JPH04210917A - Orally administrative pharmaceutical composition of unit dosage form - Google Patents

Abstract

PURPOSE: To obtain oral dosage form containing CBS in an amount effective in treatment which does not bring out undesirable instantaneous sharp peak of blood concentration found when conventional swallowable CBS tablet is administered. CONSTITUTION: This oral pharmaceutical preparation composition in unit dosage form comprises solid colloidal bismuth subcitrate(CBS) and as necessary, one or more kind of auxiliary medicine and vehicles and the preparation has 0.06-0.60g/ml pocking density of CBS.

Description

[Detailed description of the invention]

[00011

FIELD OF THE INVENTION This invention relates to oral pharmaceutical compositions in unit dosage form comprising solid colloidal bismuth citrate. [0002] [Prior Art] Solid colloidal bismuth citrate (C
BS) (trademark De-Nol, manufactured by Gist-brocades N, V,) is
It is a product of European Patent No. 0.075.992, corresponding to U.S. Pat. No. 4,801,608, the contents of which are incorporated herein by reference in their entirety. It is also covered by British Patent No. 1.478.742
It is also the active ingredient of No. According to these specifications, CB
S can be prepared into pharmaceutical compositions in solid dosage forms for oral administration, such as tablets and capsules. So far, only tablet form is actually manufactured and sold in many countries. (0003) Merck Manual, 11th Edition (1989
According to item 1296, the estimated molecular formula of CBS is:
K3 (NH4)2 (B100s (OH)
5 (C6H3O7)4:). Its bismuth content is from 39 to 42 weight percent, expressed as Bi2O3, according to the aforementioned European Patent No. 0.075.992 and US Pat. No. 1.478.742. [0004]

A commonly used tablet form of depressible CBS has already been given to millions of patients, and its clinical efficacy and safety have been well established. However, in recent years, a sharp instantaneous peak in the blood concentration of bismuth in humans ('rmax around 30 minutes) after ingestion of depressible tablets containing CBS,
There was a report regarding. C.U., Nwokolo et al.
Aliment, Pharmac. 1, Therap, 3.1989, 29-39
See page. On the other hand, the traditionally cited safe blood concentration of bismuth has recently been called into question. For example, A. 5likkerveer and F. de Wolf
f, Med, Toxicol, Adverse
Drug Exp, 4 (5), 1989, 30
See pages 3-323. In any case, since the therapeutic action of CBS is localized to the gastrointestinal tract, the instantaneous peak in bismuth blood concentrations does not seem to have any useful consequences;
Should be avoided if possible. [0005]

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide an oral dosage unit containing a therapeutically effective amount of CBS that does not result in the above-mentioned bismuth blood concentration peaks. This purpose is to increase the packing density of the CBS in the dosage unit from 0.06 to 0.
It has been found that this can be achieved by between .degree. 60 grams/milliliter. [0006] The term “packing density (po
packing density) J means the weight (durham) of the active ingredient (CBS) divided by the volume given by the dosage form expressed in milliliters and, in the case of a filled capsule form, the weight of the capsule container. Means excluding volume and weight. Thus, the packing density can be varied by varying the amount of excipient added to the CBS' and by varying the pressure used to compress the units. [0007] Therefore, the present invention provides that CBS in a pharmaceutical dosage unit
a therapeutically effective amount of solid colloidal bismuth citrate (CBS), characterized in that the packing density of is between 0.06 and 0.60 grams per milliliter; The present invention relates to oral pharmaceutical compositions in unit dosage form containing excipients that can be used. [0008] Preferably, the packing density is from 0.30 to 0.
．． It is 50 grams/ml. [0009] CBS according to the present invention is desirably in granular form with a preferred particle size of less than 1.5 millimeters. [00101CBS may be supplemented with any of the excipients conventionally known in the art that are compatible with CBS'. For example, lactose, starch, microcrystalline cellulose, sorbitol, mannitol, dibasic calcium sulfate dihydrate,
Calcium sulfate dihydrate, sucrose standard
diluents such as acacia, cellulose derivatives, gelatin, glucose, polyvinylpyrrolidone, starch, sucrose, sorbitol, tragacanth, sodium alginate and mixtures thereof; microcrystalline cellulose and Microcrystalline cellulose derivatives, starch and its derivatives, alginic acid and its derivatives, ion exchange resins, crosslinked sodium carboxymethyl cellulose, sodium starch glycolate (sod
disintegrants such as tarch glycolate), cross-linked polyvinylpyrrolidone and formaldehyde-casein; magnesium stearate, calcium stearate and sodium stearate, stearic acid, hydrogenated castor oil, talc, water, polyethylene glycol, sodium lauryl sulfate, lauryl sulfate. Lubricants, anti-adhesives, and gliding agents such as magnesium and silica (g
There are 1dants). [00111 These excipients are preferably added in a total amount ranging from 3 to 1000 milligrams, more preferably from 20 to 150 milligrams per 100 milligrams of CBS. [0012] The low packing density of oral dosage units identified above is contrary to current trends in the art in pharmaceutical production. There is a recent trend towards making oral dosage units more dense, for example by compressing the contents of oral capsules. See "Hard Capsules, Development and Technology", edited by K. Ridgway, 1987, Chapter 9, G. C. Cole, pp. 92-103. [0013] The oral dosage units of the present invention exhibit lower maximum blood and serum bismuth concentrations (Cm
aX) as well as low blood and serum bismuth elevation (AUG) and low urinary bismuth excretion. Therefore, systemic bismuth absorption after ingestion of these dosage units proved to be lower than after ingestion of tablets. This is contrary to the expectation that a more dispersible substance would dissolve faster than the same compacting substance, thus leading to higher absorption. [0014] The oral dosage units of the present invention surprisingly provide lower maximum bismuth serum concentrations and total bismuth absorption than denser dosage units. [0015] In addition to CBS, oral dosage units according to the invention may also contain adjuvant agents, preferably CB such as non-steroidal anti-inflammatory compounds, H2 antagonists and synthetic prostaglandins.
It may also include those intended to act in combination with S. In particular, the dosage unit contains antibacterially active agents such as antibiotics and chemotherapeutic substances, more particularly antibacterially active nitroimidazoles, penicillins, cephalosporins, monobactams.
ms) and β-lactam antibiotics such as penems, Helicobacter pylori (Helicobacter pylori) such as tetracyclines, quinolones, and macrolides.
bacter pylori) (formerly known as Campylobacter pylori)
ri)). [0016] The preferred dosage of CBS in an oral dosage unit according to the present invention is preferably from 30 to 60 CBS per dosage unit.
0 milligrams, more preferably 37.5 milligrams per dosage unit
300 milligrams. [0017] The dosage of optionally added adjuvant drugs will depend on the effectiveness of the particular drug used. [0018] Although tablets with the low CBS densities described above are possible, the most practical oral dosage unit according to the present invention is a capsule. [00191 The material for the capsules according to the present invention may be any of the materials known in the art, such as gelatin, modified starches such as hydroxyalkyl starches, and cellulose derivatives such as cellulose ethers, such as methyl cellulose. Gelatin capsules can be soft or hard.

[0020] Dosage units according to the invention may be further coated to modify release. [00211] [Example] The following example specifically illustrates the present invention. [0022] Example 1 Tablets and capsules were prepared as shown below using CBS prepared according to European Patent No. 0.075.992 and US Pat. No. 4.801.608. [0023] Uncoated round 1 containing CBS
Descendable tablet A was manufactured as follows. 5.85 kg of povidone by dissolving 8100 kg of CB in 51.0 kg of ethanol
It was granulated using K30 with 23.8 kg of corn starch. The granules with a particle size of less than 1 millimeter were mixed with 7.8 kilograms of polocrinin potassium, 1.
It was mixed with 98 kilograms of polyethylene glycol 6000 and 0.66 kilograms of magnesium stearate and compressed into tablets. [0024] Coated round claptable tablets B containing CBS were made by film coating the tablets prepared as described above with about 12 milligrams of hydroxypropyl methylcellulose and 2 milligrams of polyethylene glycol per tablet. . These tablets are identical to the commercially used De-Noll tablets. [0025] Coated elongated depressible low density tablets C were manufactured as follows. 240 grams of CBS
30 grams of povidone dissolved in 85 grams of ethanol was granulated with 480 grams of corn starch. Granules with a particle size of less than 1 millimeter were combined with 19.4 grams of boracrylin potassium, 4.
9 grams of polyethylene glycol 6000.35.8
grams of corn starch and 3.6 grams of magnesium stearate and compressed into tablets. The tablets were film coated with about 21 milligrams of hydroxypropyl methylcellulose and about 3 milligrams of polyethylene glycol per tablet. [0026] CBS's low-density depressible capsules D and very low density depressable capsules E are rolled using the granules for uncoated depressable tablets A described above. It was manufactured by filling N000 hard gelatin capsules using a type capsule filling machine. The filling density of the capsule contents was controlled by the setting of the piston within the dosator. [0027] The densities of uncoated and coated tablets and two different capsules were calculated in terms of the amount of CBS per unit volume. [0028] The disintegration times of the five formulations are as per United States Pharmacopeia No. 2
1 edition (USPXXI) in water at 37°C. [0029 The hardness of the 13 tablet formulations was measured using a Schleiniger E-2 instrument. [0030 The properties of the 15 formulations are summarized in Table 1 below. [00311] [0032] Example 2 Bismuth Absorption in Dogs Healthy fasted dogs (Peagles) were given one coated tablet B or C1 of Example 1 or one of the very low density capsules E. given the amount. Dogs received 2 tablets or 2 capsules each for a total dose of 600 milligrams of CBS per dog. After ingestion, blood samples were taken at 9 intervals up to 8 hours. [0033] Bismuth content was measured in blood by atomic absorption. [0034] The mean bismuth blood concentrations in dogs after ingestion of different CBS formulations are shown in FIG. [0035] Table 2 shows blood Tmax (time after ingestion to reach maximum bismuth blood concentration); blood Cmax (
The highest bismuth blood concentration reached); the average of blood AUG (area under the bismuth concentration-time curve) calculated over 8 hours after administration are summarized. [0036] Table 2 [0037] It is clear from these results that low density tablets and very low density capsules provide lower systemic bismuth absorption than prior art dosage forms in dogs. . [0038] Example 3 Bismuth Absorption in Humans Healthy fasted human volunteers were administered the uncoated and coated tablets A and B of Example 1 and the two capsules D and E. Volunteers received 2 tablets or 2 capsules each for a total dose of 600 milligrams of CBS per volunteer. Blood samples were taken at several intervals up to 3 hours after ingestion, and urine was collected over a 3 hour period. [0039] Bismuth content was measured in serum and urine by atomic absorption. [00401 Average bismuth serum concentrations in humans after ingestion of different CBS formulations are shown in Figure 2. [0041] Table 3 presents serum and urine data together under the same headings as Table 2 (AU calculated at 3 hours post-dose).
Urine collected 3 hours after C1 dosing). [0042]

[0043] From the above results, it can be seen that even in humans, very low density capsules are more effective than the two prior art dosage forms.
It is clear that low density capsules give very low systemic bismuth absorption and are moderate. From Tables 3 and 1, there appears to be an inverse relationship between the density of the dosage form and the resulting systemic bismuth absorption.

[Brief explanation of the drawing]

FIG. 1 is a graph of mean blood bismuth concentrations in dogs after ingestion of different CBS formulations.

FIG. 2 is a graph of mean serum concentrations in humans after ingestion of different CBS formulations.

[Figure 1]

[Figure 2]

Claims (9)

[Claims] 1. A therapeutically effective pharmaceutical composition, characterized in that the packing density of solid colloidal bismuth citrate (CBS) per unit of pharmaceutical composition is between 0.06 and 0.60 grams per milliliter. An oral pharmaceutical composition in unit dosage form comprising an amount of solid colloidal bismuth citrate (CBS) and, optionally, a pharmaceutically acceptable excipient. 2. The oral pharmaceutical composition according to claim 1, having a packing density of 0.30 to 0.50 g/milliliter. 3. Oral pharmaceutical composition according to claim 1, characterized in that the content of solid colloidal bismuth citrate is between 30 and 600 milligrams per dosage unit. 4. Oral pharmaceutical composition according to claim 3, characterized in that the content of solid colloidal bismuth citrate is between 37.5 and 300 milligrams per dosage unit. 5. Oral pharmaceutical composition according to claim 1, further comprising one or more auxiliary drugs. 6. The oral pharmaceutical composition according to claim 5, wherein the auxiliary agent is an antibacterial agent. 7. The antibacterial agent is nitroimidazole, penicillin, cephalosporin, monobactam (mo
n. Helicobacter selected from bac tams, penems, tetracyclines, quinolones and macrolides.
(Campylobacter
)) The oral pharmaceutical composition according to claim 6, which is effective against pylori. 8. Oral pharmaceutical composition according to claim 1, which is a capsule. 9. The capsule according to claim 8, wherein the material of the capsule is selected from gelatin, modified starch, and cellulose derivatives.