DE29824797U1 - Enteric coated drugs - Google Patents

Description

Utility model branching
UZ:E2756GM-DE/D

GASTRIC ACID-RESISTANT COATED MEDICINAL PRODUCT Brief description of the invention

The present invention relates to an enteric coated pharmaceutical composition comprising an acid labile medicament with a high drug loading which is sensitive to a low pH environment of less than 3, such as ddl, the composition also being in the form of beads or tablets and comprising an enteric coating such as Eudragit L-30-D 55 and a plasticizer, but not requiring a backing layer; the beads also having a non-stick coating. The so-called beads have excellent disintegration resistance at a pH of less than 3, but have excellent drug release properties at a pH of above 4.5.

Background of the invention

Enteric coatings have been used for many years to inhibit the release of drug from orally ingestible dosage forms. Depending on the composition and/or thickness, the enteric coatings are resistant to stomach acid for required periods of time before they begin to break down and allow the slow release of the drug into the lower stomach or upper part of the small intestine. Examples of some enteric coatings are disclosed in US-A-5,225,202, which is incorporated herein by reference in its entirety. As explained in US-A-5,225,202, some examples of coatings used to date are beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and cetyl alcohol, mastic and shellac, and shellac and stearic acid (US-A-2,809,918); Polyvinyl acetate and ethyl cellulose (US-A-3,835,221); and neutral copolymer of polymethacrylic acid esters (Eudragit L30D) (F.W. Goodhart et al., Pharm. Tech., pp. 64-71, April 1984); copolymers of methacrylic acid and methyl methacrylate (Eudragite), or a neutral copolymer of

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Polymethacrylic acid esters containing metallic stearates (Mehta et al., US-A-4,728,512 and 4,794,001).

Most enteric coating polymers begin to become soluble at pH 5.5 and above, with maximum solubility rates achieved at pH values above 6.5.

Numerous enteric coated and/or extended release drugs and the methods for preparing these compositions are disclosed in the prior art. Although some of these previously disclosed compositions are formed into small beads or pellets, they often contain numerous other ingredients in addition to the drug, such as fillers, buffers, binders and wetting agents, all of which increase the volume of the composition and reduce the amount of active drug that can be contained in the composition. The methods for preparing these above drugs require several time consuming steps including steps for forming bottom and outer layers. Furthermore, many of these drugs are intended for administration to the lower gastrointestinal tract, i.e., the colon, rather than to the upper intestine, i.e., the duodenum of the small intestine.

US-A-5,225,202 discloses enteric coated pharmaceuticals using a neutralized hydroxypropylmethylcellulose phthalate polymer (HPMCP) coating. The disclosed pharmaceuticals comprise an acid labile drug core, a disintegrant, one or more buffers to further protect the stomach in addition to the enteric coating, the enteric coating and a plasticizer. The pharmaceutical may also include one or more lactose, sugar or starch fillers. According to the invention disclosed in this document, when the core includes a drug that is incompatible with the enteric coating layer, an additional sublayer is used that serves as a physical barrier between the core and the outer enteric coating layer to prevent interaction of the acid labile drug and the acidic enteric coating. The dissolution process of the enteric HPMCP coating begins at pH 5.0. The

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Process for manufacturing this medicinal product requires numerous coating steps to apply the base layer and then the enteric coating.

US-A-5,026,560 discloses a pharmaceutical composition and a process for preparing the pharmaceutical composition, the pharmaceutical composition comprising a unique seed kernel prepared by coating sucrose with corn starch, spraying the kernel with an aqueous binder in a solution of water or ethanol and with a spray powder containing a drug and a weakly substituted hydroxypropyl cellulose, followed by applying an enteric coating.

US-A-4,524,060 mentions a slow release pharmaceutical composition providing a sustained release composition for treating hypertensive patients comprising a mixture of powdered indoramin or a pharmaceutically acceptable salt thereof, a water channelling agent, a wetting agent, a disintegrant, the mixture being in the form of a non-compressed pellet and having an enteric coating or a sustained release coating permeable to gastrointestinal juices.

US-A-5,536,507 relates to a pharmaceutical composition having a sustained release coating or enteric coatings, wherein the active ingredient in the composition is intended to release a substantial amount of the drug at a point near the entrance to or in the large intestine and at a pH of about 6.4 to 7.0. ~

Medicines containing a drug that is unstable in an acidic environment, such as the stomach, and that is not adequately buffered, require an enteric coating to prevent the release of such a drug before it reaches the intestine.

ddl (also known as didanosine or 2',3'-dideoxyinosine and sold by Bristol-Myers Squibb Co. under the trademark Videx®) is an acid-labile drug that has the following formula

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and has been shown to be effective in treating patients with the HIV virus that causes AIDS. The composition and method of inhibiting HIV replication with 2',3'-dideoxyinosine has been reported. See US-A-4,861,759, 5,254,539 and 5,616,566, which are incorporated herein by reference. Recently, Videx® has been widely used as a component of the new therapeutic cocktails used to treat AIDS. In addition, it is an acid labile drug that is sensitive to a low pH environment and disintegrates in the stomach.

Videx® is generally available in a variety of oral dosage forms including chewable/dispersible buffered tablets in concentrations of 25, 50, 100 or 150 mg of didanosine. Each tablet is buffered with calcium carbonate and magnesium hydroxide. Videx® tablets also contain aspartame, sorbitol, microcrystalline cellulose, Polyplasdone®, mandarin orange flavor and magnesium stearate. Videx® buffered powder for oral solution is provided for oral administration in single-dose packets containing 100, 167 or 250 mg of didanosine. Packets of each product concentration 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 provided for oral administration in 4- and 8-ounce (approximately 120 g and approximately 240 g) glass bottles containing 2 and 4 grams of didanosine, respectively, and must be mixed with commercially available antacid prior to oral administration.

With particular emphasis on tablets, the current chewable/dispersible buffered tablets, when taken alone or as part of a combination ("cocktail") therapy regimen, do not facilitate easy patient use. While the other products that are part of the therapeutic cocktail against

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AIDS, are capsules or tablets and are easy to swallow, Videx® chewable/dispersible buffered tablets (referred to herein as "ddl") must be thoroughly chewed, manually crushed, or evenly dispersed in water prior to administration. Because ddl rapidly disintegrates at acidic pH, ddl in its chewable/dispersible form and its buffered powder for oral solution contains buffers and is administered with pediatric powder antacids. However, the presence of the large amounts of antacid components in the formulation can result in significant gastrointestinal upset, manifested 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 volume of liquid (4 ounces) required for the dose. All of these factors, combined with the fact that other nucleoside analogue drugs are marketed in more convenient dosage forms (i.e. capsule or smaller tablets), require the development of an innovative ddl dosage form that is easy to swallow and does not have unpleasant side effects.

The current adult dose of 200 mg twice daily or possibly 400 mg daily would require beads or particles with very high drug loading to encapsulate the 400 mg dose in a single capsule. A low drug loading formulation would require multiple capsules/dose, which would be less convenient for the patient in terms of dosing.

Accordingly, a coating is provided which prevents release of the drug in the stomach and allows release of the drug in the small intestine, thereby eliminating the need for an antacid which may cause gastrointestinal upset when used chronically. Thus, pharmaceutical compositions containing a drug which is unstable in an acidic environment such as the stomach require such a protective coating to prevent release of such a drug before it reaches the intestine.

Description of the drawing

Figure 1 is a flow chart generally illustrating the process for preparing the enteric coated pharmaceutical composition of the present invention.

Description of the invention

According to the present invention there is provided a high drug loading enteric coated pharmaceutical composition comprising a medicament which disintegrates in a low pH environment but is protected therefrom by the enteric coating. The pharmaceutical composition of the invention, which is advantageously in the form of beads, pellets or tablets, comprises a core comprising 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 comprising a methacrylic acid copolymer and a plasticizer. The pharmaceutical composition may further comprise a non-stick coating.

The novel enteric coated pharmaceutical composition of the invention provides protection of the drug or therapeutic agent, such as ddl, at pH values less than 3 (such as found in the stomach), but allows drug release at pH values of 4.5 or above (such as found in the upper intestine).

Accordingly, the pharmaceutical composition of the invention usually contains drugs that are chemically unstable in acidic environments. The pharmaceutical composition of the invention offers excellent protection in very acidic environments (pH < 3) while not retarding rapid release in pH ranges above 4, whether in the upper intestine or the duodenum.

Most of the enteric coating materials known in the art are acidic in nature and can thus cause chemical instability when they come into contact with acid-labile components. This is particularly true under high temperatures and humid conditions that occur during an aqueous

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To minimize this acid-induced instability, a protective coating or undercoat is usually applied between the particles, beads, pellets, etc. and the enteric coating. This protective coating physically separates the acid-labile drug from the acidic enteric coating and thus improves the stability of the formulation.

Thus, a method is described by which tablets, beads, pellets and/or particles containing acid labile drugs can be successfully coated with an aqueous enteric coating without applying the protective coating or undercoat. This method involves raising the pH of the enteric coating suspension solution using alkalizing agents. The pH of the coating suspension is raised below the point at which the enteric integrity of the polymer could be lost. The method 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 enteric coating formulations. These steps provide a more stable composition for the acid-labile drug in the core. As a result, there is no incompatibility and no need for a protective undercoat between the acid-labile drug and the acidic enteric coating. This process not only eliminates the costly additional step of forming an undercoat, but allows for faster release of the drug since the additional undercoat delays drug release.

Typically, drug beads are formed by preparing a wet mass that is extruded into threads or noodles. These are spun on a high speed rotating plate, breaking them into small pieces and rounding off the ends to produce spherical particles by a process known as spheronization. This spheronization creates a centrifugal force. Under the action of these forces, if the particles do not have enough moisture absorbers, the moisture is extracted from the particles (pulled to the surface), causing agglomeration. Microcrystalline cellulose is a good

Moisture absorber and is therefore an excellent spheronization aid. Often more than 15% and usually more than 30% is required to achieve good spheronization properties.

It was observed that if moisture was drawn to the surface during spheronization, dry powder could be dusted onto the particles to bind the moisture and prevent agglomeration. The present inventors believed that this method could be used to completely eliminate the use of moisture absorbers in the formulation to produce beads with high drug loading. The inventors further believed that the drug could be mixed with dry binder (if required) and optional disintegrant. Much of this dry mixture could be made into a wet mass, extracted, and the remaining dry mixture used to bind the moisture on these surfaces during spheronization. This approach allows for very high drug loadings and would not alter the composition of the beads regardless of the amount of dry mixture used for dusting.

The process enables the formation of beads with very high drug loading (up to 100%) and generally involves the preparation of a dry mixture of powdered drug substance with or without a very 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 should be capable of becoming sticky when moistened. A major portion (70 to 95%) of this mixture is made into a wet mass, extracted and spheronized as is commonly done in the art to form beads. A minor portion (5 to 30%) of the mixture is set aside for dusting. As the spheronization process progresses, extradate strands break and the particles become rounded. During this process, moisture is extracted from these particles. The previously set aside portion of the dry mix is dusted onto the wet particles to bind the surface moisture. This makes the particles relatively dry and free in a conventional strand formation pattern

mobile. Consequently, the spheronization of the beads proceeds without agglomeration.

Often, enteric coated or modified release beads or particles are prepared for oral administration of the drug in a capsule dosage form. After oral ingestion, the capsule shell dissolves, exposing the contents of the capsule to the stomach contents. Due to the presence of fluids in the stomach, exposed particles become moistened. If the moist particles do not stick together, they disperse into the stomach contents and may begin to pass into the duodenum, depending on the size distribution and other factors that control gastric transit time. However, if the particles become sticky when moistened, they may stick together as one or more clumps. In this case, such clumps may behave like large particles and their gastric emptying time will vary depending on the size and firmness of the clumps formed. In this case, such a dosage form would not behave as a true multiparticle system. To solve this problem, the process involves coating enteric coated beads, pellets, particles or tablets with a hydrophobic material prior to encapsulation. The amount of hydrophobic coating is maintained at a level that is just enough to prevent particles from sticking together after dissolution of the capsule shell, but not so high that it would retard dissolution. Using this simple process, the particles behave as individual particles and the gastric transit time is closer to that 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 illustrates the preparation of high potency (up to 100%) (uncoated) beads for acid labile drugs such as ddl using an aqueous process. No special equipment is required as conventional extrusion and spheronization apparatus proved adequate for the formation of beads. The use of an alkaline binder such as sodium carboxymethylcellulose and dusting during spheronization with a dry mixture comprising the drug and optionally binder and a disintegrant ensured the chemical stability of the drug and maximized

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drug loading. The process resulted in a high (>90%) yield of beads with a narrow particle size distribution.

The invention is particularly directed to pharmaceutical compositions such as beads, pellets or tablets, preferably beads, containing ddl as a medicament, ddl being present in the coated beads in an amount of up to about 100% of the composition.

The coated beads first pass through the stomach. Transit time through the stomach is about two hours and the pH of this region is about 1 to 3. The enteric coating component allows the drug core to remain substantially intact, thus preventing the pharmacological agent from being released in this region or acid from penetrating the bead core. The beads then pass through the small intestine, where most of the enteric coating component dissolves and releases the pharmacological agent therein. In normal flow through the small intestine, the small intestine consists of the duodenum, jejunum and ileum. Transit time through the small intestine is about 2 to 4 hours and the pH of these regions is about 5 to about 7.2.

As used herein, the "enteric coating" refers to one or more polymeric materials that enclose the drug core. The polymeric enteric coating material in the present invention does not contain an active compound, i.e., therapeutic agent, of the present invention. Preferably, a substantial amount or all of the polymeric enteric coating material is dissolved before the drug or therapeutic agent is released from the dosage form to provide delayed dissolution of the drug core. A suitable pH-sensitive polymer is one that dissolves with intestinal juices at higher pH values (pH above 4.5), such as in the small intestine, and therefore allows release of the pharmacological agent in the regions of the small intestine rather than in the upper region of the gastrointestinal tract, such as the stomach.

The polymeric coating material is selected so that the therapeutic agent is released when the dosage form reaches the small intestine or an area in which

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where the pH is above pH 4.5. Preferred are pH sensitive coating materials which remain intact in the lower pH environments of the stomach, but degrade or dissolve at the pH commonly found in the patient's small intestine. The polymeric enteric coating material begins to dissolve in aqueous solution at a pH between about 4.5 to about 5.5. The pH solubility behavior of the enteric polymers of the present invention is such that substantial dissolution of the enteric polymer coating does not occur until the dosage form has emptied from the stomach. The pH of the small intestine increases from about 4.5 to about 6.5 in the upper region of the duodenum to about 7.2 in the distal regions of the small intestine (ileum). To provide predictable dissolution corresponding to the small intestinal transit time of approximately 3 hours and to enable reproducible release therein, the coating should begin to dissolve in the pH range of the duodenum and continue to dissolve at the pH range in the small intestine. Therefore, the amount of enteric polymer coating should be such that it substantially dissolves during the approximately 3 hour transit time in the small intestine.

The pharmaceutical drug present in the core is an acid labile 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.

One or more binders may be present in the core in an amount ranging 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 that may be used include Avicel™ PH101, Avicel™ RC 591, Avicel™ CL-611 (FMC Corp.), Methocel™ 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 contain one or more disintegrants or swelling agents in an amount ranging from about 1 to about 4% by weight of the composition, such as sodium starch glycolate, sold under the trademark

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EXPLOTAB (Edward Mendell Co.), Ac-Di-SoI (cross-linked sodium carboxymethylcellulose) (FMC Corp.), croscarmellose sodium, corn starch or cross-linked polyvinylpyrrolidone.

The core used in the pharmaceutical composition of the invention may be formed from a bead 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 is preferably in the form of a bead or pellet.

In forming the enteric coated pharmaceutical composition of the invention, an enteric coating solution of Eudragit L-30-D 55 is used. Eudragit L-30-D 55 is an aqueous acrylic resin dispersion, an anionic copolymer derived from methacrylic acid and ethyl acrylate having a free carboxyl group to ester ratio of about 1:1 and an average molecular weight of about 250,000, is provided as an aqueous dispersion containing 30% w/w dry lacquer substance and is sold by Rohm-Pharma Co., Germany. As a water-based coating, no hazardous or environmentally harmful organic solvents are used.

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 hydroxypropylmethylcellulose phthalate HP 50 (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, Ltd.) or Aquateric™ (cellulose acetate phthalate) (FMC Corp.) and the like may be used.

The enteric coating preferably also contains 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 sebacate or polyethylene glycol may be used. Optionally, an anti-adhesion agent (anti-agglomeration agent), which is preferably a hydrophobic material such as talc, magnesium stearate or fumed silica

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talc is preferred, after coating the bead or pellet.

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

The above enteric coating comprises methacrylic acid copolymer in an amount of about 5 to 30, and preferably 10 to 20 wt.% based on the solid content of the enteric coating solution, and plasticizer in an amount of about 1 to 6, and preferably 2 to 3 wt.%.

All weights above refer to the total concentration of solids in the enteric coating solution/suspension.

The enteric coating therefore contains about 5 to about 35% by weight solids and about 65 to about 95% by weight water.

Generally, when the core contains a drug which is incompatible with the enteric coating layer, a sublayer is used which may comprise one or more film formers or plasticizers and serves as a physical barrier between the core and the outer enteric coating layer. However, unlike previously reported coatings such as that disclosed in US-A-5,225,202, the novel drug of the invention does not require a sublayer as a result of the novel process used in preparing the composition of the present invention and the pH adjustment of the coating, since the need for such an insulating layer is eliminated by stabilizing the beads with an alkalizing agent and by aqueous coating at pH 5. Because the coating is designed to break down at pH 5.5, the enteric coating applied at pH 5 allows for relatively rapid disintegration in the intestine since only a slight additional alkalinity is required to bring the pH to 5.5.

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The enteric coating is present in a weight ratio to the core ranging from about 5% to about 30% for release in the small intestine, but this ratio can be increased to about 60% for release in the colon.

A preferred formulation of enteric coated pellets is listed below.

material possible range % Preferred Total
composition % CORE Drug (Didanbsin)
NaCMC
Na-starch glycolate 50-100.0
0-10.0
0-10.0 95.00"
1.00
4.00 COATING
Eudragit L-30-D 55
Diethyl phthalate 5.0-30.0 -
0.5-6.0 10-20
1.5-3.0 NON-STICK AGENT
talc 0.1-4.0 0.2-0.5

The enteric coated pharmaceutical composition in the form of beads or pellets may be prepared by a process comprising the steps of initially preparing uncoated beads by preparing a dry mixture of an acid labile drug, a binder such as NaCMC and a disintegrant such as sodium starch glycolate using a free fall mixer, a planetary mixer or a high shear mixer. A portion in an amount of about 5% to 30% and preferably 10% to 20% of the dried mixture is set aside for later dusting during spheronization. Water is then added to the remaining 70% to 95% of the dry mixture and granulated to a suitable wet granulation mass using a planetary or high shear mixer. The wet mass is extruded using, for example, a Nicaextruder or other type of extruder to form an extrudate which is then fed into a spheronizer such as CaIeva, Nica or other type to form wet beads which are dusted during spheronization with the 5% to 30% of the dry mixture previously set aside. Then the beads are sized through mesh screens,

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to obtain the desired bead sizes. The beads can then be dried by plate drying or fluid bed drying. The general procedure using ddl as the acid labile drug is diagrammatically shown in Fig. 1.

The dried beads or pellets can then be coated with an enteric film coating suspension comprising Eudragit L-30-D and plasticizer (diethyl phthalate) using a fluid bed coater such as a Wurster spray nozzle application system or other suitable application system and then dried. During preparation of the film coating suspension, a NaOH solution is added to the suspension until a pH of 5.0 ±0.1 is obtained. Stabilizing the beads with a binder and adjusting the enteric film coating suspension to pH 5 eliminates the need for a sub-coat or isolation layer. The advantage of this is that an enteric coating at pH 5 allows for relatively rapid disintegration in the intestine since only minimal alkalinity is required to bring the pH to 5.5.

To prevent the film-coated beads from clumping, a hydrophobic anti-adhesion agent (talc) is then added to the film-coated beads and mixed.

The beads or pellets thus formed can then be filled into hard-shell capsules, such as gelatin capsules of various sizes, depending on the desired drug dosage.

The examples represent preferred embodiments of the present invention. The following examples further describe the materials and methods used in the practice of the invention and are intended for illustrative purposes only and are not intended to limit the scope or spirit of this invention or the claims in any way. Unless otherwise indicated, all temperatures are in degrees Celsius and all mesh sizes are in accordance with ASTM.

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EXAMPLE 1

A ddl formulation in the form of enteric coated beads with the following composition was prepared as described below.

COMPOSITION % by weight
COMPONENT % BY WEIGHT OF FINISHED
FORMULATION A: PELLET CORE
ddl
NaCMC
Na-starch glycolate
B: COVER 95
1
4 77,744
0.818
3,273 Eudragit L-30-D 55 (on
dry weight basis)
Diethyl phthalate
(pH setting to 5.0 ±0.1)
C: NON-STICK AGENT 87
13 15,621
2,343 talc
D: CAPSULE 100 - 0.200 Size 0 Clear body and
cap

The preparation of ddl beads began by sieving and mixing a mixture of ddl, sodium starch glycolate, and sodium carboxymethylcellulose. The resulting mixture was then sieved again and mixed again. Approximately 10% to 20% of the second mixture was then removed and set aside for dusting during spheronization. The remaining mixture was then granulated to an appropriate wet mass end point using a planetary mixer or high shear mixer. Approximately 200 to 360 g of water per 1 kg of dry mixture was added during mixing until an appropriate wet mass was obtained for extrusion. The wet mass was extruded through an appropriate sieve using an extruder (Nica Model E140, screw speed 1, agitator speed 1) yielding a fraction of beads of approximately 10/18 mesh after spheronization. The extrudate was transferred to a suitable spheronizer (Caleva Model 15 at 500 rpm or Q-400 Marumerizer™ at 700 rpm) and spheronized at medium speed using a medium cross-hatched plate or a radial pattern plate for approximately 1 to 5 minutes. The set aside

10% to 20% of the previously prepared dry mixture was used to dust the beads to prevent agglomeration. After an appropriate spheronization time, the product was emptied into a suitable container.

The spheronized wet beads were then carefully passed through #10 and #18 mesh screens to collect a 10/18 mesh product fraction. The fractions over 10 and under 18 mesh were returned to the extruder for re-extrusion and re-spheronization. This process was continued until at least 90% of the product fraction was obtained. The 10/18 mesh product fraction was then dried to a predetermined, pre-specified moisture content using a hot air plate dryer or a fluid bed dryer. The dried beads were sieved through #10 and #20 mesh screens to remove any lumps or undersized beads. The dried beads of the 10/20 mesh product fraction were transferred to a suitable container lined with two polyethylene bags. The net weight was determined and the percent yield and reliability of the bead preparation process were calculated.

To prepare sufficient quantities of film coating suspension to coat the bead batch, Eudragit L-30-D 55 was filtered through a #60 mesh sieve to remove any lumps present therein. The filtered Eudragit was weighed and then added with stirring to a tarred vessel containing one-half the required amount of water. The mixture was continuously stirred for 5 minutes or until a uniform mixture was visibly formed. With continuous stirring, diethyl phthalate was added to the vessel and stirring continued for 20 minutes or until a uniform mixture was visibly formed. A pH meter was then calibrated using pH 4 and pH 7 buffers. With continuous stirring, a NaOH solution was added to the vessel until a pH of 5.0 ±0.1 was achieved. The formula weight of the coating suspension was adjusted using water and stirring continued for an additional 10 minutes.

In the bead coating operation, a fluid bed processor was set up on a Wurster spray nozzle application system or other suitable application system. The ideal parameters for the spray application system include an Aeromatic STREA-I, 300 g feed, 0.8 mm tip, 8 g/min spray rate, spray pressure 1.0 bar, inlet temperature 64°C, outlet temperature 42°C; Glatt GPCG-5 with Wurster column, 1500 g, 1.2 mm tip, 20 g/min spray rate, spray pressure 1.0 bar, inlet temperature 65°C, product temperature 48°C, outlet temperature 42°C.

If desired, the beads may be preheated to about 50 ^° C for about 5 minutes prior to beginning application of the film coating suspension. A 16% to 20% w/w film coating was applied using the coating parameters previously described. After film coating was completed, the inlet temperature was lowered to maintain a product temperature of about 5O ^° C and the beads were then dried for 25 ± 10 minutes. The net weight of the film coated beads was determined. The percentage of film coating to the beads was calculated. The weight of talc to be added based on the net weight of the beads was determined. The actual percentage gain due to film coating depends on the efficiency of the coating process. The amount of coating applied can be adjusted to achieve the target weight gain due to coating. The determined talc weight was then weighed. The film-coated beads were placed with the talc in a suitable free-fall mixer and mixed for 15 + 5 minutes. The beads were then transferred to one or more suitable containers lined with two polyethylene bags and the net weight was determined.

The pellets thus formed can then be filled into capsules or shells, such as gelatin capsules, to make them easier to swallow.

It was shown that the enteric coated ddl product thus formed provided excellent protection against gastric acid (at pH 3), but showed excellent ddl release at pH values above 5.

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19
EXAMPLE 2

A preferred ddl formulation in the form of enteric coated beads was prepared as described below, ddl (0.7774 kg), sodium starch glycolate (0.0327 kg) and NaCMC (0.0082 kg) were added to a suitable mixer. If a free fall mixer was used, the mixture was mixed for 10 ± 2 minutes. If a planetary mixer was used, the mixture was mixed for 10 ± 2 minutes. If a high shear mixer was used, the mixture was mixed for 5 ± 2 minutes. If a free fall mixer or planetary mixer was used, the mixture was passed through a Fitzmill equipped with hammers forward, a #1 plate and set at medium speed. This ground material was then added to a free fall mixer or planetary mixer and mixed for 10 ± 2 minutes. If any of the ingredients required de-clumping, they were passed through a #20 mesh stainless steel sieve before mixing.

Approximately 10% to 20% of the second mixture was then removed and set aside for dusting during spheronization. The remaining mixture was then granulated to an appropriate wet mass end point using a planetary mixer or high shear mixer. Approximately 200 to 360 g of water per 1 kg of dry mixture was added with mixing until a suitable wet mass for extrusion was achieved. The wet mass was extruded through a suitable screen using a Nica Model E140 extruder, screw speed 1, agitator speed 1, yielding a 10/18 mesh bead fraction after spheronization. The extrudate was fed to an appropriate spheronizer, either a Caleva Model 15 at 500 rpm or a Q-400 Marumerizer™ at 700 rpm and spheronized at medium speed using a medium cross-hatched plate (0.3 mm to 0.4 mm) or a radial pattern plate for approximately 1 to 3 minutes. The 10% to 20% of the previously prepared dry mix that had been set aside was then used to dust the beads to prevent agglomeration. After an appropriate spheronization time, the product was emptied into a suitable container.

The spheronized wet beads were then carefully passed through #10 and #18 mesh screens to collect the 10/18 mesh product fraction. The fractions below 10 and above 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. The 10/18 mesh product fraction was then dried using a hot air plate dryer or a fluid bed dryer set at 55 ⁰ C to 60 ⁰ C (e.g. Glatt GPC-5, inlet temperature 60 ⁰ C, product temperature 50 ⁰ C, outlet temperature 42 ⁰ C) to obtain a predetermined, pre-specified moisture content. The dried beads were sieved through #10 and #20 mesh sieves to remove any clumps or beads that were too small. The 10/20 mesh dried bead product fraction was transferred to a suitable container lined with two polyethylene bags. The net weight was determined and the percent yield and reliability of the bead preparation process was calculated.

To prepare sufficient quantities of film coating to coat 1 kg of the bead batch, the amount of Eudragit solid per 1 kg of beads was 0.1562 kg. The amount of diethyl phthalate per 1 kg of beads was 0.0234 kg. The Eudragit L-30-D 55 was filtered through a #60 mesh sieve to remove any lumps present therein. The filtered Eudragit (0.1562 kg, dry weight) was then added, with stirring, to a tarred container containing one-half the required amount of water. The mixture was continuously stirred for 5 minutes or until a uniform mixture was visibly formed. With continuous stirring, diethyl phthalate (0.0234 kg) was added to the container and stirring continued for 20 minutes or until a uniform mixture was visibly formed. A pH meter was then calibrated using pH 4 and pH 7 buffers. With continuous stirring, a NaOH solution is added to the container until a pH of 5.0 ±0.1 is obtained. The formula weight of the coating suspension is adjusted using water and stirring is continued for an additional 10 minutes.

The beads were then coated using a Wurster spray nozzle application system. The ideal parameters for the spray nozzle application system included a

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Aeromatic STREA-I, 300 g feed, 0.8 mm tip, 8/min spray rate, spray pressure 1.4 bar, inlet temperature 64 ⁰ C, outlet temperature 42°C; Glatt GPCG-5 with Wurster column, 1500 g, 1.2 mm tip, 20 g/min spray rate, spray pressure 1.0 bar, inlet temperature 65°C, product temperature 48°C, outlet temperature 42°C.

Before beginning application of the film coating suspension, the beads may optionally be preheated to about 5O ⁰ C for about 5 minutes and dried for 25 ± 10 minutes. A 16% to 20% w/w film coating was applied using the previously set coating parameters. After film coating was completed, the inlet temperature was lowered to maintain a product temperature of about 50 ⁰ C and the beads were then dried for 25 ± 10 minutes. The net weight of the film coated beads was determined. The percentage of film coating to beads was calculated.

The weight of talc to be added (at a concentration of 0.2%) based on the net weight of the beads was determined. The determined weight of talc was then weighed. The film-coated beads were placed with the talc in a suitable free-fall mixer and mixed for 15 + 5 minutes. The beads were then transferred to one or more suitable containers lined with two polyethylene bags and the net weight was determined.

The pellets thus formed can then be filled into capsules or shells, such as gelatin capsules, to make them easier to swallow.

It was shown that the enteric coated ddl product thus formed provided excellent protection against gastric acid (at pH 3), but showed excellent ddl release at pH values above 4.5.

Claims (30)

1. A pharmaceutical composition comprising a core and an enteric coating for the core, the core comprising about 80 to about 100% by weight of an acid labile medicament, about 0 to about 10% by weight of a disintegrant, and about 0 to about 10% by weight of a binder selected from sodium carboxymethylcellulose, hydroxypropylmethylcellulose, potassium alginate, sodium alginate, and partially pregelatinized corn starch. 2. A pharmaceutical composition according to claim 1, further comprising a non-stick coating applied to the outside of the enteric coating. 3. A pharmaceutical composition according to claim 1, wherein the core is in the form of a bead. 4. Medicaments according to claims 1-2, wherein the enteric coating comprises a polymer and a plasticizer. 5. A pharmaceutical composition according to claim 4, wherein the polymer is selected from methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, polyvinyl phthalate and cellulose acetate phthalate. 6. Medicaments according to claims 4 and 5, wherein the weight ratio of the enteric coating to the core is between about 0.05:1 and about 0.6:1. 7. A pharmaceutical composition according to claim 5, wherein the polymer comprises a methacrylic acid copolymer. 8. The pharmaceutical composition of claim 7, wherein the enteric coating comprises the methacrylic acid copolymer in an amount ranging from about 5 to about 30% of the total weight of the composition and the plasticizer in an amount ranging from about 0.5 to about 6% of the total weight of the composition. 9. A pharmaceutical composition according to claim 8, wherein the methacrylic acid copolymer is methacrylic acid copolymer type C (Eudragit L-30-D 55). 10. Medicaments according to claims 4 and 5, wherein the plasticizer is diethyl phthalate, triethyl citrate, triacetin, tributyl sebacate or polyethylene glycol. 11. A pharmaceutical composition according to claim 10, wherein the plasticizer is diethyl phthalate. 12. A pharmaceutical composition according to claim 10, wherein the enteric coating comprises methacrylic acid copolymer and diethyl phthalate. 13. A pharmaceutical composition according to claim 2, wherein the non-stick coating is a hydrophobic material. 14. A pharmaceutical composition according to claim 13, wherein the non-stick coating is talc, magnesium stearate or fumed silica. 15. A pharmaceutical composition according to claim 14, wherein the non-stick coating is talc. 16. The pharmaceutical composition of claims 8 and 15, wherein the anti-adhesion agent is present in an amount ranging from about 0.1% to about 4.0% of the total weight of the composition. 17. Medicaments according to claims 1-2, wherein the disintegrant is sodium starch glycolate, cross-linked sodium carboxymethylcellulose, croscarmellose sodium, corn starch or cross-linked polyvinylpyrrolidone. 18. A pharmaceutical composition according to claim 17, wherein the disintegrant is sodium starch glycolate. 19. A pharmaceutical composition according to claim 1, wherein the binder is of alkaline nature. 20. Medicaments according to claims 1-2 and 19, wherein the binder is sodium carboxymethylcellulose. 21. Medicaments according to claims 1 and 2, wherein the medicament is pravastatin, erythromycin, digoxin, pancreatin, 2,3'-dideoxyadenosine, 2',3'-dideoxycytosine or 2',3'-dideoxyinosine. 22. A pharmaceutical composition according to claims 1-2, 8, 16-17 and 20-21, wherein the medicament is 2',3'-dideoxyinosine. 23. A pharmaceutical composition according to claims 1 and 22, wherein the core comprises about 95% by weight of 2',3'-dideoxyinosine, about 1% by weight of sodium carboxymethylcellulose and about 4% by weight of sodium starch glycolate. 24. Medicinal products comprising: (a) a soluble capsule; and b) the medicament according to claims 1, 2 or 23, which is encapsulated in the soluble capsule. 25. A spheronized bead comprising: a) about 80 to about 100% by weight of an acid labile medicament; b) about 0 to about 10% by weight of a disintegrant; and c) about 0 to about 10% by weight of a binder selected from sodium carboxymethylcellulose, hydroxypropylmethylcellulose, potassium alginate, sodium alginate and partially pregelatinized corn starch. 26. The spheronized bead of claim 1, wherein the acid labile drug is selected from 2',3'-dideoxyinosine, 2',3'-dideoxyadenosine, 2',3'-dideoxycytosine, pravastatin, erythromycin, digoxin and pancreatin. 27. The spheronized bead of claim 1, wherein the acid labile drug is 2',3'-dideoxyinosine. 28. A pharmaceutical composition according to claims 1, 2, 22 and 23, wherein a plurality of the beads are encapsulated in a capsule for oral administration. 29. The pharmaceutical composition of claim 28, wherein the capsule is filled with a plurality of beads in an amount sufficient to obtain a dosage of ddI required for twice daily administration. 30. The pharmaceutical composition of claim 28, wherein the capsule is filled with a plurality of beads in an amount sufficient to obtain a dosage of ddI required for once daily administration.