Title:  Method for the preparation of an enteric coated high drug load pharmaceutical composition

United States Patent:  6,224,910

Assignee:  Bristol-Myers Squibb Company (Princeton, NJ)

Filed:  September 29, 1999

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 enteric coating 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 OF THE INVENTION

In accordance with the present invention, an enteric coated, high drug load pharmaceutical composition, and a method of making said pharmaceutical composition, is provided which includes a medicament which may degrade in a low pH environment but which is protected from doing so by the enteric coating. The pharmaceutical composition of the invention, which is advantageously in the form of beadlets, pellets or tablets, includes a core which comprises a medicament which is sensitive to a low pH environment, such as ddl, and optionally a binder, a disintegrant or swelling agent, and a filler. The core further comprises an enteric coating surrounding the core which includes a methacrylic acid copolymer and a plasticizer. The pharmaceutical composition may further comprise an anti-adherent coat.

The novel enteric coated pharmaceutical of the invention will provide for protection of the medicament or therapeutically active agent, such as ddl, at pH's less than 3 (such as found in the stomach) but will permit drug release at a pH of 4.5 or higher (such as found in the upper intestines).

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

Most of the enteric coating materials known in the art are acidic in nature and hence may cause chemical instability when in contact with acid labile ingredients. This is especially true under high temperature and humid conditions experienced during an aqueous coating process. To minimize this acid caused instability, a protective coat or subcoat is usually applied between the particles, beadlets, pellets, etc., and the enteric coat. This protective coat physically separates the acid labile drug from the acidic enteric coat, and hence improves stability of the formulation.

A process is thus described by which tablets, beadlets, pellets, and/or particles containing acid labile drugs can be successfully aqueous enteric coated without application of the protective coat or subcoat. This process involves raising the pH of the enteric coating suspension solution by using alkalizing agents. The pH of the coating suspension is raised below the point where 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 are relatively alkaline in nature, in the formulations intended for enteric coating. These steps provide a more stable composition for the acid labile drug in the core. As a result, incompatibility between the acid labile drug and the acidic enteric coating is reduced and there is no need for a protective subcoat between the acid labile drug and the acidic enteric coat. This process not only eliminates the costly additional subcoating step, but allows quicker release of the drug since the added subcoat layer delays drug release.

Normally, drug beads are formed by preparing a wet mass which is extruded into threads or noodles. These are spun on a high-speed rotating plate which breaks these into small pieces and rounds the ends to make spherical particles by a process known as spheronization. This spheronization generates centrifugal force. Under these forces, if the particles do not have enough moisture absorbent, the moisture will be extracted out of the particles (drawn to the surface), which will cause agglomeration. Microcrystalline cellulose is a good moisture absorbent and is thus an excellent spheronization aid. Often more than 15%, and usually more than 30%, is needed to obtain good spheronization characteristics.

It has been observed that when moisture is drawn to the surface during spheronization, dry powder could be dusted on the particles to quench the moisture and prevent agglomeration. It was believed by the inventors herein that this process could be used to completely eliminate the use of moisture absorbent in the formulation to prepare high drug load beads. It was further believed by the inventors that the drug with dry binder (if necessary) and optional disintegrant could be blended. A major portion of this dry blend could be wet massed, extruded, and the remaining dry blend used for quenching the moisture that surfaces during spheronization. This technique allows very high drug loads and would not change the composition of the bead, regardless of the amount of dry blend used for dusting.

The process of the present invention allows for formation of beads with very high drug load (up to 100%), and generally involves the preparation of a dry blend of powdered drug substance with or without a very small amount of suitable binder and optional disintegrant. The drug itself, the drug/dry binder mixture, or the drug/dry binder/disintegrant mixture should be capable of becoming tacky upon moistening. A major portion (70-95%) of this blend is wet massed, extruded and spheronized as is conventionally performed in the art for bead formation. A minor portion (5-30%) of the blend is set aside for dusting. As the spheronization process proceeds, extrudate strands break and the particles are rounded off. During this process, moisture is extracted out of these particles. The portion of the dry blend set aside earlier is dusted upon the moist particles to quench the surface moisture. This renders the particles relatively dry and free to move in a conventional rope formation pattern. Accordingly, spheronization of the beads progresses without agglomeration.

Often, enteric-coated or modified release beads or particles are prepared for oral delivery of the drugs in capsule dosage form. Upon oral ingestion the capsule shell dissolves allowing the contents in the capsule to be exposed to the gastric contents. Due to the presence of fluids in the stomach, exposed particles become moistened. If the moist particles do not stick together, they will disperse into the gastric contents and may begin to enter the duodenum based on the size distribution and other factors which control the gastric transit time. However, if the particles become tacky upon moistening, they may stick together as one or more lumps. In this case, such lumps may behave as large particles and their gastric emptying time will be variable depending upon the size and the strength of the lumps formed. In this case, such a dosage form would not behave as a true multiparticulate system. In order to solve this problem, according to the process of the present invention, enteric-coated beadlets, pellets, particles or tablets are over coated with a hydrophobic anti adherent before encapsulation. The amount of hydrophobic coating is kept to a level where it is just enough to prevent particle sticking after the capsule shell has dissolved, but not too much to retard dissolution. By this simple process, the particles behave as individual particles, and the gastric transit time is closer to that which is expected for the particle size for which the dosage form was designed, thus resulting in a more predictable and less variable dosage form.

The process of the present invention illustrates the preparation of high (up to 100%) potency (uncoated) beadlets, for acid labile drugs, such as ddl, using an aqueous process. No specialized equipment is required as conventional extrusion and spheronization equipment was found to be adequate for beadlet formation. Use of an alkaline binder, such as sodium carboxymethylcellulose, and dusting during spheronization with a dry blend mixture comprising the medicament, and optionally binder and a disintegrant, insured chemical stability of the medicament and maximized the drug load. The process of the present invention resulted in high (>90%) yield of beads of narrow particle size cut.

The invention is particularly adapted to pharmaceutical compositions such as beadlets, pellets or tablets, preferably beadlets, containing ddl as the medicament. ddl will be present in an amount of about up to 100% of the composition in the coated beadlets.

The coated beadlets pass through the stomach first. The transit time for the stomach is approximately two hours and the pH of this region is approximately 1 to 3. The enteric coating component allows the medicament core to remain substantially intact and thus prevents the pharmacologically active substance from being released in this region or the acid from penetrating through to the bead core. The beadlets then pass through the small intestine wherein the majority of the enteric coating component will dissolve and release the pharmacologically active substance therein. In normal flow direction therethrough, the small intestine consists of the duodenum, jejunum and ileum. Transit time through the small intestine is approximately 2-4 hours and the pH of these regions is approximately 5 to approximately 7.2.

As used herein "enteric coating", is a polymer material or materials which encases the medicament core. The polymeric enteric coating material in the present invention does not contain any active compound, i.e. any therapeutically active agent, of the present invention. Preferably, a substantial amount or all of the enteric polymer coating material is dissolved before the medicament or therapeutically active agent is released from the dosage form, so as to achieve delayed dissolution of the medicament core. A suitable pH-sensitive polymer is one which will dissolve with intestinal juices at the higher pH levels (pH greater than 4.5), such as within the small intestine and therefore permit release of the pharmacologically active substance in the regions of the small intestine and not in the upper portion of the GI tract, such as the stomach.

The polymer coating material 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 pH 4.5. Preferred coating pH-sensitive materials, which remain intact in the lower pH environs of the stomach, but which disintegrate or dissolve at the pH commonly found in the small intestine of the patient. The enteric polymer coating material begins to dissolve in an aqueous solution at pH between about 4.5 to about 5.5. The pH-solubility behavior of the enteric polymers of the present invention are such that significant dissolution of the enteric polymer coating will not occur until the dosage form has 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 distal portions of the small intestine (ileum). In order to provide predictable dissolution corresponding to the small intestine transit time of about 3 hours and permit reproducible release therein, the coating should begin to dissolve within the pH range of the duodenum and continue to dissolve at the pH range within the small intestine. Therefore, the amount of enteric polymer coating should be such that it is substantially dissolved during the approximate three hour transit time within the small intestine.

The pharmaceutical medicament present in the core will be an acid labile drug such as ddl, pravastatin, erythromycin, digoxin, pancreatin, ddA (2',3'-dideoxyadenosine), ddC (2',3'-didexoycytosine), and the like. The present invention is not limited to these drugs and other drugs may be used as well.

One or more binders may be present in the core in an amount within the range of from about 0 to about 10% and preferably about 1% by weight of the composition. Sodium carboxymethylcellulose is the preferred binder most suitable for use herein. Examples of other binders which may be used include Avicel.TM. PH101, Avicel.TM. RC 591, Avicel.TM. CL-61 1, (FMC Corp), Methocel.TM. E-5 (Dow Corp.), Starch 1500 (Colorcon, Ltd.), Hydroxypropyl Methylcellulose (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 disintegrants or swelling agents in an amount within the range from about 1% to about 4% by weight of the composition, such as sodium starch glycolate marketed under the trademark EXPLOTAB (Edward Mendell Co.), Ac-Di-Sol (cross-linked sodium carboxymethylcellulose) (FMC Corp), croscarmellose sodium, corn starch, or cross linked polyvinylpyrrolidone.

The core employed in the pharmaceutical composition of the invention may be formed of a beadlet or pellet having a diameter of from about 0.5 to about 5 mm, and preferably from about 1 to about 2 mm. The core will preferably be in the form of a beadlet or a pellet.

In forming the enteric coated pharmaceutical composition of the invention, an enteric coating solution of Eudragit L-30-D 55 will be employed. Eudragit L-30-D 55 is an aqueous acrylic resin dispersion, an anionic copolymer derived from methacrylic acid and ethyl acrylate with a ratio of free carboxyl groups to the ester of approximately 1:1, and a mean molecular weight of approximately 250,000, is supplied as an aqueous dispersion containing 30% w/w of dry lacquer substance, and is marketed by Rohm-Pharma Co., Germany. As an aqueous-based coating, no dangerous or environmentally harmful organic solvents are utilized.

Although Eudragit is the preferred coating polymer, the invention is not limited in this respect and other enteric coating polymers known in the art, 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.TM. (polyvinyl acetate phthalate) (Colorcon Ltd.), Sureteric.TM. (polyvinyl acetate phthalate) (Colorcon, Ltd.), or Aquateric.TM. (cellulose acetate phthalate) (FMC Corp.) and the like may be employed.

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 may be used such as triethyl citrate (Citroflex-2), triacetin, tributyl sebecate, or polyethylene glycol. Optionally an anti-adherent (anti-agglomerant) which is advantageously a hydrophobic material such as talc, magnesium stearate or fumed silica, with talc being referred, can be applied after coating the beadlet or pellet.

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

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

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

The enteric coating will thus contain from about 5% to about 35% by weight of solids, and from about 65% to about 95% by weight of water.

In general, where the core includes a drug which is incompatible with the enteric coating layer, a subcoat layer which may be comprised of one or more film-formers or plasticizers, and which acts as a physical barrier between the core and the outer enteric coating layer will be employed. However, unlike previously reported coatings such as that disclosed in U.S. Pat. No. 5,225,202, the novel pharmaceutical composition of the invention, as a result of the novel process utilized in making the composition of the present invention and the pH adjustment of the coating, does not require a subcoat since the need for such an insulating layer is eliminated by stabilizing the beadlets with an alkalizing agent and by aqueous coating at pH 5. Since the coating is designed to breakdown at pH 5.5, the enteric coating applied at pH 5 permits relatively rapid breakdown in the intestine as only a small amount of additional alkalinity is required to bring the pH to 5.5.

The enteric coating will be present in a weight ratio to the core of within the range of from about 5% to about 30% for release in the small intestine, but may be increased to approximately 60% for release in the colon.

A preferred enteric coated beadlet formulation is set out below.

Claim 1 of 45 Claims

We claim:

1. A process for the preparation of a high drug load enteric-coated pharmaceutical composition comprising the steps of:

(a) preparing a dry blend comprising a medicament, a binder, and a disintegrant, and setting a portion of said dry blend aside;

(b) forming a wet mass from the remainder of said dry blend not set aside in step (a);

(c) extruding said wet mass to form an extrudate and spheronizing said extrudate into high-potency beadlets by dusting said wet mass extrudate with said portion of said dry blend set aside in step (a);

(d) coating said beadlets with an enteric coating polymer and plasticizer in an aqueous media; and

(e) blending said coated beadlets with an anti-adherent,

wherein the process further comprising the step of separating said spheronized high potency beadlets formed in step c into 10/18 mesh sized beadlets prior to said coating step (d).

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