IE50107B1 - Enteric coated solid pharmaceutical unit dosage forms - Google Patents

Abstract

A medicament-containing core of a solid unit dosage form is provided with an enteric coating by applying (e.g. in a coating pan) an aqueous solution of a water soluble salt of a cellulose partial ester of a dicarboxylic acid, the aqueous solution being free from organic solvent, until an enteric coating around each medicament core has been built up. The salt may be a sodium or ammonium salt of hydroxypropyl methyl cellulose phthalate or cellulose acetyl phthalate.

Description

ENTERIC COATED SOLID PHARMACEUTICAL UNIT DOSAGE FORMS This invention relates to enteric coated solid pharmaceutical unit dosage forms, e.g. tablets, dragees and capsules.

Such enteric coated unit dosage forms have a uniform controlled amount of a medicament in a coated unit dosage medicament core, the medicament core beingzfor example, a tablet core or a capsule containing a therapeutically effective dose of the medicament, for example,as a powder or liquid. The coating remains intact when in contact with gastric juices thereby preventing escape of the medicament when the unit dosage form passes through the stomach. The coating disintegrates sufficiently when in contact with intestinal juices thereby permitting the medicament to be leached by the intestinal juices. The medicament then acts in the intestines or is absorbed through the walls of the intestinal tract. Various in vitro tests for determining whether or not a coating is classified as an enteric coating have been published in the pharmacopeia of several countries.

As used herein, the term enteric coated or enteric coating refers to a coating which remains intact (showing no disintegration or cracking of t’ne coating) for at least 1 hour in contact with HCl of pH 1.2 50107 - 2 at 36 to 38°C and thereafter disintegrates within 60 minutes when the pH is raised to 6.8, e.g. in a KH^PO^ buffered solution.

Cellulose derivatives are well-known and universally accepted coating materials for medicament cores. Cellulose partial esters, e.g. cellulose acetate phthalate/herein after referred to as CAP) and hydroxypropyl methyl cellulose phthalate(hereinafter referred to as HPMCP ) are universally accepted materials for enteric coatings. Hitherto suitable coating processes for applying these cellulose derivatives onto medicament cores were based on organic solutions. Such processes suffer from several disadvantages. Firstly the solvents are generally inflammable so special storage vessels for the solvents are required. Secondly in admix15 ture with air the solvents can be explosive so special safety precautions are required. Thirdly pollution hazards associated with toxic organic solvents may exist, so special equipment for dispersing Or scrubbing the exhaust gases is required. Fourthly the amount of any toxic organic solvent remaining in the coating has to be carefully monitored. Fifthly the organic solvents are costly.

It has been proposed to use aqueous-organic solvent systems and for non-enteric coatings using water soluble cellulose derivatives it is possible to use a purely aqueous system on a commercial scale.

Various proposals have been put forward to eliminate organic solutions also for enteric coating with cellulose partial esters. For example according to U.S.S.R Author's - 3 Certificate No 374082 published in June 1973 in the name of Leningrad Antibiotics Research Institute,, tablets in a fluidized bed coater are spray coated in three steps: firstly by an aqueous solution of an ammonium salt of CAP, secondly by a hydrophobic wax such as a plant oil and thirdly again by an aqueous solution of an ammonium salt of CAP.

It was clearly essential to have the wax layer in order to obtain an enteric coating.

Zhitomirskii et al in Khimiko Farmatserticheskii Zhurnal Vol 7(8) August 1973 pp 46-47 teaches that the fluidized bed technique is more advantageous than the coating pan technique and apparently contemplates coatings produced in fluidized bed coaters using aqueous solutions of ammonium salt of cellulose acetyl phthalate and shellac in conjunction with hydrophobic wax-fatty undercoats. However, in fact the coating pan technique has certain advantages over the fluidized bed technique, e.g. it causes less tablet abrasion and coating material loss, it requires smaller volumes of drying air and thus lower energy supplies, and it is cheaper to run.

In another proposal according to DOS 2524813 published in 1976 in the name of Shinetsu a two step coating process is described.In the first step medicament cores are said to be coated by an aqueous solution of a .water soluble salt of a cellulose partial ester in a fluidized bed coater or in a pan coater. In the second step the coated medicament core is treated with an acid in order to produce an enteric coating by converting the cellulose ester salt coating - 4 back into the insoluble acid form. The second step is clearly shown to be necessary to produce an enteric coating as each coated medicament core subjected to the coating step but not to the subsequent acid treatment step was stated not to have an enteric coating as the medicament core disintegrated completely or had most of the contents dissolved out in the presence of gastric fluid in the disintegration test for uncoated tablets in accordance with U.S. Pharmacopeia 18 Revision. The acid treatment is, however, costly, tedious and difficult to effect in a commercial scale. Xt can lead to medicament being leached out during the acid wash and may destroy any acid-sensitive medicament present.

According to Japanese Application No 2918/1977 in the name of Toyama, extensive studies were conducted to improve the drawbacks of the Shinetsu process. The solution proposed, however, was to employ at least 5% of a miscible organic solvent in an HPMCP or CAP coating solution.

The use of an organic solvent is undesirable Recently Shinetsu (see e.g. Technical Information H-20 dated January 21, 1979 and Technical Information H-23 dated February 20, 1979) have proposed using an aqueous dispersion of HPCMP in the presence of triacetin as an enteric coating technique.

The dispersion, however, must be continuously stirred during the coating operation,and even then pistol blockages tend to occur. Moreover, the HPCMP should be in the form of a very fine powder and an undercoat, e.g.*Pharmacoat 606, is required.

*Pharmacoat 606 is a Trade Mark Thus, there has been a real need for providing an enteric coating with cellulose esters in purely aqueous solvents, especially in pan coaters, but there is no simple accepted solution capable of commercial use.

We have now surprisingly found that, despite what is said in DOS 2524813, if the spraying conditions are carefully monitored to prevent ruptures and abrasion of the coatings being formed, it is possible, even v/hen the unit dosage forms are coated in intimate contact in a coating pan, to obtain simply a solid unit dosage having an enteric coating form wherein the enteric characteristic of said coating is imparted essentially by one component only, namely a water soluble salt of a cellulose partial ester of a dicarboxylic acid. The acid treatment step called for by DOS 2524813 is no longer necessary.

The present invention accordingly provides a process for applying an enteric coating to the surface of a medicament core of a solid unit dosage form by coating the medicament cores with an aqueous solution of a water soluble salt of a cellulose partial ester of a dicarboxylic acid completely free from any, or significant amounts of, an organic solvent under appropriate conditions of wetness to reduce abrasive contact and sticking of the coatings being formed and until such time as an enteric coating of the salt has been built up and without applying any other enteric coating layer or subsequently carrying out an acid treatment step.

It is to be appreciated that the coating with the cellulose partial ester alone provides the enteric coating.

No other enteric coating, e.g. of a hydrophobic material such as wax, shellac, plant-oil, need be provided. - 6 SOI 07 Any conventional coater is suitable, (see J.F.Pickard et al, Manufacturing Chemist and Aerosol News, May 1974, p.42), e.g. a fluidized bed coater or preferably a coating pan.

If desired, a ventilated sugar coating pan or a modified sugar coated pan (e.g. a Pellegrini Type with a dipsword, available from Pellegrini, Italy or Glatt, BRD) may be used. Preferably the coating pan is perforated and sidevented, e.g. machines such as Accela Cota, Manesty, England or the Hi-Coater, Vector Corporation, USA.

The coater may be fitted with spray pistols.

Suitable spray pistols are those used for other aqueous coating systems, e.g. compressed air pistols having a nozzle diameter of from about 0.5 to about 1.8 mm for coating pans.

The enteric coating may be applied in conventional manner for the application of analogous cellulose esters, e.g. hydroxypropyl methrly cellulose from purely aqueous solutions to similar unit dosage forms in the same environment and machine. The process parameters can vary between wide limits from environment to environment, machine to machine and day to day and depend on, inter alia, the pan load, pan speed, baffling system present, application’rate, drying air input and exhaust rate, temperature of the drying air, relative humidity, core variation, viscosity of spraying solution, degree of atomization, spray profile etc.

It is most important that the process parameters which could affect the quality of the coating, and e.g. lead to ruptures, must be carefully and continuously monitored and adjusted for optimum coating conditions during the coating process according to procedures well known in the art, in particular avoiding running the process anywhere near to being too wet or too dry.

For example, frictional wear between the coated medicament cores themselves as well as with the sides of the coater causes abrasion of the coating on the prominent parts (e.g. edges) of the dosage form, and reduces thickness of the film edges without exposing the cores.

This abrasion is the result of the process being run too dry, and may be overcome e.g. by increasing the spray rate or decreasing the temperature differences between incoming and exhaust air. Sticking of the coated medicament core on the sides of the coater or to each other (stacking) with the resultant formation of imperfections (e.g. micro-blisters) in the coatings, as a result of the process being run too vet, ray be overccne e.g. by decreasing the spray rate or increasing the temperature difference between incoming and exhaust air.

The effects of running the process too dry (abrasion) or too wet (sticking) may not be observable by eye from the coated medicament core. The effects can, however, be observed when the cores are magnified or when they are brought into contact with simulated gastric juices or HCI at pH 1.2. The film thickness reduction at the edges of the medicament core due to abrasion, and lifting of the film, without necessarily leaving a hole, on the faces of the medicament core, due to sticking may also be seen. - 8 Preferred cellulose partial esters are those of succinic acid, maleic acid or preferably phthalic acid.

The cellulose ester may bear additionally mono-carboxylic ester groups, e.g. acetyl or may be partially etherified, e.g. have methoxy or 3-hydroxypropoxy groups present.

Suitable cellulose partial esters include cellulose acetate phthalate and preferably hydroxypropyl methyl cellu lose phthalate. Examples of the former are HP5O and HP55 obtainable from Shinetsu, Tokyo, Japan and an example of the latter is the brand CAP obtainable from Eastman Kodak, Rochester, N.Y., USA.

Hydroxypropyl methyl cellulose phthalate may be characterised as follows:50107 - 9 Simplified formula of dimer moiety of polymer; R:- H. - CH , - CH - CH - CH, Z I 3 OH Oil Composition Phthalyl content^ Hydroxypropoxy contents Methoxy content % - CH, - CH - CH, 2 I 3 HP 50 HP 55 20-27 27-35 7-18 6-10 20-25 18-22 -· 10 The above mentioned cellulose acetate phthalate is characterised as followssSimpllfled formula of monomer moiety of polymer: R = HOOCCJI.CO 6 4 R‘= CHjCO Composition Mixed partial ester of cellulose with 30-40% Phthalyl groups, 17-23% Acetyl groups and maximal 6% free acid groups calculated as phthalic acid.

If desired more than one cellulose partial ester may be used. A suitable mixture comprises hydroxypropyl methyl cellulose phthalate and cellulose acetate phthalate, e.g. in a weight ratio of from 20 : 1 to 60 : 1.

The salt form may be suitably the triethanolamine salt, preferably the ammonium salt and especially the sodium salt. The salt form may be made in conventional manner, by reaction of the cellulose partial ester with appropriate or equivalent quantities of the base in water until a solution occurs.

The coatings may for example be applied from an aqueous solution having a viscosity of from about 5 to about - 11 240 cps, as determined in a Brookfield viscometer at 20°C. Generally this corresponds to a 5 to 20% (W/w) solution of the cellulose partial esters.

Naturally the coating solution may contain other con ventional pharmaceutical excipients which will be incorporated into the enteric coating. Suitably these comprise from 0.005 to 30%, more suitably from 0.01 to 10%, of the coating solution. For example dyestuffs such as water soluble amaranth and/or pigments such as red iron oxide, erythrosin, or titanium dioxide may be present in an amount of for example about 0.1 to about 1% of the coatings. Anti-sticking agents or fillers such as talc may be present in an amount of up to 25% of the enteric coating. Plastisicers may be present, e.g. dioctyl phthalate,or preferably triacetin, in an amount of up to about 50% of the enteric coating, or polyethylene glycol in an amount of up to about 5% of the enteric coating Controlled amounts of polymers which affect the break-down of the coating in gastric and intestinal juices may be present in the coating solution. Generally these may be present in a concentration of up to 5%ze.g. 0.1 to 5%,of the solution and up to 30% of the enteric coating. Appropriate polymers include synthetic polymers soluble in aqueous acids such as polyethylene glycol, polypropylene glycol, polyvinylpyrrolidone, semi-synthetic polymers soluble in aqueous acids, e.g, hydroxypropyl cellulose (such as Klucel LF) (Trade Mark), hydroxypropyl methyl cellulose such as Pharmacoat E 15 (Trade Mark), - 12 50107 synthetic polymers insoluble in aqueous acids such as poly(vinyl acetate-co-crotonic acid) natural polymers insoluble in aqueous acids such as alginic acid and its salts, and semi-synthetic polymers insoluble in aqueous acids e.g. carboxymethyl cellulose.

Any excipient in the coating solution is preferably added in quantities, and a form, e.g. a salt form when the salt is soluble but the acid not, consistent with maintaining an adequately low viscosity solution for producing a film coating.

It is to be appreciated that the enteric coating may be provided as a single layer of uniform composition or may be provided as multiple layers of different compositions, e.g. each containing a water soluble salt of a cellulose partial ester and one layer containing a pigment.

In general a film coating of from 0.045 mg to 0.65 mg per sq millimeter of solid unit dosage form (0.035 to 0.5 mm thick) will provide a satisfactory enteric coating, but thicknesses outside this range may also provide satisfactory coatings.

The resistance of the coating to gastric juices naturally increases with the coating thickness.

Coated medicament cores prepared according to the process of the invention may be prepared which satisfy more stringent standards for enteric coatings than those indicated above, e.g. the standards laid down in e.g. Japan Pharmacopeia VIII and Pharmacopeia Europe I.

Thus coatings which show no visible softening or cracking within 2 hours in gastric juices have been prepared. Naturally the medicament may still be leached out in gastric juices even though the coating remains intact. In general for enteric coatings it has been observed in in vitro tests with HCl of pH 1.2 that less than 20 percent of the medicament is leached out within 1 hour. Coatings have been made that leach out less than % or 5% of the medicament within 2 hours.

The coatings produced by the process of the invention are at least as stable as equivalent coatings produced from organic solvents of cellulose partial esters.

For example, propyphenazone tablets coated with aqueous solutions of the sodium or ammonium salt of HPMCP and the sodium salt of CAP were prepared and stored for 12 months at 25°C. In all cases the amount of propyphenazone leached out of tablets after storage for 12 months after 2 hours contact with HCl at pH 1.2 was similar to, or up to 60% less than, the amount leached out of the tablets before storage. Satisfactory maintenance of the coating has also been observed for tablets stored at 35° for 6 months.

The medicament cores may be any suitable medicament core for a unit dosage form.

Whilst the process of the invention may be applied to coating capsules, e.g. capsules each moulded in one piece, it is preferred to be applied to tablet cores.

The tablet cores should be of a size that can be coated - 14 satisfactorily in the coating pan used. Suitable tablet cores may be, for an Accela Cota, from about 3 mm upwards in diameter e.g. from about 50 mg each to about 1000 mg each.

The coated unit dosage forms may then be dried in known manner and packed e.g. into blister packs. Optionally before packing the dosage form may be coated with a further non-enteric layer which may contain medicament. Thus, for example, an outer layer containing medicament for immediate release into the stomach may be press-coated onto the coated medicament co r-e.

Any medicament present in the medicament core optional outer medicament layer may be any medicament e.g. one which acts in the intestines or is absorbed through the intestines. Examples of suitable medicaments include analgesics, antibiotics, anti-histamines, tranquillizers, myotonolytics, enzymes, cardiac agents, beta and/or alphablockers, vasoconstrictors, hypotensives, vasodilators, neuroleptics and anti-depressants.

The medicament may be, for example, an ergot alkaloid, e.g. ergotamine, dihydroergotamine, co-dergocrine,or bromoergocryptine. Other examples include diclofenac sodium, pindolol, phenylpropanolamine, or acid-sensitive enzyme preparations.

Any pharmaceutical excipient conventionally used for the unit dosage form contemplated may be used in the medicament core and any outer layer present.

The present invention also covers unit dosage forms produced by the process of the invention. The compositions of the invention allow the release of a medicament in the intestines by enterally administering the medicament in the form of an enteric coated solid unit dosage form and especially the sustained action of a medicament if this is slowly released from the core or slowly absorbed through the intestinal walls, or protection of medicaments which are sensitive to gastric juices during passage through the stomach.

The following examples illustrate the invention. In the Examples the following abbreviations are used:HPMCP is the hydroxypropyl methyl cellulose phthalate brand HP 50 produced by Shinetsu.

CAP is cellulose acetate phthalate produced by Eastman Kodak, PEG 6000 is polyethylene glycol having a molecular weight of about 6000, PVP is polyvinylpyrrolidone, brand Kollidon 30, with a mean molecular weight of about 28000, Triacetin is glycerin triacetate, Amaranth is water soluble amaranth, Kelacid is a brand of alginic acid, CMC is carboxymethyl cellulose, brand Hercules 7LF, (Trade Mark), HPC is hydroxypropyl cellulose brand Klucel LF, (Trade Mark) HPMC is hydroxypropylmethyl cellulose, brand Pharmacoat E 15 (Trade Mark) - 16 All the components used herein have characteristics as described in Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete by H.P. Fiedler, Edito Cantor KG 1971, which lists the names of suitable suppliers.

EXAMPLE 1; Spray Solution The water insoluble cellulose ester is reacted with an appropriate base to bring it into water soluble form. Examples of various spray solution compositions are given in the following table, in which tions are given in g per charge. Medicament cores the amounts of composi- The tablet cores (235 mg compositions:- each) had the : following Component Weight Propyphenazone 24 Lactose 162,23 Corn Starch 40.07 Polyvinylpyrrolidone 4.47 Magnesium stearate 1.79 Talc 2.44 (mg) The tablet components were granulated according to known procedures and compressed to form cores of 9 mm diameter, having bevelled edges, and upper and lower weakly concave sides (radius of curvature 18-20 mm) .

S0107 - 1? Coating method kg of the above tablet cores were loaded into a 24 inch rotating perforated drum coater (Accela Cota).

The spraying conditions were as follows:5 Drum rotation speed: 16 r.p.m.

Inlet air quantity: ca 3000 m^/h.

Exhaust air quantity: ca 3200 m^/h.

Inlet air temperature: 56-60° Outlet air temperature: 34-40° Temperature difference between inlet and exhaust air ca 2O-22°C.

Spray Pistol: Binks 2 step type 2610.

Nozzle No 63; Needle No 363; Cover No 63 PB; openings 10 to 20.

Nozzle diameter: 0.7 to 1.8 mra.

Distance of nozzle from cores; ca 15 to 30 cm.

Spray pressure: 3 atmospheres.

Solution pumped by a 4-finger pump at . 35 to 60 r.p.m. Finger pump arm diameter ca 5 cm. Finger pump tubing: 4 to 8 mm diameter, Spray programme: Spray 60 secs.

: Spray interval 2 secs.

Total coating time: 4.25 to 5.5 hours. - 13 Enteric disintegration best: A group of 6 tablets were treated with HCl pH 1.2 at 37° for 2 hours and observed. The results are shown in the table as an indication of the aspect of the coat after the treatment« + indicates an intact film; - indicates a non-intact film.

The state is indicated as follows:S = Solid F = Firm The tablets were then transferred to a KH-PO, 4 pH 6.8 solution at 37°C. The time taken for disintegration of the coat was taken. The maximum or average time in minutes is given in the table along with a standard deviation, if available. - 19 Ό in Μ* CJ r-1 in co σ% co m co \S - 20 EXAMPLE 2; *Giiiazym cores were used each weighing 750 mg and of a long, oblong lozenge shape, and containing an acid sensitive enzyme preparation of 300 mg Pancreatin (lipase; amylase; protease), 180 mg dehydrocholic acid and 40 mg dimethylpolysiloxane. kg of the cores were coated in a 24 inch Accela cota machine and sprayed successively without interruption with three solutions; I HPMCP 134.6 g NH40H (25%) 15.1 g Erythrosin 0.067 g Water ad 1076 g II HPMCP 269.2 g NHjOH (25%) 30.015 g Erythrosin 0.135 g Talc 50 g Titanium Dioxide 47.5 g Water ad 2152 g III HPMCP 403.8 g NH4°H (25%) 45.2 g Erythrosin 0.2 g Water ad 3228 g The speed of rotation of the Accela Cota-because of the large size of tablets and the small drum-had to be carefully monitored to prevent surging with the result that crests of the rolling cores received insufficient solution and rail too dry, and troughs of the rolling cores received too much · solution and henos ran too wet. (This surging *Gillazyn is a Trade Mark - 21 problem is not encountered with larger Accela Cotas). The drum rotation speed was 16-20 r.p.m. for spraying solution I; and 9-12 r.p.m. for spraying solutions II and III. Pump speed (r.p.m.) = 40 (solution I); 47.5 (II); 55 (III). Inlet air temperature = 59°C. Exhaust air temperature; 40°C. Nozzle setting = 20. The total coating time was 140 minutes; other spraying conditions substantially as for example 1.

The coated Gillazym cores were compared with commerically available Gillazym preparation, which are manufactured by applying a HPMCP coating of similar thickness from an organic solution, in the gastric juice resistance test according to US Pharmacopeia XIX.

After application of solutions I and II, the cores coated according to the process of the present invention remained completely intact like the commercial preparation after 60 minutes in contact with simulated gastric juices.

An acid penetration of the coating of about 0.4 - 0.6 mm was observed compared to an acid penetration of about 0.2 to 0.3 mm in the commercial preparation. After application of the third solution III the cores coated according to the invention showed comparable acid penetration to the commercial preparation. The disintegration time of the coating at pH 5.5 was comparable (8-16 minutes) for the Gillazym cores produced according to the invention and for commer cial Gillazym preparations.

EXAMPLE 3: 22 - Pindolol/sodium lauryl sulphate cores containing the following components:Component Weight (mg) Pindolol (base) 10 Sodium lauryl sulphate 5 Ethyl cellulose 9 Polyvinylpyrrolidone acetate 5 Microcrystalline cellulose 14 Mannitol 55 Talc 1 Magnesium stearate 1 are prepared as disclosed in DOS 2732335. kg of the cores are coated in analogous manner to that disclosed in Example 1.

Spra^ solution Component Weight HPMCP 807.7 g NH.OH (25%) 4 90.5 g Erythrosin 0.4 g Water ad 6380 g Spray condi,tions Drum speed 16 r.p.m.

Inlet air temperature 59 °C Outlet air temperature 36-37°C Nozzle setting 20 Finger pump speed 72.5 r.p.m. - 23 Coating time 104 minutes Other conditions as for Example 1.

Disintegration_test This was effected by treating the tablets with 5 simulated gastric juices for 2 hours and then ^K2~°4 thereafter.

Exgeriment a}_: 3 coated cores prepared according to the process of the invention with a 15 mg film (A) and cores coated with HilPCP from organic solutions according to the above-mentioned DOS with an 11 mg film (B) were compared estimating the amount of pindolol released.

The results were as follows:% Pindolol release (+ Standard Deviation) Time (minutes) 5 A (invention) 1.4 (0.1) B (known) 3.2 (0.5) 15 1.4 (0.1) 4.1 (0.9) 30 1.5 (0.1) 6.5 (0.9) 20 60 1.8 (0.1) 8.2 (1.3) 120 3.2 (0.1) 15.4 (2.8) pH Change 150 24 (0.8) 31.4 (4.4) 25 180 37.8 (6.4) 39.0 (5.2) 200 74.1 (3.2) 72.8 (4.4) Exgeriment_b2_: Cores were prepared according to the above process, but having different film thicknesses (C-E).

S0107 These were compared to a coated core produced according to the process described in the above DOS with an 11 mg coating (F) applied from organic solutions.

The pindolol release observed in simulated gastric 5 juices was as follows :% Pindolol released from Core (Fite in mg) Time minutes C (5.5 D mg) (8.25 mg) E (11 mg) F (11 mg) 5 0.2 0.96 1.1 1.3 10 15 0.3 1.1 1.2 1.6 30 0.8 1.4 1.3 2.9 60 4.8 2.8 1.3 6.1 90 8.8 4.5 1.3 9.0 120 11.4 6.7 1.4 13.3 15 These experiments show that the coatings produced according to the invention are significantly more resistant to gastric juices than coatings produced from organic solvents. The coating also quickly disintegrates in intestinal juices allowing release of the medicament as expected.

EXAMPLE 4: As described in Example 1 propyphenazone tablets were coated with the following solutions:- I Weight g II Ill KPMCP 1552.5 1552.5 . — CAP ___ — 700 NaOH 29.82 132 I II III NH OH (25%) 193 — — Amaranth 1.55 1.55 0.7 Water to 12420 12420 11200 The tablets were stored for 1 year at 25°C and then treated in the disintegration test in simulated gastric juices for 2 hours and then in simulated intestinal juices thereafter. The values for propyphenazone release were compared to the initial values. % propyphenazone release I II III Time (min) initial value after 1 year init. value after 1 year init. value after 1 year 15 4.2 2.5 4.7 1.7 9.0 8.9 30 5.5 3.3 6.5 1.9 11.7 11.7 60 6.2 4.4 8.2 2.2 17.7 17.7 120 7.2 5.7 10.4 3.2 27.4 25.6 pH change ——— —— ——— ——— ——— 300 90.5 84.7 90.8 97.3 92.3 94.0 The results indicate that the coatings produced 20 according to the invention are stable and in the case of HPCMP coatings become more resistant to gastric juices with time, whereas in intestinal juices they disintegrate as expected.

EXAMPLE 5: Optalidon cores of 355mg each were made in analogous manner to that described in Example 1 having the following composition: - 26 component Weight (mg) Butalbital 50 Propyphenazone 125 Caffeine 25 Klucel LF (Trade Mark) 9 Corn Starch 134 Stearic acid 1.0 Talc 6.0 kg of the above tablet cores were coated in analogous manner to that described in Example 1 using the solutions listed in the following table (each component amount is given in grams) and effecting the disintegration test as indicated in Examplel. 107

Claims (16)

1. A process for applying an enteric coating to the surface of a medicament core of a solid unit dosage form by coating the medicament cores with an aqueous solution of a water soluble salt of a cellulose 5 partial ester of a dicarboxylic acid, completely free from any, or significant amounts of, an organic solvent, under appropriate conditions of wetness to reduce abrasive contact and sticking of the coatings being formed and until such time as an enteric coating of the salt has been built up and without applying any other enteric 10 coating layer or subsequently carrying out an acid treatment step.

2. A process according to claim 1 wherein the cellulose partial ester is cellulose acetate phthalate.

3. A process according to claim 1 wherein the cellulose partial ester is hydroxypropylmethyl cellulose phthalate. 15

4. A process according to claim 1 wherein the enteric coating comprises a mixture of salts of cellulose acetate phthalate and hydroxypropyl methyl cellulose phthalate.

5. A process according to claim 1, 2, 3 or 4 wherein the sodium salt is present as the salt. 20

6. A process according to claim 1, 2, 3 or 4 wherein the ammonium salt is present as the salt.

7. A process according to any preceding claim wherein the final enteric coating is from 0.035 to 0.5 mm thick.

8. A process according to any preceding claim wherein the enteric 25 coating is applied as a single layer.

9. A process according to any preceding claim wherein the aqueous solution contains from 5 to 20% by weight of the ester.

10. A process according to any preceding claim wherein the coating is effected in a coating pan.

11. A process according to any preceding claim wherein the medicament core is a tablet core. 5

12. A process according to claim 11 wherein the coated core is then provided with an outer medicament non-enteric layer.

13. A process according to any preceding claim wherein the medicament in the core is pindolol.

14. A process according to claim 13 wherein the enteric coating 10 is surrounded by an outer medicament non-enteric layer.

15. A process for the production of an enteric coated solid unit dosage form from an aqueous coating solution of a water soluble salt of a cellulose partial ester of a dicarboxylic acid free from an organic solvent substantially as hereinbefore described 15 with reference to any one of the Examples.

16. An enteric coated solid unit dosage form whenever produced by the process of any one of claims 1 to 15.