MXPA00010963A - Enteric coated pharmaceutical composition and method of manufacturing - Google Patents

Abstract

A high drug load enteric coated pharmaceutical composition is provided which includes a core comprised of a medicament which is sensitive to a low pH environment of less than 3, such as ddl, which composition is preferably in the form of beadlets having an entericcoating formed of methacrylic acid copolymer, plasticizer and an additional coat comprising an anti-adherent. The so-called beadlets 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 COMPOSITION WITH ENTÉRICO COATING AND MANUFACTURING METHOD BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to an enteric coating pharmaceutical composition comprising a drug of a high drug loading of labile acid, which is sensitive to an environment of pH less than 3, such as ddl, whose composition is also in the form of beads or tablets that include enteric coverage such as Eudragit L-30-D 55 and a plasticizer, but which does not require undercoverage; the pearls also have a non-stick coating. The so-called beads possess excellent resistance to disintegration at a pH of less than 3 but possess excellent release properties of the drug at a pH greater than 4.5. A novel method for making said pharmaceutical composition is also described.

BACKGROUND OF THE INVENTION The enteric coverages have been used for many years to retain the release of the drug from the oral ingestion dosage forms. Depending Ref. 124556 of the composition and / or thickness, the enteric coatings are resistant to stomach acid for required periods of time before they begin to disintegrate and allow the slow release of the drug in the lower part of the stomach or in the upper part of the stomach. small intestine. Examples of some enteric coverages are described in U.S. Patent No. 5,225,202, which is incorporated herein by reference in its entirety. As set forth in US Pat. No. 5,225,202, some examples of coverages previously employed are beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and cetyl alcohol, chew and shellac, as well as shellac and stearic acid (U.S. Patent No. 2,809,918); polyvinyl acetate and ethyl cellulose (U.S. Patent No. 3,835,221); and neutral copolymer of polymethacrylic acid esters (Eudragit L30D) (F. W. Goodhart et al., Pharm. Tech., pages 64-71, April 1984); copolymers of methacrylic acid and methacrylate of methacrylic acid (Eudragits), or a neutral copolymer of polymethacrylic acid esters containing metal stearates (Mehta et al., U.S. Patent Nos. 4,728,512 and 4,794,001).

Many polymeric enteric coatings begin to be soluble at a pH of 5.5 and higher, with maximum solubility percentages at pH greater than 6.5.

Numerous pharmaceutical compositions of enteric coating and / or elongated release and methods for making these compositions have been described in the art. Although some of these previously described compositions are formed as small beads or pills, they often comprise numerous extra ingredients in addition to medicaments, such as fillers, buffering agents, binders, and humidifying agents, all of which are added to the mass of the composition and reduce the amount of active medication that may be contained in the composition. The preparation processes of these aforementioned pharmaceutical compositions require multiple time-consuming steps, including stages of application of undercoverage and outer coverage. In addition, several of these pharmaceutical compositions are intended to be released in the lower gastrointestinal tract, ie, in the colon, as opposed to the upper intestines, i.e., the duodenum of the small intestine.

US Patent No. 5,225,202 discloses enteric coating pharmaceutical compositions using neutralized hydroxypropyl methylcellulose phthalate polymer coats (HPMCP). The disclosed pharmaceutical compositions comprise a labile acid drug center, a disintegrant, one or more buffering agents to provide added gastric protection in addition to enteric coverage, as well as enteric coverage and a plasticizer. The pharmaceutical composition may also include one or more lactose fillers, sugar or starch. According to the invention described in this reference, when the center includes a drug that is incompatible with the enteric coverage layer, an additional layer of undercoverage is employed which acts as a physical barrier between the center and the external enteric coverage layer. to prevent the interaction of labile acid drug and acidic enteric coverage. The enteric coverage of HPMCP begins its dissolution process at a pH of 5.0. The process for preparing this pharmaceutical composition requires numerous coating steps to apply the undercoverage and subsequently the enteric coverage.

U.S. Patent No. 5-026,560 discloses a pharmaceutical composition and method for making said pharmaceutical composition, wherein the pharmaceutical composition comprises a center of a single grain produced by covering sucrose with corn starch, spraying the center with an aqueous binder in a solution of water or ethanol and with a spray powder containing a drug and minor substituted hydroxypropylcellulose, followed by the application of an enteric coating.

US Patent No. 4,524,060 mentions a slow release pharmaceutical composition which provides a sustained release composition for the treatment of hypertensive patients, and which comprises a mixture of micronized indoramine one of its pharmaceutically acceptable salts, a channeling agent of water, a humidifying agent, a disintegrant, the mixture being in the form of uncompressed tablets and having an enteric coverage or sustained release coverage permeable to gastrointestinal juices.

US Patent No. 5,536,507 is directed to a pharmaceutical composition having a delayed release coverage or enteric coverages wherein the active agent in the composition intends to release a predominant amount of drug at a point near the entrance or inside the intestine coarse and at a pH of about 6.4 - 7.0.

Pharmaceutical compositions that include a medicament that is unstable in an acidic environment such as the stomach and that is not adequately buffered, will require an enteric coverage of protection to prevent the release of such medicament before reaching the intestines.

The ddl (also known as didanosine or 2 ', 3'-dideoxinosine, and marketed by Bristol-Myers Squibb Co. under the brand name Videx®) is a labile acid drug which has the formula and which has shown to be effective in the treatment of patients with the HIV virus that causes AIDS. The composition and method of inhibition of HIV replication with 2 ', 3' -dideoxinosine has been reported. 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 been widely used as a component of the new therapeutic cocktails used to treat AIDS. It is also a labile acid drug sensitive to a low pH environment and will degrade in the stomach.

Videx® is generally available in a variety of oral dosages, including Chewable / Dispersible Tablets Cushioned with strengths of 25, 50, 100 or 150 mg didanosine. Each tablet is buffered with calcium carbonate and magnesium hydroxide. Videx® tablets also contain aspartame, sorbitol, microcrystalline cellulose, Poliplasdone®, tangerine-orange flavor, and magnesium stearate. Buffered Videx® Powder for Oral Solution is supplied for oral administration in single-dose packages containing 100, 167 or 250 mg of didanosine. Packages of each product strength also contain 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 available for oral administration in 4 or 8 ounce glass bottles containing 2 or 4 grams of didanosine, respectively, and mixed with commercial antacid prior to oral ingestion .

With particular emphasis on tablets, whether for ingestion alone or as part of a combined therapeutic regimen ("cocktail"), buffered chewable / dispersible normal tablets are not convenient from the patient's point of view of ease of use. While the other products that are part of the therapeutic cocktail of AIDS are capsules or tablets of easy swallowing, the Videx® Chewable / Dispersables Cushioned Tablets (referred to here as "ddl") should be chewed perfectly, manually crushed, or manually dispersed in water before administration. Because ddl degrades rapidly at acidic pH, ddl in its chewable / dispersible form and buffered powder for oral solution contains buffering 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 result in a significant gastrointestinal imbalance evidenced by severe diarrhea. Many patients also complain about chewing the large ddl tablets (dose = 2 tablets of 2.1 g each), the taste of the ddl or the time required to disperse the tablets and the fluid volume (4 oz.) Required per dose . All these factors, together with the fact that other analogous nucleoside drugs are marketed in a more convenient dosing presentation (ie, smaller capsules or tablets), require the development of an innovative dosage form of the ddl that is easy swallowing and that does not cause annoying side effects.

The normal dose of 200 mg for an adult twice a day or possibly 400 mg per day will require high-loading beads or particles so that the dose of 400 mg could be encapsulated in a single capsule. A formulation of low drug loading will require multiple capsules / doses, which would be less convenient from the point of view of the patient's dose.

Consequently, a coverage is provided that prevents the release of the drug in the stomach and allows the release of the drug in the small intestine thus eliminating the need for an antacid which could cause a gastrointestinal imbalance with chronic use. Therefore, pharmaceutical compositions which include a medicament which is unstable in an acidic environment such as the stomach will require a protective covering to prevent the release of such medicament before reaching the intestines.

DESCRIPTION OF THE DRAWING Figure 1 is a schematic flow chart illustrating in general the process for the manufacture of the enteric coating pharmaceutical composition of the present invention.

DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a pharmaceutical composition of high drug loading, enteric coverage, and a method for making said pharmaceutical composition, which includes a medicament that can degrade in a low pH environment but which is protected from do it thanks to the enteric coverage. The pharmaceutical composition of the invention, which advantageously is in the form of beads, lozenges or tablets, includes a center which comprises a medicament which is sensitive to a low pH environment, such as ddI, and optionally a binder, a disintegrant or a swallowing agent, and a filling. The center further comprises an enteric coating surrounding the center which includes a copolymer of methacrylic acid and a plasticizer. The pharmaceutical composition may additionally include a non-stick coating.

The novel enteric coverage pharmacist of the invention will provide protection to the drug or therapeutic active agent, such as ddI, at pH 's below 3 (as it is found in the stomach), but will allow the release of the drug to a pH 4.5 or higher (as it is found in the upper intestines).

Consequently, the pharmaceutical composition of the invention will usually include drugs that are chemically unstable in acidic environments. The pharmaceutical composition of the invention provides excellent protection in very acidic environments (pH < 3) while not delaying rapid release in regions of pH greater than 4, either in the upper intestine or duodenum.

Most of the materials for enteric coatings known in the art are acidic in nature and can therefore cause chemical instability when contacted with labile acid ingredients. This is especially true at high temperatures and humidity conditions experienced during an aqueous coating process. To minimize this instability caused by acid, a protective cover or undercoverage is usually applied between the particles, beads, pills, etc., and enteric coverage. This enteric coverage physically separates the labile acid drug from the acidic enteric coating, and therefore improves the stability of the formulation.

Therefore, a process is described by means of which an enteric coverage in aqueous medium is successfully applied to tablets, beads, pills and / or particles containing labile acid drugs without applying a protective cover or undercoverage. This process includes the elevation of the pH of the suspended solution of enteric coverage using alkalizing agents. The pH of the coating suspension rises below the point at which the enteric integrity of the polymer could 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 is relatively alkaline in nature, in formulations intended for enteric coverage . These stages provide a more stable composition for the labile acid drug in the center. As a result, there is no incompatibility or need for a protective undercoverage between labile acid drug and acidic enteric coverage. This process not only eliminates the costly additional stage of undercoverage, but allows a faster release of the drug because the addition of a subcoverage delays the release of the drug.

Normally, drug beads are formed by preparing a wet mass which is extruded into strands or extruded. These are rotated at high speed on a rotating plate that fractures them into small pieces and rounds off their ends to make spherical particles by a process known as spheronization. This spheronization generates a centrifugal force. Under these forces, if the particles do not have enough moisture absorbent, the moisture will be extracted from the particles (drain to the surface), which will cause agglomeration. Microcrystalline cellulose is a good moisture absorber and is therefore an excellent spheronization aid. Often more than 15% is needed, and usually more than 30% to obtain good spheronization characteristics.

It has been observed that when moisture is drained to the surface during spheronization, dry powder could be sprinkled on the particles to remove moisture and prevent agglomeration. The inventors believe here that this process could be used to completely eliminate the use of the moisture absorbent in the formulation for preparing beads with high drug loading. The inventors also believe that the drug could be mixed with a dry binder (if necessary) and optionally a disintegrant. A large part of this dry mix could be kneaded with water, extruded, and the remaining dry mix used to remove moisture from the surfaces during spheronization. This technique allows high drug loads and will not change the composition of the bead, despite the amount of dry mix used to sprinkle.

The process of the present invention allows the formation of beads with very high drug loads (up to 100%), and generally involves the preparation of a dry mixture of a powdered drug substance with or without a small amount of a suitable binder and an optional disintegrant. The drug itself, the drug / dry binder mixture, or the drug / dry binder / disintegrant mixture would be able to become sticky with moisture. A greater part of this mixture (70-95%) is kneaded with water, extruded and spheronized as conventionally carried out in the art for the formation of beads. A minor part (5 - 30%) of the mixture is separated to sprinkle. As the spheronization process takes place, the strands fracture and the particles become rounded. During this process, moisture is extracted from these particles. The portion of the dry mixture previously separated is sprinkled on the wet particles to remove the surface moisture. This produces relatively dry particles and freedom to move in a conventional jumps formation pattern. Consequently, the spheronization of the pearls progresses without agglomeration.

Frequently, beads or particles with enteric coverage or modified release are prepared for the oral delivery of drugs in a dose in the form of a capsule. When orally ingested the body of the capsule dissolves allowing the contents of the capsule to be exposed to the gastric contents. Due to the presence of fluids in the stomach, the exposed particles get wet. If the wetted particles do not stick together, they will disperse within the gastric contents and may enter the duodenum based on the size distribution and other factors that control gastric transit time. However, if the particles become sticky with moisture, they will stick together with one or more lumps. In this case, these lumps will behave like large particles and their gastric emptying time will be variable depending on the size and resistance of the lumps formed. In this case, such a dosage form could not behave like a true microparticle system. In order to solve this problem, according to the process of the present invention, the beads, lozenges, particles or tablets of enteric coating are coated with a hydrophobic material before encapsulation. The amount of hydrophobic coverage is maintained at a level where it is just enough to prevent the particles from sticking after the body of the capsule has dissolved, but not too much to delay the dissolution. Through this simple process, the particles behave as individual particles, and the gastric transit time is close to that expected for particle sizes for which the dosage form was designed, resulting in a more predictable dosage form and less variable.

The process of the present invention illustrates the preparation of potential (up to 100%) potential beads (without coverage) for labile acidic drugs, such as ddl, using an aqueous process. No specialized equipment is required since conventional extrusion and spheronization equipment has been found to be suitable for the formation of the beads. The use of an alkaline binder, such as sodium carboxymethylcellulose, and the powdering during spheronization with a dry mixture comprising the medicament, and optionally the binder and a disintegrant, ensure the chemical stability of the medicament and maximize the loading of the drug. The process of the present invention results in a high production of beads (> 90%) with close particle sizes.

The invention is particularly adapted to pharmaceutical compositions such as beads, pills or tablets, preferably beads containing ddl as a medicament. The ddl may be present in an amount of up to 100% of the composition in the coated beads.

The coated beads first pass through the stomach. The transit time for the stomach is about two hours and the pH of this region is about 1 to 3. The enteric coverage component allows the drug center to remain substantially intact and thus preventing the pharmacologically active substance from being released. in this region or that the acid penetrates through the center of the pearl. Subsequently the beads pass through the small intestine where most of the enteric coating component will dissolve and the pharmacologically active substance will be released. A normal flow direction that crosses 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 coverage" is a polymeric material or materials that covers the drug center. In the present invention the polymeric enteric coating material does not contain any active compound, ie, no therapeutically active agent of the present invention. Preferably, a substantial amount or all of the material of the polymeric coating dissolves before the drug or the therapeutically active agent is released from the dosage form, such that a delayed solution of the drug center is achieved. A suitable polymer sensitive to pH is one that will dissolve with intestinal juices at high pH levels (pH greater than 4.5), such as in the small intestine and therefore allows the release of the pharmacologically active substance in the bowel regions. thin and not in the upper portion of the gastrointestinal tract, such as the stomach.

The material of the polymeric coating is selected such that the therapeutically active agent will be released when the dosage form reaches the small intestine or a region in which the pH is greater than a pH of 4.5. The materials of pH-sensitive coatings are preferred, which remain intact in the lower pH environments of the stomach, but which disintegrate or dissolve in pH's commonly found in the patient's small intestine. The material of the enteric polymeric coating begins to dissolve in an aqueous solution at a pH between about 4.5 to about 5.5. The behavior of the pH solubility of the enteric polymers of the present invention is such that significant dissolution of the enteric polymeric coating will not occur until the dosage form is emptied 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 remote parts of the small intestine (ileum). In order to provide a predictable solution corresponding to transit time through the small intestine of about 3 hours and to allow reproducible release there, the coverage should begin to dissolve in the pH range of the duodenum and continue to dissolve in the pH range in small intestine. Therefore, the amount of enteric polymeric coverage should be such that it dissolves substantially during the approximately three hours of transit time in the small intestine.

The pharmaceutical drug present in the center will be a labile acid drug such as ddl, pravastin, erythromycin, digoxin, pancreatin, ddA, ddC, and the like.

The present invention is not limited to these drugs and other drugs can also be used.

One or more binders may be present in the center in an amount in the range of 0 to 10% and preferably 1% by weight of the composition. The most suitable preferred binder for use herein is sodium carboxymethyl cellulose. Examples of other binders that can be used include Avicel ™ PH101, Avicel ™ RC 591, Avicel ™ CL-611 (from FMC Corp.), Methocel ™ E-5 (from Dow Corp.), Starch 1500 (from Colorcon, Ltd.) , Hydroxypropyl Methylcellulose (HPMC) (from Shin-Etsu Chemical Co., Ltd), Polyvinylpyrrolidone, Potassium Alginate and Sodium Alginate.

The center of the composition of the invention may also include one or more disintegrants or swallowing agents in an amount in the range of 1% to 4% by weight of the composition, such as sodium starch glycolate marketed under the trademark from EXPLO (by Edward Mendell Co.), Ac-Di-Sol (crosslinked sodium carboxymethylcellulose) (from FMC Corp.), croscarmellose sodium, maize starch, or cross-linked polyvinylpyrrolidone.

The center used in the pharmaceutical composition of the invention can be formed of a bead or a tablet with a diameter of about 0.5 to about 5 mm, and preferably about 1 to about 2 mm. The center will preferably be in the form of a bead or pellet.

In the formation of the enteric coating pharmaceutical composition of the invention, an enteric coating solution of Eudragit L-30-D 55 will be used. Eudragit L-30-D 55 is an aqueous dispersion of acrylic resin, an anionic copolymer derived of methacrylic acid and ethyl acrylate having a carboxyl to ester ratio of about 1: 1, and an average molecular weight of about 250,000, is supplied as an aqueous dispersion containing 30% w / w of dry lacquer substance, and is marketed by Rohm-Pharma Co., of Germany. As a water-based cover, organic solvents that are hazardous or harmful to the environment are not used.

Although Eudragit is the preferred polymer coat, the invention is not limited in this respect and other coatings of enteric polymers known in the art may 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) (from Colorcon Ltd.), Sureteric ™ (polyvinyl acetate phthalate) (from Colorcon , Ltd.), or Aquateric ™ (cellulose acetate phthalate) (from 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 such as triethyl citrate (Citroflex-2), triacetin, tributyl sebecate, or polyethylene glycol can be used. Optionally, a non-stick coating can be applied after coating the bead or bar. (anti-caking agent) which is advantageously a hydrophobic material such as talc, magnesium stearate or fuming silica, with talc being preferred.

The enteric coverage used is substantially easier to process than the coverage systems reported previously, and is especially advantageous for coating small size and low mass particles (beads) with minimal processing problems. (agglomeration) without the need for organic solvents.

The above enteric coverage will include copolymer of methacrylic acid in an amount of about 5% -30%, and preferably 10% -20% by weight based on the solids content of the enteric coating solution, and plasticizer in an amount of about 1. % - 6% and preferably 2% - 3% by weight.

All the above weights are based on the total concentration of solids in the solution / suspension of enteric coverage.

Therefore, enteric coverage will contain from 5% to 35% by weight of solids, and from 65% to 95% by weight of water.

In general, as long as the center includes a drug that is compatible with the enteric coating layer, a layer of undercoverage will be used, which may be comprised of one or more film formers or plasticizers, and which act as a physical barrier between the film. center and the outer layer of enteric coverage. However, unlike the coverage reported previously such as that described in US Pat. No. 5,225,202, the novel pharmaceutical composition of the invention, which is a result of the novel process used in the preparation of the composition of the present invention and of the adjustment of the pH of the cover, does not require an undercoating since the need for an insulating layer of this type is eliminated by stabilizing the beads with an alkalizing agent and with an aqueous cover with a pH of 5. Since the cover is designed to break at a pH of 5.5, the enteric coverage applied at a pH of 5 allows relatively rapid breakdown in the intestine by requiring only a small additional amount of alkalinity to obtain the pH of 5.5.

The enteric coverage will be present in a weight ratio to the center in a range of 5% to 30% to be released in the small intestine, but will increase to approximately 60% to be released in the colon.

Next, a preferred formulation of a bead with enteric coverage is presented.

Interval Composition Total Possible Material% Preferred% CENTER Drug (didanosine) 50 - 100. 0 95. 00 NaCMC 0 - 10. 0 1. 00 Sodium Starch Glicolate 0 - 10. 0 4. 00 COVERAGE Eudragit L-30-D 55 5.0 30.0 10 - 20 Diethyl Phthalate 0.5 6.0 1.5 - 3.0 ANTIADHERENT Talco 0.1 4.0 0.2 - 0.5 The enteric coating pharmaceutical composition in the form of beads or pellets can be prepared by a process comprising the steps of first preparing the uncoated beads by preparing a dry blend comprised of a labile acid drug, a binder, such as NaCMC, and a disintegrant, such as sodium starch glycolate, using a drum-type mixer, and planetary mixer, or a large-cut mixer. A portion of an amount of 5% -30%, and preferably 10% -20%, of the dry mixture is removed to be sprinkled later during spheronization. Then, at 70% -95% of the remaining dry mix, water is added and granulated to a suitable wet granulation mass using a planetary mixer or a large-cut mixer. The wet mass is extruded, for example, by using a Nica or other type of extruder to form an extrudate which is subsequently placed in a spheronizer such as a Caleva, Nica or other type to form wet beads which are sprinkled during spheronization with the 5% - 30% dry mix previously separated. Then the beads are passed through mesh screens to obtain the desired pearl sizes. Then, the beads are dried by pan drying or by fluidized bed drying. The general process of the present invention using ddI as the labile acid medicament is illustrated in diagrammatic form in Figure 1.

Then, the dried beads or pellets can be coated with an enteric film coverage suspension comprising Eudragit L-30-D and a plasticizer (diethyl phthalate), using a fluidized bed coverage applicator, such as a spray coating system Wurster or other appropriate cover system, and then dry. During the preparation of the film coating suspension, a solution of NaOH is added to the suspension until a pH of 5.0 ± 0.1 is obtained. The stabilization of the beads with a binder and the adjustment of the enteric film coating suspension to a pH of 5 eliminates the need for an undercoating or insulating layer. The advantage here is that an enteric coverage at a pH of 5 allows a relatively rapid break in the intestine since only a small amount of alkalinity is required to obtain the pH of 5.5.

To prevent the coagulation of the beads coated with the film, a non-stick (talc) is then added to the coated beads with the film and mixed.

The beads or pellets formed in this manner can fill the inside of hardened body capsules, such as gelatin capsules of varying sizes depending on the desired dose or medicament.

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 in any way the scope or essence of the present invention or the claims. All temperatures are expressed in degrees Celsius unless otherwise indicated and all mesh sizes are of the North American ASTM standard.

EXAMPLE 1 A formulation of ddI was prepared in the form of enteric coating beads having the following composition as described below.

% IN WEIGHT% BY WEIGHT OF THE COMPOSITION OF THE COMPONENT FINAL FORMULATION A: CENTER OF THE PADDLE ddl 95 77.744 Na CMC 1 0.818 Sodium Starch Glycolate 4 3,273 B: COVERAGE Eudragit L-30-D 55 (dry basis) 87 15,621 Diethyl Phthalate 13 2,343 (pH adjustment at 5.0 + 0.1) C: AN IADHERENT Talco 100 0.200 D: CAPSULA Transparent body and cover size 0 The preparation of the ddl beads began with the screening and mixing of a mixture of ddl, sodium starch glycolate, and sodium carboxymethylcellulose. Subsequently the resulting mixture was again screened and remixed. Then, approximately 10% -20% of the second mixture was removed and separated for sprinkling during spheronization. Then the remaining mixture was granulated to a suitable wet mass point using a planetary mixer or a large cut mixer. Approximately 200 - 360 g of water per 1 kg of dry mix was added during mixing until a suitable wet mass for extrusion was achieved. The wet mass was extruded through a suitable screen using an extruder (Nica Model E140, Feeder Speed 1, Agitator Speed 1), with which a fraction of mesh beads approximately 10/18 was achieved during spheronization. The extrudates were taken to an appropriate spheronizer (Caleva Model 15 at 500 rpm, or Marumerizer ™ Q-400 at 700 rpm), and spheronized at medium speed using a medium cross-hatched plate or a radially designed plate for 1 to 5 minutes. minutes 10% -20% of the previously prepared dry blend that was separated was subsequently used to sprinkle the beads to prevent agglomeration. After the appropriate spheronization time, the product was discharged into an appropriate container.

Subsequently, the spheronized wet beads were slowly passed through mesh screens # 10 and # 18 to recover a 10/18 mesh product fraction. Fractions of mesh size greater than 10 and less than 18 were returned to the extruder for re-extrusion and re-spheronization. This process continued until at least 90% of the product fraction was obtained. Subsequently the 10/18 mesh product fraction was dried to a pre-specified moisture content using a hot air tray dryer or a fluidized bed type dryer. The dried pearls were sieved through mesh screens # 10 and # 20 to remove any granules or pearls of reduced size. The 10/20 mesh dry product fraction was taken to an appropriate container lined with two polyethylene bags.

The net weight was determined, and the yield% of the product and the response of the pearl manufacturing process were calculated.

To prepare sufficient amounts of film coating suspension to coat the batch of beads, Eudragit L-30-D 55 was filtered through a # 60 mesh screen to remove any granules present. The Eudragit was weighed and then added with agitation to a tarry vessel containing one and a half amounts of the required water. The mixture was stirred continuously for 5 minutes or until a uniform mixture was visually evident. Diethyl phthalate was added to the container, with continuous agitation, and agitation continued for 20 minutes or until a uniform mixture was visually evident. Subsequently, a pH meter was standardized using buffer solutions of pH 4 and pH 7. A solution of NaOH was added to the vessel with continuous stirring until a pH of 5.0 ± 0.1 was obtained. The formula weight of the coating suspension was adjusted using water and stirring was continued for an additional 10 minutes.

In the bead coverage process, a fluidized bed processor was mounted for a spray coverage Wurster system or other cover system.

Ideal parameters for the spray coverage system include an Aeromatic STREA-1, 300 g load, 0.8 mm nozzle, 8 g / min. Spray speed, 1.0 bar spray pressure, 64 ° inlet temperature C, outlet temperature of 42 ° C; a Glatt GPCG-5 with Wurster column, 1500 g, nozzle of 1.2 mm, spray speed of 20 g / min., spray pressure of 1.0 bar, inlet temperature of 65 ° C, product temperature of 48 ° C, Output temperature of 42 ° C.

Before beginning the application of the film coating suspension, the beads may optionally be heated to about 50 ° C for about 5 minutes. A film coverage of 16% -20% w / w was applied using the previously described parameters. After completing the film coverage the inlet temperature was reduced to maintain a product temperature of approximately 50 ° C and subsequently the beads were dried for 25 ± 10 minutes. The net weight of the pearls with film coverage was determined. The percentage of film coverage of the beads was calculated. The talc weight to be added was determined based on the net weight of the beads. The% actual gain due to the film coverage depends on the efficiency of the coating operation. The amount of coverage applied can be adjusted to achieve the expected weight gain due to coverage. Then, the amount of talc determined was weighed. The pearls with film coverage will be. placed in a suitable drum-type mixer together with the talc and the mixture for 15 ± 5 minutes. The beads were then transferred to an appropriate container (s) lined with two polyethylene bags and the net weight was determined.

The beads formed in this way can then be introduced into capsules or caps, such as gelatin capsules to facilitate swallowing.

It was found that the ddl product of enteric coating formed in this manner provides excellent protection against gastric acid (at a pH of 3) but has an excellent release of ddl at pH above 5.

EXAMPLE 2 A preferred ddI formulation was prepared in the form of beads with enteric coverage as described below. Sodium starch glycollate (0.0327 kg) and NaCMC (0.0082 kg) were placed in a suitable mixer / mixer, ddl - (0.7774 kg). If a drum type mixer was used, the combination was mixed for 10 ± 2 minutes. If a planetary mixer was used, the combination was mixed for 10 ± 2 minutes. If a large-cut mixer was used, the combination was mixed for 5 ± 2 minutes. If a drum type mixer or planetary type mixer was used, the combination was milled through a Fitz mill equipped with advance hammers, plate # 1, and set at medium speed. This ground material was subsequently placed inside a drum-type mixer or planetary mixer and mixed for 10 ± 20 minutes. Before mixing, if any of the materials required a degranulation, they were passed through a # 20 mesh steel screen.

Then, approximately 10% -20% of the second mixture was removed and separated to be sprinkled during spheronization. The resulting mixture was granulated to an appropriate point of wet mass using a planetary mixer or large cut mixer. Approximately 200-360 g of water per 1 kg was added. of dry mix until a suitable wet mass for extrusion was achieved. The wet mass was extruded through an appropriate screen using a Nica Model E140 extruder, Feed Speed 1, Stir Speed 1 which achieved a 10/18 mesh bead fraction during spheronization. The extrudates were transferred to an appropriate spheronizer, a Caleva Model 15 at 500 rpm, or a Marumerizer ™ Q-400 at 700 rpm, and spheronized at medium speed using a medium cross-hatched plate (0.3 mm-0.4 mm) or a Radial design plate for approximately 1 - 3 minutes. 10% -20% of the previously prepared dry mixture which was separated was then used to sprinkle the beads and prevent agglomeration. After the appropriate time of spheronization, the product was discharged into an appropriate container.

The spheronized wet beads were carefully passed through sieves with mesh sizes # 10 and # 18 to recover a 10/18 mesh product fraction. Fractions with sizes greater than 10 mesh and smaller than 18 mesh were returned to the extruder for re-extrusion and spheronization. This process was continued until at least 90% of the product fraction was obtained. Subsequently the 10/18 mesh product fraction was dried using a hot air tray dryer or a fluidized bed type dryer set at 55 ° C to 60 ° C (for example, in the Glatt GPC-5, the inlet temperature of 60 ° C, the Product temperature of 50 ° C, the Exit temperature of 42 ° C) to achieve a pre-specified predetermined moisture content. The dried pearls were sifted through # 10 and # 20 mesh screens to remove any granules or small sized pearls. The 10/20 mesh pearl product fraction was transferred to a suitable container lined with two polyethylene bags. The net weight was determined, and the yield% of the product and the response of the pearl manufacturing process were calculated.

To prepare sufficient amounts of film coverage to coat 1 kg. of the pearl lot, the amounts of Eudragit solids deposited in 1 kg of pearls was 0.1562 kg. The amounts of diethyl phthalate deposited in 1 kg. of pearls was 0.0234 kg. The Eudragit L-30-D 55 was filtered through a # 60 mesh screen to remove any granules present there. Then the filtered Eudragit (0.1562 kg., Dry weight) was added with stirring to a tarry vessel containing one and a half amount of water required. The mixture was stirred continuously for 5 minutes or until a uniform mixture was visually evident. With continuous stirring diethyl phthalate was added (0.0234 kg.) To a vessel and stirring continued for 20 minutes or until a uniform mixture was visually evident. Then, a pH meter was standardized using buffer solutions of pH 4 and pH 7. With continuous stirring, a solution of NaOH was added to a vessel until a pH of 5.0 ± 0.1 was obtained. The formula weight of the coating suspension is adjusted using water and stirring is continued for an additional 10 minutes.

Subsequently, the beads were coated using a Wurster spray coating system. Ideal parameters for the spray coverage system include an Aeromatic STREA-1, 300 g load, 0.8 mm nozzle, 8 g / min. Spray speed, 1.4 bar spray pressure, 64 ° inlet temperature C, outlet temperature of 42 ° C; a Glatt GPCG-5 with Wurster column, 1500 g, nozzle of 1.2 mm, spray speed of 20 g / min., spray pressure of 1.0 bar, inlet temperature of 65 ° C, product temperature of 48 ° C, Output temperature of 42 ° C.

Before beginning the application of the film coating suspension, the beads may optionally be heated to about 50 ° C for about 5 minutes and dried for 25 ± 10 minutes. A film coverage of 16% -20% w / w was applied using the previously described parameters. After completing the film coverage the inlet temperature was reduced to maintain a product temperature of about 50 ° C and subsequently the beads were dried for 25 ± 10 minutes. The net weight of the pearls with film coverage was determined. The percentage of film coverage of the beads was calculated.

The talc weight (at 0.2% level) was determined to be added based on the net weight of the beads. Then, the amount of talc determined was weighed. The beads with film cover were placed in a suitable drum-type mixer together with the talc and the mixture for 15 ± 5 minutes. The beads were then transferred to an appropriate lined container (s) with two polyethylene bags and the net weight was determined.

The beads formed in this way can then be introduced into capsules or caps, such as gelatin capsules to facilitate swallowing.

It was found that the enteric coating ddl product formed in this manner provides excellent protection against gastric acid (at a pH of 3) but has an excellent release of ddl at pH above 4.5.

It is noted that in relation to this date, the best method known to 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, the content of the following is claimed as property.

Claims (50)

1. An enteric coating pharmaceutical composition, characterized in that it comprises a center in the form of a bead, pellet, granule or particle and an enteric coverage for said center, said center comprising a medicament of labile acid in an amount in the range of 50 to 100. % by weight of said composition, a binder in an amount in the range of 0 to 10% by weight of said composition, a disintegrant in an amount in the range of 0 to 10% by weight of said composition, and said enteric coating comprising a copolymer of methacrylic acid, and a plasticizer, said enteric coverage imparting protection to said center such that said center has protection in a low pH environment of 3 or less while being able to release the drug to a pH of 4.5 or greater, said pharmaceutical composition also comprising an anti-adherent in an amount in the range of 0.1 to 4% by weight.
2. The pharmaceutical composition according to claim 1, characterized in that said center is in the form of a bead or pellet.
3. The pharmaceutical composition according to claim 2, characterized in that said center is in the form of a bead.
4. The pharmaceutical composition according to claim 1, characterized in that said enteric coverage is present in a weight ratio with respect to the center in a range of 0.05: 1 to 0.6: 1.
5. The pharmaceutical composition according to claim 1, characterized in that said enteric coating includes the methacrylic acid copolymer in an amount in the range of 5 to 30% by weight, and said plasticizer is in an amount in the range of 0.5. to 6% by weight, all previous% being based on the solid content of said enteric coverage.
6. The pharmaceutical composition according to claim 5, characterized in that said copolymer of methacrylic acid is Eudragit L-30-D 55.
7. The pharmaceutical composition according to claim 5, characterized in that said plasticizer is diethyl phthalate, triethyl citrate, triacetin, tributyl sebacate, or polyethylene glycol.
8. The pharmaceutical composition according to claim 7, characterized in that said plasticizer is diethyl phthalate.
9. The pharmaceutical composition according to claim 8, characterized in that said enteric coverage includes copolymer of methacrylic acid and diethyl phthalate.
10. The pharmaceutical composition according to claim 1, characterized in that said anti-adherent is a hydrophobic material.
11. The pharmaceutical composition according to claim 10, characterized in that the anti-adherent is talc, magnesium stearate or fumed silica.
12. The pharmaceutical composition according to claim 11, characterized in that the anti-adherent is talc.
13. The pharmaceutical composition according to claim 1, characterized in that. said antiadherent is present in an amount in the range of 0.1% to 4.0% by weight, all the above% being based on the solids content of said enteric coverage.
14. The pharmaceutical composition according to claim 1, characterized in that the pH of said enteric coverage is adjusted using alkalizing agents to improve the stability between said medically labile acid in said center and said acid enteric coverage.
15. The pharmaceutical composition according to claim 14, characterized in that the pH adjustment of said enteric coverage eliminates the incompatibility between said labile acid drug in said center and said acid enteric coverage.
16. The pharmaceutical composition according to claim 15, characterized in that the adjustment of said pH of said acidic enteric coating eliminates the need for a protective undercoverage between said labile acid drug in said center and said acid enteric coverage.
17. 17. The pharmaceutical composition according to claim 16, characterized in that the elimination of said protective undercoverage allows a faster release of said labile acid drug from said center.
18. 18. The pharmaceutical composition according to claim 1, characterized in that said medicament is present in an amount in the range of 50 to 100% of the composition of the center when said center is not coated.
19. 19. The pharmaceutical composition according to claim 1, characterized in that said medicament is ddl.
20. 20. The pharmaceutical composition according to claim 1, characterized in that said medicament is pravastatin, erythromycin, digoxin, pancreatin, ddA or ddC.
21. 21. The pharmaceutical composition according to claim 1, characterized in that said center includes a disintegrant present in an amount in the range of 0 to 10.0% by weight.
22. 22. The pharmaceutical composition according to claim 1, characterized in that said disintegrant is sodium starch glycolate, croscarmellose sodium, corn starch, or cross-linked polyvinylpyrrolidone.
23. 23. The pharmaceutical composition according to claim 22, characterized in that said disintegrant is sodium starch glycolate.
24. 24. The pharmaceutical composition according to claim 1, characterized in that said center includes a binder present in an amount in the range of 0 to 10% by weight.
25. 25, The pharmaceutical composition according to claim 24, characterized in that said binder is sodium carboxymethylcellulose, Avicel ™ PH101, Avicel ™ RC 591, Avicel ™ CL-611, Methocel ™ E-5, Starch 1500, Hydroxypropyl Methylcellulose, Polyvinylpyrrolidone, Alginate of Potassium or Sodium Alginate.
26. 26. The pharmaceutical composition according to claim 24, characterized in that said binder is sodium carboxymethyl cellulose.
27. 27. The pharmaceutical composition according to claim 24, characterized in that said binder is alkaline in nature.
28. 28. The pharmaceutical composition according to claim 27, characterized in that said center comprising said labile acid medicament becomes more stable with the inclusion of said alkaline binder.
29. 29. The pharmaceutical composition according to claim 1, characterized in that said center comprising said drug labile acid becomes more stable with the inclusion of an alkaline ingredient such as magnesium oxide.
30. 30. The pharmaceutical composition according to claim 1, characterized in that it has the following composition: Material (interval) CENTER Drug (didanosine) 50 - 100.00 NaCMC 0 - 10.0 Sodium Starch Glicolate 0 - 10.0 COVERAGE Eudragit L-30-D 55 5.0 30.0 Diethyl Phthalate 0.5 6.0 ANTIADHERENT COVERAGE Talco 0.1 - 4.0
31. 31. A ddl with enteric coverage characterized in that it comprises a center in the form of a bead or pellet which includes ddl in an amount in the range of 50 to 100% by weight of said center, and an enteric coverage that includes an acid copolymer methacrylic
32. 32. The ddl in accordance with that defined in claim 31, characterized by being in the form of beads.
33. The ddI according to that defined in claim 32, characterized in that the enteric coverage includes a copolymer of methacrylic acid and a plasticizer.
34. The ddl according to that defined in claim 33, characterized in that it additionally comprises an anti-adherent.
35. A process for the preparation of a pharmaceutical composition with enteric coverage, characterized in that it comprises the steps of: (a) preparing a dry mixture comprising a medicament, a binder and a disintegrant, and separating a portion of said dry mixture; (b) forming a moist mass of the remnant of said dry mixture not separated in step (a); (c) extruding said wet mass to form an extrudate and spheronizing said extrudate into high potential beads by dusting said wet mass extrudate with said portion of said dried mixture separated in step (a); (d) coating said beads with an enteric coating polymer and a plasticizer in an aqueous medium; and (e) mixing said coated beads with an anti-adherent.
36. The process according to claim 35, characterized in that it additionally comprises the step of separating said high spheronization potential beads formed in step (c) using a # 10 mesh screen and a # 18 mesh screen to form a fraction of product of 10/18 mesh size beads before coating step (d).
37. The process according to claim 35, characterized in that said drug in a labile acid drug.
38. The process according to claim 37, characterized in that said labile acid drug is selected from the group consisting of ddl, pravastatin, erythromycin, digoxin, pancreatin, ddA or ddC.
39. 39. The process according to claim 38, characterized in that said medicament is ddl.
40. 40. The process according to claim 35, characterized in that said binder is sodium carboxymethyl cellulose.
41. 41. The process according to claim 35, characterized in that said disintegrant is sodium starch glycolate.
42. 42. The process according to claim 35, characterized in that the wet mass is formed by the addition of a granulation solvent.
43. 43. The process according to claim 42, characterized in that said granulation solvent is water.
44. 44. The process according to claim 35, characterized in that said plasticizer is diethyl phthalate.
45. 45. The process according to claim 44, characterized in that said enteric coverage includes copolymer of methacrylic acid and diethyl phthalate.
46. 46. The process according to claim 45, characterized in that said methacrylic acid polymer is Eudragit L-30-D 55.
47. 47. The process according to claim 35, characterized in that said anti-adherent is talc.
48. 48. The process according to claim 35, characterized in that it additionally comprises the step of filling said coated beads prepared in step (e) in a capsule.
49. 49. The pharmaceutical composition according to claim 3, characterized in that numerous of said beads are encapsulated in a capsule for oral administration. 50, The pharmaceutical composition according to claim 49, characterized in that said capsule is filled into a capsule with numerous beads in an equivalent amount to obtain a required dose of ddI for a twice daily administration. The pharmaceutical composition according to claim 49, characterized in that said capsule is filled with numerous beads in an amount equivalent to obtaining a dose of ddL required for a once-a-day administration. The ddl according to that defined in claim 32, characterized in that said beads are encapsulated in a capsule. The ddI according to that defined in claim 52, characterized in that said capsule is filled with said beads in an amount equivalent to achieving a dose of ddL required for a twice daily administration. The ddI according to that defined in claim 52, characterized in that said capsule is filled with said beads in an amount equivalent to obtaining a dose of ddI required for a once-a-day administration.