylcellulose phthalate HP50 (HPMCP-HP50) (USP / NF 220824), HP55 (HPMCP-HP55) (USP / NF type 200731) and HP55S available from Shin Etsu Chemical, Coateric ™ (polyvinyl acetate phthalate) (Colorcon Ltd.), Sureteric ™ (polyvinyl acetate phthalate (Colorcon Ttd .) or Aquateric ™ (cellulose acetate phthalate) (FMC Corp.), and the like.

The enteric coating will also preferably contain a plasticizer which is preferably diethyl phthalate, although the invention is not limited in this respect and other plasticizers can also be used such as triethyl citrate (Citroflex-2), triacetin, tributyl sebecate, or polyethylene glycol.

The enteric coating used in the present invention is easier to process than previously published coating systems, and is especially advantageous for coating low mass and small diameter particles (tablets) with minimal processing problems (adhesion / pitting) without the need of organic solvents.

In general, when the core includes a drug that is incompatible with the enteric coating layer, a sublayer may be used which may contain one or more film formers or plasticizers, and which acts as a physical barrier between the core and the layer. of exterior enteric coating. However, unlike previously published coatings such as that disclosed in US Patent No. 5,225,202, the new pharmaceutical composition of the present invention, as a result of the new process used in the manufacture of the composition of the present invention and the adjustment pH of the coating that does not require a sub-layer since for such a need, an insulating layer is removed by increasing the pH of the aqueous coating suspension.

Since the coating is designed to dissolve at pH 5.5, the enteric coating applied at pH 5 allows relatively relatively rapid breakthrough in the intestine when only a small amount of additional alkalinity is required to bring the pH to 5.5.

A preferred formulation for preparing a 50 mg uncoated tablet is set forth below Material Quantity (mg) per tablet TABLET NUCLEUS Drug (didanosine) 50.00 Microcrystalline cellulose 17.00 Sodium starch glycolate 2.10 Magnesium stearate (for compaction) 0.60 Magnesium stearate (for tabletting) 0.30 Net weight of Tablet without coating 70.00 A preferred formulation for the preparation of a suspension for enteric coating to cover 50 mg tablets without coating is set forth below.

Material Quantity (g) per 100 grams COATING Eudragit L-30-D 55 66.67 Diethyl phthalate 3.00 Purified water sufficient quantity (pH adjusted to 5 ± 0.1 with NaOH solution) The percentage range of the ingredients in the above formulations for the uncoated tablet and the enteric film coating is shown in the following diagram Material% (range) NUCLEUS Drug (didanosine) 1-100 Microcrystalline Cellulose 0-40 Sodium Starch Glicolate 0-6 Magnesium Stearate 0-3 COATING Eudragit L-30-D 55 2-30 Diethyl phthalate 0.5-6.0 The enterically coated pharmaceutical composition in the form of tablets can be prepared by a process comprising the steps of mixing a labile acid drug, a binder / filler, such as microcrystalline cellulose, a disintegrant, such as sodium starch glycolate, and a first portion of a lubricant, such as magnesium stearate, for compaction, in a drum mixer to prepare a dry mix. The mixture is then sieved and placed again in the mixer for a second mix. The resulting mixture is converted into a core or compacted and then calibrated to form small granules. A second portion of magnesium stearate lubricant is then calculated and mixed in the drum mixer with the sifted granules. The resulting mixture is then formed into tablets (uncoated) having a desired weight and hardness.

The tablets can then be coated with an enteric film coating suspension comprising Eudragit L-30-D 55 and plasticizer (diethyl phthalate), using an apparatus for fluid bed coating with top spray mode, such as a plate unit. Top Aeromatic STREA-1, and then dried. During the preparation of the suspension for film coating, a solution of NaOH is added to the suspension until a pH of 5.0 + 0.1 is obtained. The adjustment of the suspension for enteric film coating to pH 5 eliminates the need for a sublayer or insulating layer. The advantage here is that an enteric coating at pH 5 allows relatively rapid breakdown in the intestine since only a small amount of alkalinity is required to bring the pH to 5.5. The adjustment of the suspension at pH 5 ± 0.1 is not critical. The pH of a specific formulation could be adjusted up to 5.4 when it may be necessary. Although a fluidized bed apparatus with superior spray mode is preferred, the invention is not limited in this respect, and any suitable spray coating means, including a lower spray, or a saucer-like dispenser, may also be used.

Depending on their size, the tablets may be individually ingested or, in another embodiment of the invention, they may be filled into soluble hard-shell capsules, such as gelatin capsules of varying sizes depending on the dosage of the desired medicament. If the tablets are to be encapsulated, a hydrophobic anti-adherent, such as talcum (range of 0.1 to 4% by weight) is added for the tablets and film-coated mixtures.

The examples represent preferred embodiments of the present invention. The following examples further describe the materials and methods used to carry out the invention and are intended to be for illustrative purposes only, and are not intended to limit the scope or spirit of the invention or claims in any way. All temperatures are expressed in degrees Celsius unless otherwise indicated and all mesh sizes are US ASTM Standards.

EXAMPLE 1 A ddI formulation for 50 mg tablets having the following composition was prepared as described below.

COMPOSITION% BY WEIGHT OF% IN WEIGHT OF COMPONENT THE FINAL FORMULATION A. TABLET NUCLEUS Ddl 71.4 65,763 Microcrystalline cellulose 24.3 22,359 Sodium starch glycolate 3.0 2,762 Magnesium stearate 1.3 1,184 B .RECUBRIMIENTO (Based on a layer of 8) Eudragit L-30-D 55 (dry base) 87 6.892 Diethyl phthalate 13 1.039 (pH adjusted to 5.0 ± 0.1) The preparation of ddl tablets was started by the addition of ddl, microcrystalline cellulose, sodium starch glycolate and a first portion of magnesium stearate for compaction, in a drum type mixer. The ingredients were mixed for 10 + 2 minutes. Before mixing, any of the initial ingredients that were caked from passed through a No. 20 mesh screen.

A second portion of magnesium stearate needed for tabletting was then calculated and placed in the drum-type mixer with the granulate prepared for the calibration of the cores and mixed for 10 + 2 minutes. The resulting mixture was tabletted to obtain the desired tablet weight and hardness.

To prepare sufficient amounts of film coating suspension to cover the tablets, Eudragit L-30-D 55 was filtered through a No. 60 mesh screen to remove any lumps present therein. The filtered Eudragit was weighed and then added with stirring to a creosoted vessel containing half the amount of water required. The mixture was stirred continuously for 5 minutes or until a uniform mixture became visually evident. With continuous stirring diethyl phthalate was added to the vessel and stirring was continued for 20 minutes or until a uniform mixture became visually evident. A pH meter was standardized using pH 4 and pH 7 regulators. With continuous stirring, a NaOH solution was added to the vessel until a pH of 5.0 + 0.1 was obtained. The weight of the suspension suspension formula was adjusted using water and stirring was continued for an additional 10 minutes.The procedure for coating the tablet used a fluid bed apparatus with a superior spray pattern and an appropriate distribution plate to maintain the fluidity of the product (tablet) in the center Prior to coating, the tablets were preheated in the coating unit at a temperature between 45-50 ° C. A feed temperature between 50 + 2 ° C was determined to be adequate. The spray rate was adjusted to allow uniform coating and proper spray of the coating. A weight gain of 8 ± 0.5% due to the film layer was determined to be sufficient. After coating, the tablets were dried for approximately 10 minutes at a feed temperature of about 50 ° C.

The enteric coated ddl product thus formed was found to give excellent protection against gastric acid (at pH 3) but had excellent release of ddl at pHs greater than 5.

EXAMPLE 2 A preferred formulation of 50 mg ddl in the form of enteric coated tablets was prepared as described below. Ddl (50.00 mg), microcrystalline cellulose (17.00 mg) sodium starch glycol (2.10 mg) and a first portion of magnesium stearate for compaction (0.60 mg) were placed in a suitable drum-type mixer and mixed for 10 ± 2 minutes . Before mixing, if any of the ingredients required ungrouping, it was passed through a No. 20 mesh screen.

The mixed composition was then passed through a No. 40 mesh screen and placed back in the drum-type mixer and mixed again for 10 ± 2 minutes. The resulting mixture was transformed into cores using% -inch flat-face punches to obtain cores with a weight and hardness of 1 + 0.2 and 15-20 SCU, respectively. The cores were then passed through a No. 10 and No. 20 mesh screen.

A second portion of magnesium stearate (0.3 g) for tableting was then placed in the drum-type mixer with the cores and mixed for 10 ± 2 minutes. The resulting mixture was then tabletted using deep, flat, round concave punches for the desired weight to a hardness tablet of 3 to 6 SCU.

An amount of suspension for film coating in an amount (g) per 100 g to coat 50 mg ddl tablets was started by adding about 50 g of water in a suitable container having a stirring mechanism. While the water is being shaken moderately, 33.33 g Eudragit L 30 D-55 was added slowly. before adding the water, the Eudragit L 30 D-55 was sieved through a No. 60 mesh screen.

To the water / Eudragit mixture, 1.50 g of diethyl phthalate was added with continuous stirring until the diethyl phthalate was in complete solution. While stirring, a sufficient amount of sodium hydroxide solution (0.1 to 1 n was added slowly in order to adjust the pH of the suspension to 5.0) Water was added, with continuous stirring to give the weight to the formula, and the suspension was stirred for an additional 10 minutes.

The tablet coating process utilized an Aeromatic upper bed fluid bed apparatus (STREA-1) with superior spray mode and appropriate dispensing pan to allow product (tablet) fluidity in the center. The coating conditions used in the process were.

Load 250 g Heat setting 60 ° C Fan adjustment 14 Supply temperature 50 ° C Pre-heating time 5 minutes Sprinkling speed first 5 minutes 4 g / minutes Sprinkling speed, final 8 g / minutes Nozzle opening 1.1 mm Volume of air 120 Temperature of exit 36 ° C Weight gain Final drying at fan setting of 10 10 minutes Prior to coating, the tablets were preheated in the coating unit to a temperature between 45-50 ° C. It was determined that a feed temperature of 50 ± 1 ° C was adequate. The spray speed was adjusted to allow uniform coating and adequate drying of the layer. A weight gain of 8 + 0.5% due to the film layer was determined to be sufficient. After coating, the tablets were dried for approximately 10 minutes at a feed temperature of about 50 ° C.

The enteric coated ddl product thus formed was found to provide excellent protection against gastric acid (at pH 3) but had excellent ddl release at pHs greater than 5.

It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, it is claimed as property in the following:

Claims (53)

1. An enteric coated pharmaceutical composition which is characterized in that it comprises a core in the form of a tablet and having an enteric coating surrounding said core, said core containing a labile acid medicament, a binder or filler, a disintegrant, and a lubricant, said enteric coating comprising a copolymer of methacrylic acid, and a plasticizer, and imparting protection to said core so that said core is protected in a medium of low pH of 3 or less while being capable of delivering medicament to a pH of 4.5 or higher.

2. The pharmaceutical composition according to claim 1, characterized in that the pH of said acidic enteric coating is adjusted using alkalizing agents to provide stability between said labile acid drug in said core and said acidic enteric coating.

3. The pharmaceutical composition according to claim 2, characterized in that the pH adjustment of said enteric coating eliminates the incompatibility between the labile acid drug in said core and the aforementioned acidic enteric coating.

4. The pharmaceutical composition according to claim 3, characterized in that said pH adjustment of said acid enteric coating eliminates the need for a protective sub-layer between said labile acid medicament in said core and said acidic enteric coating.

5. The pharmaceutical composition according to claim 4, characterized in that the elimination of said protective sub-layer makes it possible to expedite the release of said labile acid drug in said core.

6. The pharmaceutical composition according to claim 1, characterized in that said medicament is ddl.

7. The pharmaceutical composition according to claim 1, characterized in that said medicament is pravastatin, erythromycin, digoxin, pancreatin, ddA or ddC.

8. The pharmaceutical composition according to claim 1, characterized in that said binder is microcrystalline cellulose, sodium carboxymethylcellulose, Avicel ™ CL-611, Ceolus ™, ProSolv ™ Methocel ™ E-5, Starch 1500, Hydroxypropyl Methylcellulose, Polyvinylpyrrolidone, Potassium Alginate or Sodium Alginate.

9. The pharmaceutical composition according to claim 8, characterized in that said binder is microcrystalline cellulose.

10. The pharmaceutical composition according to claim 1, characterized in that said lubricant is magnesium stearate.

11. The pharmaceutical composition according to claim 1, characterized in that said disintegrant is sodium starch glycolate, croscarmellose sodium, corn starch, or crosslinked polyvinylpyrrolidone.

12. The pharmaceutical composition according to claim 11, characterized in that said disintegrant is sodium starch glycolate.

13. The pharmaceutical composition according to claim 1, characterized in that said enteric coating includes methacrylic acid copolymer and a plasticizer.

14. The pharmaceutical composition according to claim 13, characterized in that said methacrylic acid copolymer is Eudragit L-30-D 55.

15. The pharmaceutical composition according to claim 13, characterized in that said plasticizer is diethyl phthalate, diethyl citrate, triacetin, tributyl sebecate, or polyethylene glycol.

16. The pharmaceutical composition according to claim 15, characterized in that said plasticizer is diethyl phthalate.

17. The pharmaceutical composition according to claim 1, characterized in that it has the following composition Material% (range) N CLEO Drug (didanosine) 1-100 Microcrystalline Cellulose 0-40 Sodium Starch Glycolate 0-6 Magnesium Stearate 0-3 COATING Eudragit L-30-D 55 2-30 Diethyl phthalate 0.5-6.0

18. The pharmaceutical composition according to claim 1, characterized in that said tablet contains ddI in an amount sufficient to achieve a dosage for a twice daily administration.

19. The pharmaceutical composition according to claim 1, characterized in that said tablet contains ddI in an amount sufficient to reach a dosage for a once-daily administration.

20. An enteric coated ddl which is characterized in that it consists of a core in the form of a tablet including ddI in an amount ranging from about 1 to about 99.5% by weight of said core, and an enteric coating including an acid copolymer methacrylic

21. ddl co or, was defined in claim 20, which is characterized in that it is in the form of tablets.

22. ddl as defined in claim 21, which is characterized in that the enteric coating includes a copolymer of methacrylic acid and a plasticizer.

23. ddI as defined in claim 21, which is characterized in that said tablet contains ddI in an amount sufficient to achieve a dosage for administration twice daily.

24. The pharmaceutical composition according to claim 21, characterized in that said tablet contains ddI in an amount sufficient to achieve a dosage for a once-daily administration.

25. A process for the preparation of an enteric coated pharmaceutical composition which is characterized in that it comprises the steps of: (a) preparing a mixture suitable for tableting; (b) tabletting said mixture into a plurality of individual tablets; and (c) coating said tablets.

26. The process according to claim 25, characterized in that step (a) of said preparation comprises the steps of (a) combining a mixture which is characterized in that it comprises a medicament, a binder, a disintegrant, and a first portion of a lubricant; (b) passing said mixture through a No. 40 mesh size screen; (c) recombining said mixture; (d) forming cores of said mixture and passing the cores formed successively through sieves of mesh size No. 10 and No. 20; and (e) adding a second portion of lubricant and re-mixing.

27. The process according to claim 26, which is characterized in that the mixture formed in step (c) is transformed into cores in inch-face flat punches.

28. The process according to claim 25, characterized in that said tapping step is carried out using deep, flat, round, 3/16 inch concave punches to obtain tablets of the desired weight. 29H.

The process according to claim 25, characterized in that said tablets have a hardness of 3-6 SCU.

30. The process according to claim 25, characterized in that said preparation of said coating comprises the steps of: (a) mixing a methacrylic acid copolymer with about half the amount of water required to achieve the desired formulation, (b) adding a plasticizer to the mixture of step (a) and stirring until said plasticizer is in complete solution; (c) adding sodium hydroxide solution to adjust the pH of the mixture from step (b) to 5.0; and (d) while stirring the mixture of step (c) adding water in an amount sufficient to bring the mixture to its desired formula weight.

31. The process according to claim 25, characterized in that said coating step (c) comprises the steps of: (a) pre-heating said tablets in a fluid bed spray apparatus at about 45-50 ° C. (b) spraying said tablets with said coating; and (c) drying said tablets.

32. The process according to claim 25, characterized in that said medicament is a labile acid drug.

33. The process according to claim 32, characterized in that said medicament is ddl.

34. The process according to claim 26, characterized in that said binder is microcrystalline cellulose.

35. The process according to claim 26, characterized in that said lubricant is magnesium stearate.

36. The process according to claim 26, characterized in that said disintegrant is sodium starch glycolate.

37. The process according to claim 25, characterized in that said enteric coating includes copolymer of methacrylic acid and diethyl phthalate.

38. The process according to claim 37, characterized in that said plasticizer is diethyl phthalate.

39. The process according to claim 37, characterized in that said methacrylic acid polymer is Eudragit L-30-D 55.

40. A process for the preparation of an enteric coated pharmaceutical composition which is characterized in that it comprises the steps of: (a) preparing a wet mass mixture by a wet granulation process for the formation of pellets for rattling; (b) tabletting said granules into a plurality of individual tablets; (c) coating said tablets with a polymer for enteric coating and plasticizer in an aqueous medium; and (d) mixing said coated tablets with an anti-adherent.

41. The process according to claim 40, characterized in that said preparation step (a) comprises the steps of: (a) combining a mixture consisting of a medicament, a binder, a disintegrant, and a filler; (b) adding a pre-determined amount of water or solvent for granulation to form a wet mixture, (c) calibrating said mixture into granules to aid in drying; (d) drying said granules to remove excess moisture; (e) calibrating said dry granules into pellets suitable for rattling; (f) adding lubricant, disintegrant, one or more fillers, one or more binders, and other excipients for tabletting said granules.

42. The process according to claim 40, characterized in that the preparation of said coating comprises the steps of: (a) mixing the methacrylic acid copolymer with about 50 g of water; (b) adding a plasticizer to the mixture formed in step (a) and stirring until said plasticizer is in complete solution; (c) adding sodium hydroxide solution to adjust the pH of the mixture from step (b) to 5.0; and (d) while stirring the mixture of step (c) adding water in an amount "sufficient to bring the mixture to its desired formula weight.

43. The process according to claim 41, characterized in that said coating step comprises the steps of: (a) pre-heating said tablets in a fluid bed spray apparatus at about 40-50 ° C. (b) atomizing said tablets with said coating; (c) drying said tablets.

44. The process according to claim 41, characterized in that said medicament is a labile acid drug.

45. The process according to claim 44, characterized in that said medicament is ddl.

46. The process according to claim 41, characterized in that said binder is microcrystalline cellulose.

47. The process according to claim 41, characterized in that said lubricant is magnesium stearate.

48. The process according to claim 41, characterized in that said disintegrant is sodium starch glycolate.

49. The process according to claim 40, characterized in that said enteric coating includes the copolymer of methacrylic acid and diethyl phthalate.

50. The process according to claim 49, characterized in that said plasticizer is diethyl phthalate.

51. The process according to claim 49, characterized in that said methacrylic acid polymer is Eudragit L-30-D 55.

52. The process according to claim 40, characterized in that said anti-adherent is talc.

53. The process according to claim 40, characterized in that it additionally comprises the step of filling said coated tablets prepared in step (d) in a capsule.