JPS61109724A - Encapsuled antacid dispersion - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION BACKGROUND OF THE INVENTION Soft gelatin encapsulation of medicinal solutions or dispersions in liquid carriers has become popular in other dosage forms such as compressed, coated or uncoated solid tablets, or bulk liquid dosage forms. offers many benefits. Gelatin encapsulation of solutions or dispersions allows for precise delivery of unit doses, an advantage that is particularly important when relatively small amounts of active ingredient have to be administered, as is the case with certain hormones. Become. This uniformity can be achieved through tabletting methods, where the solids must be uniformly mixed and compressed, or through introduction of the total amount of active ingredient into a bulk liquid carrier, which must be metered prior to oral administration. It is more difficult to achieve.

Soft gelatin encapsulation provides a dosage form that is more easily accepted by patients because capsules are easy to swallow and there is no need to add flavorings to mask the unpleasant taste of the active ingredient. . Soft gelatin capsules are also easier for patients to carry since they only need to be removed from the packaging in the number needed for administration.

Soft gelatin encapsulation further offers the possibility of improving the bioavailability of pharmaceuticals. As soon as the gelatin shell is broken, the active ingredient is rapidly released into liquid form. Complete destruction and dissolution of the capsule, as in the case of tableted compositions, is not necessary for the active ingredient to be available for absorption. Additionally, relatively sparingly soluble active ingredients can be dispersed in a liquid carrier, resulting in more rapid absorption. In the case of oral solutions, a significant amount of the active ingredient is lost due to deposition in the mouth or esophagus before absorption into the blood.

Currently available antacids are designed for the relief of symptoms of heartburn, acid stomach, indigestion, gas, and hyperacidity associated with peptic ulcers, gastritis, hyperacidity, and hiatal hernia.

These agents contain one or more basic i-gneum salts, aluminum salts or calcium salts that act to neutralize stomach acid. For example, Maalox
Glass (Maalox Plus) (trademark) (
W, H, cl-vru Inc. (W, H, Ror@r Inc.
) Ft, y) y, Ph3, 200 ■ per administration
of magnesium hydroxide, 225rn9 of aluminum hydroxide and 15cm of 7 methico/(sin thicone
) is obtained as a liquid formulated to provide a dispersant. The tablet form of this product is similar except that it contains 200 μg of aluminum hydroxide per dose. Turns™ (Norcliff Thayer Inc., Tukahos+: -York) contains approximately 500 rI19 magnesium carbonate per tablet. Other commercially available antacid compositions The products contain varying amounts of magnesium silicate, magnesium carbonate, bismuth aluminate, magnesium oxide, sodium dihydroxyaluminum carbonate, magaldrate and similar basic salts.

The advantages that may be achieved by administering these salts as dispersions or solutions via soft encapsulation are listed above. However, in this method the It has heretofore been impossible to administer such compositions.

Additionally, edible oils, traditionally used as pharmaceutical carriers in soft gelatin capsules, effectively reduce the neutralizing capacity of antacid components.

This invention therefore aims to provide liquid dispersions of basic salts that are suitable and compatible with soft gelatin encapsulation.

Another object of this invention is to provide basic salts, such as calcium salts, adapted for oral, vaginal, rectal or buccal administration when housed in a soft gelatin capsule.
Dispersions of magnesium salts and aluminum salts are provided.

Another object of this invention is to provide a dispersion of a basic salt in a carrier that does not adversely affect the neutralization capacity of the basic salt.

Other objects, advantages, and novel features of the invention will be apparent to those skilled in the art from the following description and claims.

SUMMARY OF THE INVENTION It is an object of the present invention to prepare a basic salt in a substantially water-free carrier mixture comprising one or more polyalkylene glycols and a C2-5/liol such as glycerin or propylene glycol. This is accomplished by a pharmaceutical unit dosage form containing a dispersion of. The mixture of alcohols forms a stable dispersion of particles of the basic salt that is coated with a carrier mixture and rendered substantially non-reactive with the soft gelatin capsules in which the dispersion is subsequently contained. It acts to form. The dispersions of the present invention may be formulated with desired amounts of plasticizers and base-compatible pharmaceutical agents.

As used herein, the term "substantially free of water" refers to water present in the starting material, such as provided by the producer or captured by hygroscopic attraction, as well as any water that adversely affects the stability of the capsule walls. Defined to mean that there may be a small amount of added water in the carrier mixture, which is insufficient for the amount of water added.

DETAILED DESCRIPTION OF THE INVENTION The compositions of the present invention, when formulated in a dispersion or solution in a pharmaceutically or cosmetically effective amount, typically have a basic composition that is chemically incompatible with soft gelatin. Encapsulation, storage and release of salts via soft gelatin encapsulation. To overcome this incompatibility, the basic salt can be combined with a polyalkylene glycol and a C2-C5 polyol, e.g.
Dispersed in a substantially water-free carrier comprising propylene glycol or a mixture with glycerin. The mixture is blended to form a stable dispersion of the basic salt, and the salt particles are coated so as not to substantially react with the soft gelatin. When encapsulated in flexible, soft gelatin capsules, the dispersed salt does not cause leakage or oozing of the dispersion through the capsule walls.

In that case, the basic salt and other compatible active agents are used in oral 1. ? +M (rectal), vaginal
), retains efficacy for buccal or topical administration. The basic salts dispersed, encapsulated and released through the compositions of the invention are incompatible with soft gelatin, including salts of magnesium, aluminum, sodium, calcium, bismuth, zinc, zirconium and titanium. Any inorganic or organic metal salt that may be present.

The dispersions of the invention are particularly suitable for the release of effective amounts of commonly used orally administered antacids. These salts include aluminum, magnesium, sodium and calcium salts, such as magnesium hydroxide, sodium bicarbonate, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, magnesium silicate, hydroxyaluminum sodium casenate. , magaLdrate, hydroxyaluminum aminoacetate, magnesium phosphate, and mixtures thereof. Preferred control salts include magnesium hydroxide, aluminum hydroxide, calcium carbonate and mixtures thereof due to their absence of significant side effects and their strong neutralizing power.

The amount of basic salt(s) that is intimately mixed into the antacid dispersion is released per unit dosage form (e.g., via one capsule containing up to about 1500 In9 of the dispersion). It varies depending on the neutralizing power required. The amount of dispersion to be encapsulated contains at least about 5 mEq of hydrochloric acid, preferably about 5 to about 30 mEq of aqueous hydrochloric acid, and most preferably enough basic salt to neutralize about 5 to about 20 mDq f. .

Other gastrointestinal drugs that are compatible with the basic salts can be included in the dispersion of the invention. These gastrointestinal drugs are designed to reduce symptoms resulting from excess gas retention (9).
Contains polysiloxane bloating agents such as simethicone. Such optional agents typically comprise about θ to 5% by weight of the total dispersion.

The dispersions of the present invention may further contain basic salts, such as those used in cosmetic formulations or pharmaceutical formulations suitable for deodorizing, moisturizing, protecting or healing the skin by topical application. Enables soft gelatin encapsulation. Such salts include hydroxides, oxides and carbonates of zinc, magnesium, aluminum, zorconium matahatchitane.

The basic salt used (expressed as % by weight based on the total amount of dispersion)
The amount of salts) can vary widely depending on the biological activity and intended use of the salt. That is, the amount may vary from about 5 to 70%, preferably from about 20 to 60%.

The liquid carrier mixture used to disperse the basic salt comprises a major portion of one or more po-U-fulkylene glycols and a minor portion of a C2-C4 zool or triol, preferably a poly-fulkylene glycol. A substantially water-free mixture.

The 2-realkylene glycoyl component has a molecular weight of about 100 to 90
/IJ ethylene/polygzololene glycol, polyethylene glycol or polypropylene glycol. Preferably, the polyalkylene glycol component comprises a major portion of liquid polyethylene glycol, i.e. polyethylene glycol 200, 300, 40
0, or 600 (the last number indicates the approximate molecular weight of the glycol), and a minor portion of about 800-900
Fibrous polyethylene glycol with a molecular weight within the range of 0, i.e. polyethylene glycol-900,10
00% 1450,1500.3350°3400.4
500 or 8000. Preferably, the ratio of liquid-sealed waxy polyethylene glycol is about 1
5-40:1, most preferably about 20-35:1. Preferably the 1,j51J alkylene glycol accounts for about 20-80% by weight of the total dispersion, most preferably 3
It contains 0 to 70 double crushed pieces.

The carrier crystalline composition of the present invention also comprises a small amount of Fi but an effective amount of a C2,4 polyol, such as a nool or triol such as zoropylene glycol or glycerin, which adjusts the viscosity of the dispersion and further improves the dispersion. stabilize. A preferred polyol is propylene glycol, which preferably contains 0.2 to 1
0% by weight, most preferably 1.3-3.0% by weight.

The dispersions of the present invention optionally contain a small but effective amount of one or more nonionic surfactants, e.g.
012 of sorbitol, optionally copolymerized with ~90 moles of ethylene oxide (“Tween”)
C2o fatty acid ester and its anhydride (“Su-Yan”)
). Typical 4+7 sorbates useful in forming the dispersions of the present invention and stabilizing the gelatin carboxylic acid include polysorbate 20 (laurate ester); *
polysorbate 60 (a mixture of stearate and parent lumitate esters); polysorbate 80 (oleate ester), where the suffix number indicates the appropriate molar ratio of ethylene oxide to sorbitol. show. Polysorbate is
It can be present in an amount of about 0 to 5 parts of the dispersion. For a general discussion of the properties and composition of polyethylene glycols and polysorbates, see Ramington's Pharmaceutical Sciences.
tisal 5sciencea).

A, 0soL, @d, , -ryri Publisher (
16th Edition, 1980), pages 1252-1253, the disclosure of which is incorporated herein by reference.

Thus, preferred antacid dispersions formulated in accordance with the present invention contain a basic aluminum, magnesium or calcium salt in an amount sufficient to neutralize about 5 to 25 milliequivalents of hydrochloric acid per unit dose; about 30 to 50% A mixture of waxy and liquid polyethylene glycol; about 0.2-10% propylene glycol, about 0-5% polysorbate, and about 0-5% gold.

The dispersion of the present invention is usually polyalkylene glyco-+1/
It is generally obtained by heating and mixing together the mixture and then adding at room temperature a mixture of the active ingredient, propylene glycol and optionally polysorbate.

The resulting nine dispersion is then ground, degassed and filled into suitable unit dose gelatin capsules by means of a rotary gouy encapsulation machine or similar encapsulation machine.

The invention will be further illustrated by the following examples.

Example 1 Hydroxide dispersion polyethylene glycol-3350 (182 kg) was
It was dissolved in 5586 kF polyethylene glycol-400 with stirring at 60°C. The solution was then cooled to 30°C. 1400 to 9 magnesium hydroxide, 1575 to 9 aluminum hydroxide (7% dry aluminum hydroxide glue), 175- to semithiocone, 182kl
A mixture of F of propylene glycol and 140 to 9 of polysorbate 80 was stirred into the glycol solution over 60 minutes. The dispersion was treated with Fitumil to reduce residual particle agglomerates, vacuum degassed and then mixed with oblong soft gelatin (boiled 20
) Fill into capsules approximately 7X16' from a batch of dispersion.
Filled capsules were obtained.

The amount of encapsulated dispersion (1320 m9) neutralized 10.7 myIJ equivalents of hydrochloric acid when titrated according to standard methods, and then the preliminary antacid test readings (C, F, R
, Title Chapter 21.1, Sections 1331.26 and 331
．． 25) to obtain a pH of 7.2. In the standard antacid disintegration test, the filled capsules ruptured in 4.5 minutes and the shell completely dissolved in 9 minutes (C, F', R, Tight No. 21.1, Chapter 3).
31.24). These results demonstrate the acid neutralizing capacity and antacid effectiveness per unit, which are
It is equivalent to or more erodible than oz@Plug tablets.

Example 2 Cargenate dispersion polyethylene glycol 3350 (140kf) was
Dissolved in 400 (3220 Yu) portions of stirred polyethylene glycol at 0°C. The solution was cooled to 30°C and then heated to 350°C.
0.51 of calcium carbonate was added over 1 hour with mechanical stirring. The mixture is passed through a Fuitsumiru, vacuum degassed, and then a rotary type Gui force! Using a cell encapsulation machine 7
×10 soft gelatin capsules (414) each K1
It was filled with 000 da.

When tested according to the procedure of Example 1, one filled capsule neutralized 10.0 meq of hydrochloric acid, gave a preliminary antacid test reading of PF (6°4), and disintegrated within 3.5 minutes. The shell then dissolved in 7.0 minutes. These results demonstrate acid neutralizing capacity and antacid efficacy per unit dose, which is equal to or better than Tums ■ tablets.

Preliminary stability tests of nine-filled kagcells obtained according to Example 1 or Example 2 show a projected shelf life of 2 to 3 years at room temperature and humidity. Thus, Examples 1 and 2 demonstrate the preparation of a potent encapsulated antacid dispersion that is rapidly released from capsules in an aqueous acidic environment, but has poor capsule wall stability during storage. It doesn't have any negative impact.

The dispersions prepared according to the present invention allow soft-gelatin encapsulation and administration of a wide range of basic salts useful for pharmaceutical, dietary or cosmetic applications.

Although representative embodiments of the present invention have been described above for purposes of explanation, it will be apparent to those skilled in the art that changes can be made within the scope of the present invention without departing from the spirit of the invention.

Claims (1)

Claims: 1. A soft material containing a pharmaceutically effective amount of a dispersion of particles of a basic salt in a substantially water-free liquid carrier comprising a mixture of a polyalkylene glycol and a C_2_-_5 polyol. A pharmaceutical unit dosage form comprising a gelatin capsule, wherein said carrier is present in an amount effective to coat the particles of salt, thereby rendering these particles substantially non-reactive with said gelatin capsule. 2. The unit dosage form of claim 1, wherein the basic salt is selected from the group consisting of aluminum, magnesium, sodium and calcium salts. 3. Basic salts include magnesium phosphate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium aluminum dihydrogen carbonate, magaldrate, aluminum dihydrogen aminoacetate, sodium hydrogen carbonate, calcium carbonate, and mixtures thereof. A unit dosage form according to claim 2 selected from the group consisting of: 4. The unit dosage form according to claim 1, wherein the polyalkylene glycol comprises polyethylene glycol and the polyol comprises propylene glycol. 5. The unit dosage form of claim 4, wherein the polyalkylene glycol comprises a mixture of liquid polyethylene glycol and waxy polyethylene glycol. 6. Polyalkylene glycol weight ratio is about 15-40
Claim 5 comprising a mixture of polyethylene glycol 400 and polyethylene glycol 3350 of :1
Unit dosage forms as described in section. 7. The dispersion contains about 20 to 60% by weight of a basic salt, about 20 to 60% by weight.
80% polyethylene glycol and about 0.2-10%
4. A unit dosage form according to claim 3, comprising propylene glycol. 8. The unit dosage form of claim 7, wherein the dispersion further comprises an effective amount of polysorbate of no more than about 5% by weight. 9. The basic salt is a mixture of aluminum hydroxide and magnesium hydroxide, and the polyethylene glycol is polyethylene glycol 400 and polyethylene glycol 33.
9. The unit dosage form of claim 8, wherein the polysorbate is polysorbate 80. 10. Semi-t, which has an effective amount of bloating relief.
10. A unit dosage form as claimed in claim 9, comprising: hicone). 11. The unit dosage form of claim 7, wherein the basic salt is calcium carbonate and the polyethylene glycol is a mixture of polyethylene glycol 400 and polyethylene glycol 3350. 12. The unit dosage form of claim 6, wherein the basic salt is selected from the group consisting of calcium carbonate, magnesium hydroxide, aluminum hydroxide, and mixtures thereof.