Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-01-19
2001-05-08
Dees, Jose' G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S451000, C424S452000, C424S490000, C424S493000, C424S494000, C514S277000, C514S336000, C514S337000, C514S338000
Reexamination Certificate
active
06228400
ABSTRACT:
FIELD OF THE INVENTION:
This invention relates to novel orally administered pharmaceutical formulations in the form of granules which comprises, as an active ingredient, a potent gastric acid secretion inhibitor, i.e., a substituted 2-(2-benzimidazolyl)-pyridine such as omeprazole or lansoprazole, and the process of making the formulations.
BACKGROUND OF THE INVENTION
Benzimidazole derivatives have been known for their anti-ulcer activities as inhibitors of gastric acid secretion. For example, omeprazole, which has the formula of 5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-1H-benzimidazole), is known for its activity as an inhibitor of H
+
K
+
-ATPase and the proton pump in the gastric mucosa and can be used for the treatment of gastric and duodenal ulcers (Pilbrant and Cederberg,
Scand. J. Gastroenterology
(1985)20:113-120). The information of omeprazole can be found U.S. Pat. No. 4,255,431, U.S. Pat. No. 4,786,505, and EPO 124495. Lansoprazole, which has the formula of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole, is useful for prophylaxis and therapy of digestive ulcers (e.g., gastric ulcer, duodenal ulcer) and gastritis. Its empirical formula is C
16
H
14
F
3
N
3
O
2
S with a molecular weight of 369.37. The information of lansoprazole can be found U.S. Pat. No. 4,628,098, U.S. Pat. No. 4,689,333, and U.S. Pat. No. 5,026,560.
Omeprazole is very slightly soluble in water, but very soluble in alkaline solutions as the negatively charged ion. It is an ampholyte with pK
a
~4 (pyridinium) and 8.8 (benzimidazole). Lansoprazole is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166° C. Lansoprazole is freely soluble in dimethylformamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water.
According to Pilbrant and Cederberg,
Scand. J. Gastroenterology
(1985) 20:113-120, omeprazole is susceptible to degradation/-transformation in acid and neutral media. The rate of degradation proceeds with a half-life of less than 10 minutes at pH-values below 4. At pH 6.5 the half-life of degradation is 18 hours; at pH 11 about 300 days.
Due to the acidic gastric condition, a pharmaceutical dosage form of omeprazole must be coated with an enteric coating to prevent omeprazole from premature contact with gastric juice. However, ordinary enteric coatings are also made of acidic compounds. Therefore, if omeprazole is directly covered with the conventional enteric coating, the dosage form may not only become badly discolored but also decreased in omeprazole content with the passage of time.
To overcome the acidic labile problem and to prolong the storage stability of omeprazole, it is generally recommended to mix omeprazole with an alkaline material so as to create a high pH value for the drug. For instance, U.S. Pat. No. 4,738,974 describes the alkaline salts of omeprazole which include Li
+
, Na
+
, K
+
, Mg
2+
, Ca
2+
, Ti
4+
, N
+
(R
1
)
4
or guanidinium salts.
Alternatively, U.S. Pat. No. 4,786,505 describes an oral dosage form of omeprazole, where omeprazole is mixed with an alkaline reacting substance to create a “micro-pH” around each omeprazole particle of not less than pH=7, preferably not less than pH=8. The alkaline substances described in U.S. Pat. No. 4,786,505 include the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances, such as Al
2
O
3
.6MgO.CO
2
.12H
2
O, (Mg
6
Al
2
(OH)16CO
3
.4H
2
O), MgO.Al
2
O
3
.2SiO
2
.nH
2
O) or similar compounds; organic pH-buffering substances such as trihydroxymethylaminomethane or other similar pH-buffering substances. The high pH-value of omeprazole can be achieved by using an alkaline reacting salt of omeprazole as described in U.S. Pat. No. 4,738,974.
U.S. Pat. No. 5,232,706 describes an oral dosage form of omeprazole which contains a nucleus formed by a mixture of omeprazole or an alkali salt of omeprazole with a first basic compound, a first coating which contains at least an excipient and a second basic compound, and an enteric coating. The basic compounds referred to in U.S. Pat. No. 5,232,706 are sodium, potassium, magnesium, calcium, aluminum or dihydroxyaluminium salts of amino acids, such as glycocoll, glutamic acid, or lysine, or a pyridine carboxylic acids such as nicotinic acid, or organic bases such as guanidine.
Due to the insolubility of omeprazole in water, most of the omeprazole formulations are prepared by mixing the powder form of omeprazole with various kinds of binders, excipients and carriers. For example, U.S. Pat. No. 4,786,505 describes the preparation of the omeprazole core by mixing omeprazole with alkaline reacting substances to form a powder mixture, followed by formulating the powder mixture into small beads, i.e., pellets, tablets, hard gelatine or soft gelatine capsules by conventional pharmaceutical procedures, i.e., by pressing through an extruder and spheronized to pellets.
U.S. Pat. No. 5,385,739 discloses omeprazole microgranules where the powder form of omeprazole is diluted with a substantially equal amount of mannitol powder, together with sodium lauryl sulfate and carboxymethylstarch, so as to produce a homogeneous and stable dilute powder.
U.S. Pat. No. 5,026,560 describes a formulation of making spherical granules containing omeprazole or lansoprazole. The formulation contains a spherical granule which has a core coated with a binder and spraying powder containing the drug and low substituted hydroxypropylcellulose.
In the invention to be described, novel orally administered pharmaceutical formulations of omeprazole or lansoprazole will be described. These formulations are distinctively different from those of the patents described above: First, the invention uses a free base of omeprazole or lansoprazole instead of the alkaline salt form of the drug. Second, the free base of omeprazole or lansoprazole is mixed with a non-ionic surfactant and water to form an emulsion, rather than a powder mix, which then can be sprayed and dried onto an inert core to form a granule. Third, the invention demonstrates that it is not necessary to mix the free base of omeprazole or lansoprazole with any alkaline substance in order to create a fully bioavailable dosage form. In fact, the omeprazole formulations in which omeprazole is not mixed with any alkaline substance display equal or better dissolution rate than the commercially available omeprazole formulation such as prilosec where omeprazole is mixed with an alkaline substance.
SUMMARY OF THE INVENTION
A first embodiment of the present invention provides an orally administered pharmaceutical granule of omeprazole or lansoprazole which contains (a) an inert core which is made of starch, a mixture of sugar and starch, or microcrystalline cellulose; (b) a drug emulsion deposited on the inert core, wherein said drug emulsion comprises an effective amount of a free base of omeprazole or lansoprazole, a non-ionic surfactant, a basic amino acid, and water; (c) a protective coating deposited on top of the drug coating, wherein the protective coating comprises at least one film-forming compound which is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP) and hydroxymethylcellulose (HMC), optionally a plasticizer; and (d) an enteric coating deposited on top of the protective coating, wherein the enteric coating comprises at least a pharmaceutically acceptable polymer which is selected from the group consisting of hydroxypropylmethyl-cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), co-polymerized me
Chen Shan-chiung
Kuo Han-Chiang
Lee Fang-Yu
Carlsbad Technology Inc.
Chao Fei-Fei
Dees Jose' G.
Pryor Alton
Venable Baetjer Howard & Civiletti LLP
LandOfFree
Orally administered pharmaceutical formulations of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Orally administered pharmaceutical formulations of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Orally administered pharmaceutical formulations of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2476173