Orally administered antimicrobial pharmaceutical formulations of ciprofloxacin

The invention provides three orally administered ciprofloxacin formulations: The first formulation comprises 60-75 wt % of ciprofloxacin or at least one of pharmacologically acceptable salt; 0.3-10 wt % of pregelatinized starch as binder; 5-30 wt % of lactose as diluent; 1-10 wt % of sodium starch glycolate as disintegrant; and 0.5-2 wt % of magnesium stearate as lubricant. The second formulation comprises 60-75 wt % of ciprofloxacin or its pharmacologically acceptable salt; 1-5 wt % of polyvinyl pyrrolidone as binder; 5-30 wt % of lactose as diluent; 1-10 wt % of sodium starch glycolate as disintegrant; and 0.5-2 wt % of magnesium stearate as lubricant. The third formulation comprises 60-75 wt % of ciprofloxacin or at least one of pharmacologically acceptable salt; 1-8 wt % of polyvinyl alcohol as binder; 5-30 wt % of lactose as diluent; 1-10 wt % of sodium starch glycolate as disintegrant; and 0.5-2 wt % of magnesium stearate as lubricant. The ciprofloxacin or its pharmacologically acceptable salts, the binder, the diluent, the disintegrant, and the lubricant are first mixed in a dry state to form a powder mixture, followed by mixing with a water-solvent solution to convert the dry powder mixture into a wet powder mixture before grinding and granulating the wet powder mixture into wet granules, which are further dried to form dry granules. The above three formulations do not contain cellulose.

FIELD OF THE INVENTION
 This invention relates to orally administered antimicrobial formulations
 which contain, as an active ingredient,
 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarb
 oxylic acid (also called ciprofloxacin) or its pharmacologically acceptable
 salts (preferably, HCl salt monohydrate) in a solid dosage form. The
 ciprofloxacin is combined with effective amounts of binders (preferably,
 pregelatinized starch, polyvinyl pyrrolidone, or polyvinyl alcohol),
 diluents (preferably, lactose), disintegrants (preferably, sodium starch
 glycolate), wetting agent (preferably, sodium lauryl sulfate), and
 lubricants (preferably, magnesium stearate) to form granules or tablets.
 This invention also relates to methods for making the
 ciprofloxacin-containing tablets or granules using dry-wet-dry granulation
 processing before compression to tablets with granulation performed in a
 wet state. The tablets or capsules made from these formulations possess
 superior biological availability and excellent storage stability.
 BACKGROUND OF THE INVENTION
 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline
 carboxylic acid (also known as ciprofloxacin) belong to the class of
 quinolones, which are known to possess a broad antibacterial spectrum
 against both Gram positive and Gram negative bacteria, in particular
 against Enterobacteriaceae. (See e.g., U.S. Pat. Nos. 4,284,629,
 4,499,091, 4,704,459, 4,668,784, 4,670,444, 5,286,754, and 5,840,333).
 Ciprofloxacin is a chemotherapeutic agent. Its use as an antimicrobial
 agent has distinct advantages over the use of antibiotics (e.g.,
 penicillins, cephalosporins, aminoglycosides, sulphonamides and
 tetracyclines) in that ciprofloxacin does not induce tolerance or
 resistance in bacteria. Ciprofloxacin is also known to have low toxicity
 to humans.
 The orally administered quinolone-containing formulations can be prepared
 by a wet granulation process as described by Y. Shirai et al., Biol.
 Pharm. Bull., 16(2), 172 (1993). However, the formulations produced by the
 wet granulation process have a tendency to generate hydrates, thus making
 the granules less soluble or more difficult to disperse when compared with
 the corresponding anhydrous form. This results in a delay in the
 dissolution and a delay in the release of the active ingredient, which may
 be a nuisance in the use of antimicrobial medicinal products.
 Quinolone-containing formulations can also be prepared by a direct
 compression of the mixture of the quinolone with excipients, without the
 prior addition of mixing water. See U.S. Pat. No. 5,840,333. However, the
 direct compression of the mixture of the quinolone ingredient and the
 excipients in powder form may affect the quality of the tablets due to
 cleavage problems, which render some batches of tablets unsuitable for
 marketing.
 Recently, Streuff et al. (U.S. Pat. No. 5,286,754) have disclosed an oral
 formulation of ciprofloxacin which is prepared by combining ciproflaxacin
 with cellulose as a dry binder, starch, cellulose derivatives and/or
 cross-linked polyvinylpyrrolidone as a disintegrant, a flow-improving
 agent such as Aerosil.RTM., a highly pure X-ray-amorphous silicon dioxide,
 with and NAL.RTM. and NAL.RTM. RS [a pulverulent product prepared from
 rice starch]) and a lubricant (such as talc, calcium stearate, magnesium
 stearate and solid polyethylene glycols).
 However, Streuff et al.'s formulation is practically prepared in dry state,
 although in one variant granulation can be made in a fluidized bed
 granulator by instantaneously spraying the formulation with water and
 passing it in warm air, a process which in fact results in simultaneous
 drying of the granules. Therefore, it is conceivable that the tablets
 obtained from such preparation may not be satisfactory, possibly due to
 cleavage problems.
 In addition, Streuff et al.'s formulation requires the use of
 microcrystalline cellulose as the dry binder. Microcrystalline cellulose
 comes from natural plant fibers through complex micronization. Therefore,
 the high quantity of microcrystalline cellulose used by Streuff et al. not
 only drives up the cost of manufacturing the product but also is wasteful
 and therefore environmentally undesirable. In addition, microcrystalline
 cellulose is practically insoluble in water. Thus, the use of
 microcrystalline cellulose in Streuff et al.'s formulation has limited the
 utility of compounding such formulations in a wet state.
 The present invention includes ciprofloxacin-containing formulations
 produced by a dry-wet-dry granulation process, which is significantly
 different from either the wet granulation or the dry-mixing processes
 described above. The process of the present invention begins with mixing
 the solid dosage form of ciprofloxacin with certain excipients in their
 dry state, followed by a wet mixing and granulation step wherein a
 water-solvent solution (e.g., a 1:1 (v/v) water:isopropanol solution) is
 added to the dry ciprofloxacin-excipients mixture. Finally, the wet
 granules produced by the wet mixing and granulation step are dried and
 compressed into solid dosage form of tablets. The present invention is
 significantly different from that of Streuff et al. because it does not
 use cellulose as dry binder. The tablets or granules produced from this
 method have superior bioavailibity and shelf-life than other
 ciprofloxacin-containing products on the market.
 SUMMARY OF THE INVENTION
 The present invention provides three kinds of orally administered
 antimicrobial formulations which contain, as an active ingredient, a solid
 dosage form of
 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarb
 oxylic acid (also called ciprofloxacin) or its pharmacologically acceptable
 salts. The formulations can be marketed as tablets or capsules. They are
 non-toxic, highly dispersible, and have excellent storage stability.
 The first antimicrobial formulation comprises (1) 60-75 wt % of
 ciprofloxacin or its pharmacologically acceptable salts; (2) 0.3-10 wt %
 of pregelatinized starch as binder; (3) 5-30 wt % of lactose as diluent;
 (4) 1-10 wt % of sodium starch glycolate as disintegrant; and (5) 0.5-2 wt
 % of magnesium stearate as lubricant. The formulation is prepared by a
 dry-wet-dry granulation method. The preferable pharmacologically
 acceptable salt of ciprofloxacin is the monohydrochloride monohydrate salt
 of ciprofloxacin. The preferable pregelatinized starch is partially
 pregelatinized starch. A 0.3-3 wt % of sodium lauryl sulfate can be added
 to the formulation as a wetting agent.
 The second antimicrobial formulation comprises (1) 60-75 wt % of
 ciprofloxacin or its pharmacologically acceptable salts; (2) 1-5 wt % of
 polyvinyl purrolidone(PVP) as a binder; (3) 5-30 wt % of lactose as a
 diluent; (4) 1-10 wt % of sodium starch glycolate as a disintegrant; and
 (5) 0.5-2 wt % of magnesium stearate as a lubricant. The formulation is
 prepared by a dry-wet-dry granulation method. The preferable
 pharmacologically acceptable salt of ciprofloxacin is the
 monohydrochloride monohydrate salt of ciprofloxacin. The preferable PVP is
 PVP-K30 which has a molecular weight of 40,000. A 0.3-3 wt % of sodium
 lauryl sulfate can be added to the formulation as wetting agent.
 The third antimicrobial formulation comprises (1) 60-75 wt % of
 ciprofloxacin or its pharmacologically acceptable salt; (2) 1-8 wt % of
 polyvinyl alcohol (PVA) as a binder; (3) 5-30 wt % of lactose as a
 diluent; (4) 1-10 wt % of sodium starch glycolate as a disintegrant; and
 (5) 0.5-2 wt % of magnesium stearate as a lubricant. The formulation is
 prepared by a dry-wet-dry granulation method. The preferable
 pharmacologically acceptable salt of ciprofloxacin is the
 monohydrochloride monohydrate salt of ciprofloxacin. A 0.3-3 wt % of
 sodium lauryl sulfate can be added to the formulation as wetting agent.
 The above three antimicrobial formulations are further compressed into
 tablets. The tablets are coated by a coating material which comprises
 hydroxylpropylmethyl-cellulose (HPMC), water, polyethyleneglycol (PEG),
 dimethylpolysiloxane (DMPS), and TiO.sub.2. The preferably weight ratio of
 HPMC:PEG:DMPS:TiO.sub.2 is 73:16.7:0.3:10.
 The present invention also provides methods for making the
 ciprofloxacin-containing granules or tablets. The method of making
 granules containing the three formulations comprises the steps of: (1)
 mixing the ciprofloxacin or its pharmacologically acceptable salt with a
 dry binder (i.e., pregelatinized starch, PVP, or PVA), lactose, and half
 of the amount of sodium starch glycolate to form a dry powder mixture; (2)
 mixing the dry powder mixture with a water-solvent solution to form a wet
 powder mixture; (3) grinding and granulating said wet powder mixture to
 form wet granules; and (4) drying the wet granules to form dry granules.
 The dry granules can be either encapsulated or compressed into tablets.
 The water-solvent solution can be a mixture of water-ethanol,
 water-isopropanol, and water-acetone. A water-isopropanol solution with
 1:1 volume ratio is the preferable one.
 The method of making the ciprofloxacin-containing tablets comprises the
 steps of: (1) mixing ciprofloxacin or its pharmacologically acceptable
 salt with a dry binder (e.g., pregelatinized starch, PVP, or PVA),
 lactose, and a half amount of sodium starch glycolate to form a powder
 mixture; (2) mixing said powder mixture with a water-solvent solution to
 form a wet powder mixture; (3) grinding and granulating said wet powder
 mixture to form wet granules; (4) drying the wet granules to form dry
 granules; (5) mixing the dry granules with the other half amount of sodium
 starch glycolate, together with magnesium stearate and sodium lauryl
 sulfate to form a granule mixture; and (6) compressing the granule mixture
 into said tablet.

DETAILED DESCRIPTION OF THE INVENTION
 The first embodiment of this invention provides three orally administrable
 antimicrobial formulations which contain, as an active ingredient,
 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarb
 oxylic acid (also called ciprofloxacin) or its pharmacologically acceptable
 salts in a solid dosage form. These formulations can be sold in the form
 of granules, granule-containing capsules, powders, sublinguals, or
 tablets.
 The salt forms of ciprofloxacin contain, for example, the inorganic or
 organic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid,
 sulfuric acid, phosphonic acid, acetic acid, succinic acid, malic acid,
 etc.) of ciprofloxacin, or inorganic or organic bases (e.g., KOH, NaOH,
 Ca(OH).sub.2, Al(OH).sub.3, piperidine, morpholine, ethylamine,
 triethylamine etc.) of ciprofloxacin. The preferable salt form of
 ciprofloxacin is the monohydrochloride monohydrate.
 In addition to ciprofloxacin or its pharmaceutically acceptable salts, each
 of the three formulations contains (1) a binder, (2) a diluent, (3) a
 disintegrant, and (4) a lubricant. In the first formulation,
 pregeletinized starch is used as binder. In the second formulation,
 polyvinyl pyrrolidone (PVP) is used as binder. In the third formulation,
 polyvinyl alcohol (PVA) is used as binder. The formulations can optionally
 contain wetting agent. In the case where the formulations are compressed
 into tablets, a coating material can optionally be coated onto the tablets
 to improve the dissolution rate of ciprofloxacin.
 To mix a binder with the solid dosage form of ciprofloxacin is not only
 preferable but also necessary, because the solid dosage form of
 ciprofloxacin has the tendency to break up during granulation and
 compression. Suitable binders for this purpose should be ones which
 possess high adhesive effects and which can improve the hardness of the
 formulations. The three binders, namely, pregelatinized starch, PVP, and
 PVA, which have been chosen for the ciprofloxacin formulations, share the
 additional common advantages of inexpensiveness and good water solubility.
 There are two kinds of pregelatinized starch: the partially pregelatinized
 starch and the fully pregelatinized starch. Partially pregelatinized
 starch is more preferable because it is less expensive, easily available,
 and has excellent adhesive properties. The partially pregelatinized starch
 can be handled in the same way as handling starch powder. In fact, once
 the partially pregelatinized starch has been dispersed in cold water or
 water-organic solvent, it can display the same viscosity as starch after
 gelatinization. The use of the partially pregelatinized starch in the
 formulation can also prevent adhesion of granules to the mold during the
 compressing process.
 Preferably, the amount of pregelatinized starch used as a binder for
 ciprofloxacin is limited to no more than 13 wt % of the total formulation.
 If the amount of the partially pregelatinized starch added is too high, it
 impedes or even halts the disintegration of tablets. Most preferably, the
 optimal amount of pregelatinized starch used as ciprofloxacin binder is in
 the range of 0.3 to 10 wt %.
 Polyvinyl pyrrolidone (PVP) is another excellent binder. PVP is commonly
 characterized by the so-called "K-value" as defined by Fikentscher. The
 K-value of PVP may be calculated by the following equations:
 ##EQU1##
 where z is the relative viscosity of the solution of concentration c, k is
 the K-value X 10.sup.-3, and c is the concentration in % (w/v). The
 K-value of PVP is, therefore, a useful measure of the polymeric
 composition's viscosity. PVP can be purchased from Tokyo Chemical Industry
 Co., Ltd. under the trade name of PVP K15, PVP K30, PVP K60, and PVP K90.
 The preferable PVP to be used as a dry binder for ciprofloxacin is PVP
 K30, which has an average molecular weight of 40,000. PVP can be used in
 either wet or dry state. The use of PVP as binder improves the release
 rate of ciprofloxacin, which in turn increases the uptake rate of
 ciprofloxacin by humans. The amount of PVP to be used as ciprofloxacin
 binder should be no more than 10%, and preferably in the range of 0.1-5 wt
 %.
 Polyvinyl alcohol (PVA) is also an excellent binder for solid dosage form
 compound such as ciprofloxacin. It is non-toxic, water soluble, solvent
 resistant, and adhesive. The amount of PVA to be used as ciprofloxacin
 binder should be no more than 10%, preferably in the range of 1-8 wt %.
 Diluents which can be used in the ciprofloxacin formulations include
 lactose, mannitol and sorbitol. The preferable one is lactose due to its
 low cost, although mannitol and sorbitol may provide a more pleasant taste
 for the formulations. The optimal amount of lactose used as a diluent is
 in the range of 5-30 wt %.
 A preferable disintegrant used in the ciprofloxacin formulations is sodium
 starch glycolate, preferably in the range of 2-10%. A lubricant used in
 the ciprofloxacin formulations can be magnesium stearate, stearic acid,
 glycerol tribehenate or mixtures of these excipients. A preferable one is
 magnesium stearate. A preferable wetting agent is sodium lauryl sulfate.
 A preferable coating material which can be coated onto the ciprofloxacin
 tablet comprises, hydroxypropylmethylcellulose (HPMC) as the major
 component, polyethyleneglycol (PEG), dimethylpolysiloxane (DMPS), and
 TiO.sub.2. A preferable weight ratio of HPMC:PEG:DMPS:TiO.sub.2 is
 73:16.7:0.3:10.
 The present invention also provides a method for making the ciprofloxacin
 granules or tablets. The present method uses a dry-wet-dry granulation
 process. First, the solid dosage form of ciprofloxacin or its
 pharmceutically acceptable salt is homogeneously mixed with a dry binder
 (such as pregelitinized starch, PVP or PVA), a diluent (such as lactose),
 and one-half amount of a disintegrant (such as sodium starch glycolate) to
 form a dry powder mixture. The dry powder mixture is then mixed with water
 or an aqueous water-organic solvent solution to form a wet powder mixture.
 The wet powder mixture is further granulated by a high speed granulation
 machine to form wet granules. At the end of the granulation process, the
 wet granules are dried and sorted by machine. The dry granules are then
 mixed with a lubricant (such as magnesium stearate), and the other half
 amount. of the disintegrant (such as sodium starch glycolate), and
 optionally, a wetting agent (such as sodium lauryl sulfate) before being
 compressed into tablets. Optionally, the tablets can be further coated by
 a coating material which contains hydroxypropylmethylcellulose (HPMC) as
 the major component, polyethyleneglycol (PEG), dimethylpolysiloxane
 (DMPS), and TiO.sub.2. A preferable weight ratio of
 HPMC:PEG:DMPS:TiO.sub.2 is 73:16.7:0.3:10.
 The present dry-wet-dry granulation process has advantages over either wet
 granulation processes or dry-mixing processes. Advantageously, the initial
 dry mixing step avoids the generation of hydrates. Similarly, the wet
 granulation step avoids cleavage problems. Also, the final dry compression
 step ensures that the tablets can be readily disintegrated or dispersed in
 aqueous solution once ingested by humans.
 The organic solvents which can be used to form the aqueous water-organic
 solvent solution of the present methods include ethanol, isopropanol, and
 acetone. These organic solvents can be mixed with water in any
 combination. A preferable water-solvent solution is a water-isopropanol
 solution. A preferable ratio of the water-isopropanol solution is a 1:1
 ratio (v/v).
 The Examples which follow, given without any limitation being implied,
 illustrate the present invention.
 EXAMPLE 1

Ciprofloxacin 65%
 Pregelatinized starch 5%
 Sodium starch glycolate 5%
 Lactose 23%
 Magnesium stearate 2%
 100%
 The above formulation was prepared by mixing 416.25 g of ciprofloxacin HCl
 with 30 g of pregelitinized starch, 15 g of sodium starch glycolate, and
 105.75 g of lactose in a high speed mixer to form a powder mixture. Then,
 180 ml of water and isopropanol solution (1:1, v/v) was added to the
 powder mixture to form a wet powder mixture. The wet powder mixture was
 then loaded onto a high speed granulation machine to be granulated, dried,
 and sorted. Then, 15 g of sodium starch glycolate, 6 g of sodium lauryl
 sulfate and 12 g of magnesium stearate were added to the dried granules
 and mixed until in uniformity. The mixed dried granules were compressed
 into tablets in a compression machine.
 FIG. 1 shows the dissolution rates of the tablet containing the formulation
 of EXAMPLE 1 between 0 and 70 minutes. The tablets were film-coated by a
 coating material comprising HHPMC, PEG, DMPS, and TiO.sub.2 as described
 in EXAMPLE 7 (infra). The dissolution rate was measured according to The
 U.S. Pharmacopoeia (23rd Edition). Briefly, a tablet was put into a
 container containing 900 ml of pure water. The dissolution test was
 conducted using a paddle device with the speed set at 50 rpm. The
 dissolution rate (%) at various times (minutes) was determined based on
 the amount of ciprofloxacin in the solution compared to the total amount
 of ciprofloxacin in the tablet. The results shown in FIG. 1 demonstrate
 that more than 80% of ciprofloxacin was dissociated from the tablet after
 5 minutes in water. The dissolution rate of ciprofloxacin plateaued at 90%
 after 10 minutes of testing.
 EXAMPLE 2

Ciprofloxacin 70%
 Pregelatinized starch 5%
 Sodium starch glycolate 5%
 Lactose 17%
 Sodium lauryl sulfate 1%
 Magnesium stearate 2%
 100%
 The above formulation was prepared by the method as described in EXAMPLE 1,
 except that sodium lauryl sulfate was added to the formulation as wetting
 agent.
 FIG. 3 shows the dissolution rates of tablets containing the formulation of
 EXAMPLE 2 between 0 and 70 minutes, which were almost identical to that of
 FIG. 1. The results of FIG. 3 indicate that the addition of sodium lauryl
 sulfate did not give rise to better dissolution of ciprofloxacin in water.
 EXAMPLE 3

Ciprofloxacin 70%
 PVP-K30 2%
 Sodium starch glycolate 5%
 Lactose 21%
 Magnesium stearate 2%
 100%
 The above formulation was prepared by the method as described in EXAMPLE 1,
 except that PVP-K30 was added to replace the pregelatinized starch as
 binder.
 FIG. 4 shows the dissolution rates of the tablet containing the formulation
 of EXAMPLE 3 between 0 and 70 minutes, which were almost identical to that
 of FIGS. 1 and 3. The results of FIG. 4 indicate that the replacement of
 the pregelatinized starch with PVP K30 as binder did not affect the
 dissolution of the tablet.
 EXAMPLE 4

Ciprofloxacin 70%
 PVP-K30 2%
 Sodium starch glycolate 5%
 Lactose 20%
 Sodium lauryl sulfate 1%
 Magnesium stearate 2%
 100%
 The above formulation was prepared by the method as described in EXAMPLE 1,
 except that PVP-K30 was added to replace the pregelatinized starch as
 binder and sodium lauryl sulfate is added as wetting agent.
 FIG. 2 shows the dissolution rates of the tablet containing the formulation
 of EXAMPLE 4 between 0 and 70 minutes, which were almost identical to that
 of FIG. 1 and FIG. 3. The results of FIG. 2 show slightly lower
 dissolution rates with the maximum dissolution plateaued at 85% after 5
 minutes of testing.
 EXAMPLE 5

Ciprofloxacin 70%
 Polyvinyl alcohol 2%
 Sodium starch glycolate 5%
 Lactose 21%
 Magnesium stearate 2%
 100%
 The above formulation was prepared by the method as described in EXAMPLE 1,
 except that polyvinyl alcohol (PVA) was added to replace the
 pregelatinized starch as binder.
 FIG. 5 shows the dissolution rates of tablets containing the formulation of
 EXAMPLE 5 between 0 and 70 minutes, which were almost identical to that of
 FIGS. 1, 3-4. The results of FIG. 5 indicate that replacement of the
 pregelatinized starch or PVP with PVA as binder did not affect the
 dissolution rate of the tablet.
 EXAMPLE 6

Ciprofloxacin 70%
 Polyvinyl alcohol 2%
 Sodium starch glycolate 5%
 Lactose 20%
 Sodium lauryl sulfate 1%
 Magnesium stearate 2%
 100%
 The above formulation was prepared by the method as described in EXAMPLE 1,
 except that PVA was added to replace the pregelatinized starch or PVP as
 binder and sodium lauryl sulfate is added as wetting agent.
 FIG. 6 shows the dissolution rates of tablets containing the formulation of
 EXAMPLE 6 between 0 and 70 minutes, which were almost identical to that of
 FIGS. 1, 3-5. The results of FIG. 6 indicate that replacement of the
 pregelatinized starch or PVP with PVA as binder and the addition of sodium
 lauryl sulfate did not affect the dissolution rate of the tablet.
 EXAMPLE 7

Hydroxypropylmethyl cellulose (HPMC) 73%
 Polyethylene glycol (PEG) 16.7%
 Dimethylpolysiloxane 0.3
 TiO.sub.2 10%
 100%
 EXAMPLE 7 shows the formulation of the coating material. The formulation
 was prepared by placing 5.475 g of HPMC and 1.2525 g of PEG in a 200 ml
 beaker in which an adequate amount of hot water was added to facilitate
 the dispersion of HPMC and PEG. Then, a 0.75 g of TiO.sub.2 was added to a
 50 ml beaker which was mixed with 20 ml of pure water until uniformity.
 The TiO.sub.2 and water mixture was passed through a 250/in.sup.2 sieve
 once. The sieved TiO.sub.2 suspension was then mixed with the HPMC/PEG
 mixture, of which 0.0225 g of dimethylpolysiloxane was added to bring the
 final volume to 100 ml with water. The HPMC/PEG/TiO2/DMPS mixture was pass
 through the 250/in.sup.2 sieve twice. The sieved HPMC/PEG/TiO2/DMPS
 mixture, the coating material, was then placed in the spraying gun of the
 coating machine to spray-coat the surfaces of the tablets as described
 above.
 It should be understood that the foregoing relates only to preferred
 specific embodiments of the present invention and that numerous
 modifications or alterations may be made therein without departing from
 the spirit and the scope of the invention as set forth in the appended
 claims.