Field of invention
The present invention relates to enteric coated formulations of lansoprazole and process for making such formulations. The formulation comprises polyethylene glycol 400 in the enteric layer.
Background of the invention
U.S. Patent Nos. 4,255,431, 4,628,098 and 4,758,579 disclose substituted pyridylsulfinyl benzimidazoles as potent inhibitors of gastric acid secretion. This class of compounds inhibit gastric acid secretion by inhibiting H+-K+ ATPase (proton-pump) activity.
Drugs in this class are known to be highly unstable in an acidic environment. They are also unstable in the presence of moisture and organic solvents. Thus the formulation in which the drugs are to be administered to a patient, and the process for manufacture of the formulation, must be designed to protect the drug from moisture as well as an acidic environment. Due to the rapid drug degradation that occurs in acidic gastric fluids, the formulations may be enteric coated.
The stability problems associated with benzimidazole compounds are well recognized in the prior art, which teaches various approaches to preparing stable formulations containing benzimidazole compounds. One of the most common approaches utilized to stabilize benzimidazole compounds is the use of an alkaline core, a separating layer and an enteric coating. It is well-recognized in the art that use of an alkaline medium within the core protects benzimidazole compounds from acid degradation.
Lansoprazole is a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl] sulfinyl] benzimidazole, a compound that inhibits gastric acid secretion. Lansoprazole is highly unstable in acidic enviornment. Due to the rapid drug degradation that occurs in acidic gastric fluids, the lansoprazole formulations are enteric coated.
Plasticizers are non-volatile liquids used to impart flexibility to otherwise hard or brittle polymeric materials. In enteric coating composition plasticizers are added to modify the polymer solution before coating. Plasticizers add to film toughness (increased resistance to chipping or cracking) while lowering the glass transition temperature or softening point of the polymeric film. In general the optimum concentration of the plasticizer is the minimum amount which provides the necessary flexibility to form a continuous coating. Plasticizers function by weakening the intermolecular attractions between the polymer chains and help in obtaining smooth films.
Enteric coated formulations of lansoprazole are previously known in the art.
US 5,026,560, discloses enteric coated spherical granules of lansoprazole using PEG 6000 as plasticizer in enteric coating composition.
US 2004/0028737, discloses enteric coated pellets of lansoprazole. The pellets are coated with organic aqueous dispersion of enteric polymer and the coating dispersion contains PEG 600 as a plasticizer.
WO 04/066982, discloses enteric coated pellets of lansoprazole. The enteric coating composition comprises PEG 300 as a plasticizer.
The choice of the plasticizer was found to be critical to the manufacturing process of the formulation as well as to the release characteristics and hence the bioavailability of the formulation after oral administration. It was observed that polyethylene glycol 400 has an advantage of making better films compared to prior art plasticizers such as PEG 300 that makes too soft films. Further, it has surprisingly been found that choice of appropriate plasticizer in the enteric layer is critical to the in vivo bioavailability of the formulation. Polyethylene glycol 400, as plasticizer, in enteric coating pellet compositions is capable of giving a formulation that is bioequivalent to Prevacid® capsules, commercially available in US from Takeda Pharmaceuticals.
Summary of the invention
According to one embodiment there is provided an enteric coated lansoprazole formulation, the formulation comprising: a) a core comprising lansoprazole and one or more pharmaceutically acceptable excipients; b) an intermediate layer surrounding the core; and c) an enteric layer surrounding the intermediate layer, wherein the enteric layer comprises polyethylene glycol 400.
According to another embodiment there is provided a process for the preparation of an enteric coated lansoprazole formulation, the process comprising the steps of: a) preparing a core by coating an inert carrier with an aqueous dispersion of lansoprazole, and one or more pharmaceutically acceptable excipients; b) coating the core with an intermediate layer; and c) covering the intermediate layer with an enteric layer comprising polyethylene glycol 400.
Detailed description of invention
The enteric coated lansoprazole formulation comprises: a) a core comprising lansoprazole, and one or more pharmaceutically acceptable excipients; b) an intermediate layer surrounding the core; c) an enteric layer surrounding the core, wherein the enteric layer comprises polyethylene glycol 400.
The term 'lansoprazole' includes lansoprazole free base, pharmaceutically acceptable salts, solvates and mixtures thereof.
The term 'core1 as used herein refers to pharmaceutically acceptable inert carrier coated with a mixture of lansoprazole and pharmaceutically acceptable excipients.
The pharmaceutically acceptable 'inert carrier' may include starch, microcrystalline cellulose or sugar sphere, such as nonpareil sugar seeds.
The 'pharmaceutically acceptable excipients' may be selected from one or more of alkaline reacting substances, binders, disintegrants and lubricants.
The 'alkaline reacting substance' may be selected from one or more of basic inorganic salt of magnesium including heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite and aluminum magnesium hydroxide; basic inorganic salts of calcium including precipitated calcium carbonate and calcium hydroxide; basic inorganic salts of sodium including sodium carbonate and sodium hydrogen carbonate; potassium basic inorganic salts such as potassium carbonate; aluminum basic inorganic salts such as aluminum silicate.
The 'binder' may be selected from one or more of cellulose derivatives like hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose; gums like xanthan gum, gum acacia, tragacanth; and water soluble vinylpyrrolidone polymers like polyvinyl pyrrolidone, copolymer of vinyl pyrrolidone and vinyl acetate.
The 'disintegrant' may be selected from one or more of crospovidone, corn starch, sodium starch glycolate and croscarmellose sodium.
The 'lubricant' may be selected from one or more of talc, colloidal silicon dioxide, magnesium stearate and sodium stearyl fumarate.
The term 'intermediate layer' as used herein refers to the layer that separates the core from the enteric coating. The intermediate layer is made up of substantially water soluble polymer which is capable of dissolving or forming a gel in contact with water. The intermediate layer may also include inert excipients such as talc, titanium dioxide, colloidal silicon dioxide and mixtures thereof.
The 'substantially water-soluble polymers' may be selected from one or more of hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose, copolymer of vinylpyrrolidone and vinyl acetate.
An enteric layer is applied onto the core coated with the intermediate layer by using suitable coating techniques. The 'enteric layer' includes polymers selected from one
or more of cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, methacrylic acid methyl esters/methacrylic acid copolymers, such as compounds known under the trademarks of Eudragit NE30D, Eudragit L, Eudragit S. Eudragit L 100 55 and marketed by Rohm Pharma, and mixtures thereof. The enteric layer comprises Polyethylene glycol 400 as the plasticizer. The amount of PEG 400 may range from 5 - 30 % w/w of the enteric layer. Polyethylene glycol 400 is a colorless or weak yellowish, transparent, viscous liquid, having weak odor. It has an advantage of giving better films that are not too soft and not too brittle or cracky. The enteric layer may also contain one or more additional plasticizers in combination with polyethylene glycol 400 such as triethyl citrate, tiacetin, tributylsebecate, diethyl pthalate etc. The enteric layer may also include other additives such as talc, titanium dioxide, colloidal silicon dioxide, and surfactants.
The 'surfactant' may be selected from one or more of polysorbate 80, sodium lauryl sulphate, and sodium dodecyl benzene sulphonate.
According to one embodiment of the specification there is provided a process for the preparation of an enteric coated lansoprazole formulation, the process comprising the steps of:
a) preparing a core by coating an inert carrier with an aqueous dispersion of
lansoprazole and one or more pharmaceutically acceptable excipients;
b) coating the core with an intermediate layer; and
c) covering the intermediate layer with an enteric layer comprising polyethylene
glycol 400.
According to one embodiment, the enteric coated formulation of the present invention is bioequivalent to the innovator formulation.
The term "innovator formulation" as used herein refers to capsule formulation filled with enteric coated pellets, commercially available in U.S under the trade name Prevacid® capsules, from Takeda Pharmaceuticals.
The following non-limiting examples further illustrate the enteric-coated lansoprazole formulation and process of making such formulation.
Example 1(Table Removed)
Example 2(Table Removed)
Example 3
(Table Removed)
Manufacturing Procedure:
a) Drug Layering
1. Hydroxypropyl cellulose/Hydroxypropyl methyl cellulose was dissolved in
purified water under stirring.
2. Lansoprazole, Light Magnesium Carbonate, Crospovidone/Low substituted
hydroxy propyl cellulose were dispersed in the solution of step 1 under stirring.
3. Sugar spheres (25-30#) were loaded in wurster coater and drug
suspension of step 2 was sprayed on to it.
b) Intermediate layer
4. Hydroxypropyl methylcellulose/Hydroxy propyl cellulose was dissolved in
purified water under stirring and was kept under stirring till a clear solution
was obtained.
5. Talc was dispersed in Hydroxypropyl methylcellulose/Hydroxypropyl
cellulose solution under stirring.
6. The layered pellets were loaded in wurster coater and intermediate layer
coating suspension of step 5 was sprayed on to it.
c) Enteric layer
7. Talc, Titanium dioxide, Polyethylene glycol 400 and Polysorbate 80 were
dispersed in water.
8. The dispersion of step 7 was added to Methacrylic acid copolymer
dispersion and stirred at low speed.
9. The intermediate layer coated pellets were coated with enteric polymer
suspension of step 8.
10. The enteric-coated pellets were dried in vacuum Tray dryer at 40°C.
d) Lubrication
11. Colloidal silicon dioxide and talc were sifted through # 44 BSS.
12. The dried beads of step 10 were blended with lubricants of step 11 for 10
minutes.
e) Filling
13. The lubricated pellets were filled in hard gelatin capsules shells.
Pharmacokinetic study design:
(Table Removed)

WE CLAIM:
Claim 1. An enteric coated lansoprazole formulation comprising: a) a core comprising lansoprazole, and one or more pharmaceutically acceptable excipients; b) an intermediate layer surrounding the core and c) an enteric layer surrounding the core, wherein the enteric layer comprises polyethylene glycol 400.
Claim 2. The enteric coated formulation of claim 1, wherein the pharmaceutically acceptable excipient comprises one or more of alkaline reacting substances, binders, disintegrants and lubricants.
Claim 3. The enteric coated formulation of claim 2, wherein the alkaline reacting substance comprises one or more of basic inorganic salts of magnesium selected from heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite and aluminum magnesium hydroxide; basic inorganic salts of calcium selected from precipitated calcium carbonate and calcium hydroxide; basic inorganic salts of sodium selected from sodium carbonate and sodium hydrogen carbonate; potassium basic inorganic salts; and aluminium basic inorganic salts.
Claim 4. The enteric coated formulation of claim 2, wherein the binder comprises one or more of cellulose derivatives selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose; gums selected from xanthan gum, gum acacia, tragacanth; and water soluble vinylpyrrolidone polymers selected from polyvinyl pyrrolidone, copolymer of vinyl pyrrolidone and vinyl acetate.
Claim 5. The enteric coated formulation of claim 2, wherein the disintegrant comprises one or more of crospovidone, corn starch, sodium starch glycolate and croscarmellose sodium.
Claim 6. The enteric coated formulation of claim 2, wherein the lubricant comprises one or more of talc, colloidal silicon dioxide, magnesium stearate and sodium stearyl fumarate.
Claim 7. The enteric coated formulation of claim 1, wherein the intermediate layer comprises substantially water soluble polymer selected from one or more of hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose, and copolymer of vinylpyrrolidone and vinyl acetate.
Claim 8. The enteric coated formulation of claim 1, wherein the amount of polyethylene glycol 400 ranges from 5 - 30% by weight of the enteric layer.
Claim 9. A process for the preparation of the enteric coated lansoprazole formulation of claim 1 , the process comprising the steps of:
a) preparing a core by coating an inert carrier with an aqueous dispersion of
lansoprazole and one or more pharmaceutically acceptable excipients;
b) coating the core with an intermediate layer; and
c) covering the intermediate layer with an enteric layer comprising polyethylene
glycol 400.
Claim 10. An enteric coated lansoprazole formulation and process of preparation thereof, as substantially described and exemplified herein.