JPS645008B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to controlled antacid delivery forms and controlled dosing methods for antacids.
More specifically, slowly dissolving antacid dosage forms are obtained from acid neutralizing components in a matrix consisting of a sugar or sugar alcohol, a gel-forming swelling agent, and a water-insoluble lipid material. When these materials, along with conventional tablet binders, lubricants and other excipients, are mixed with the antacid ingredients and compressed at high pressure, they produce an antacid lozenge that dissolves very gradually in the mouth.
When the sweetening excipient is a sugar alcohol, the lozenge is "sugar free" and desirably non-carcinogenic. The controlled dosage form gradually dissolves in the mouth, resulting in a sustained release of antacid, which unexpectedly neutralizes stomach acid with surprisingly small amounts of antacid over an extended period of time. When the lozenge is comprised of a mixture of antacids with different reactivities, such as magnesium and aluminum salts, the invention also provides that the dosage form provides a more complete antacid treatment than is possible with conventional antacids. Including the discovery that it provides for the use of. Administration of the dosage form of the present invention also provides for more effective treatment since the gradual release of antacid counteracts the effects of gastric emptying and the continuous secretion of acid.
It also continuously moisturizes the lining of the esophagus and soothes tissue inflamed by gastric reflux. In the case of conventional acid medicines, the entire dose is taken at once, whether in liquid, powder or tablet form. Therefore, they have only a short therapeutic effect, since the stomach is constantly emptied and secretes more hydrochloric acid. The amount of antacid actually utilized can be as low as 10-15% and is generally no more than 50-60%. The exact amount depends on the amount of antacid, its dosage form, the individual patient and the time of day he takes the drug. Many commercially available antacids contain a mixture of magnesium and aluminum salts. It has been discovered by the present invention, and disclosed herein, that when there is an excess of antacid, the acid preferentially reacts with the magnesium component, thus destroying the expected effect from the mixture. More specifically, 20 to 40 of antacids.
% is consumed, only the magnesium component reacts with the acid, while the aluminum shows almost no reactivity. Since no more than 50-60% of regular antacids are actually utilized in the stomach, the benefits derived from such metal salt combinations are substantially reduced if the entire dose is taken at once. do not have. This is a waste of aluminum salts and may cause undesirable side effects through phosphate binding in the intestines. The standard recommended dose for most over-the-counter antacids is ``1-2 teaspoons'' or ``1-2 tablets'' 3 times a day.
after meals and at bedtime. The above recommendations are not given much attention by laymen and doctors. for example,
Some gastroenterologists prescribe 3 to 6 teaspoons every waking hour for patients with stomach ulcers. It has also been discovered and disclosed herein that there is virtually no benefit derived from such overdosing. On the other hand, massive overmedication
May cause undesirable side effects. For example, excessive amounts of magnesium can cause magnesium overload and diarrhea. As previously mentioned, excessive amounts of aluminum can cause phosphate binding, which in extreme cases can result in electrolyte imbalance, bone weakness, optisma, and difficulty walking. Too much calcium can lead to calcium overload, milk-alkali syndrome, and Burnett's syndrome. The effects of borderline overmedication, especially in cases of inertia, are rarely documented but are suspected to be a serious medical problem. In view of the above, it is desirable to provide a controlled antacid dosage form, as well as to provide a controlled dosage of a mixture of antacids such that all ingredients neutralize the acid, thus providing the benefits of the combination. It is an object of the present invention to do so. In its preferred form, a slowly dissolving lozenge is provided that is sized and shaped to remain comfortably in the mouth for an extended period of time. When administered in accordance with the present invention, better antacid therapy is obtained with surprisingly small amounts of antacids than is obtained with large excess doses of conventional antacids, and gastric emptying effects and It is a further object of the present invention to provide a controlled dosage form that counteracts continuous secretion of acid. It is still a further object of the present invention to provide a dosage form that provides relief to patients suffering from esophageal inflammation caused by gastric reflux.
Other objects and features are partly obvious and partly pointed out later in the specification. The invention therefore features the products and methods described hereinafter, and the scope of the invention is indicated in the claims. In dosage forms according to the invention, the antacid component, or acid-neutralizing substance, can be any of a variety of non-toxic sodium, calcium, magnesium or aluminum salts used to neutralize gastric juices. . Exemplary antacids include sodium bicarbonate, sodium citrate, calcium carbonate,
These are calcium phosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium trisilicate, aluminum carbonate, and aluminum hydroxide. Other suitable antacids are sodium dihydroxyaluminum carbonate, dihydroxyaluminum aminoacetate and magnesium hydroxyaluminate. Various other coprecipitates of aluminum hydroxide or carbonate with hydroxide or carbonate, hexitol, magnesium aminoacetate, etc. can be used. As with most frequently prescribed antacids, the neutralizing substance in the dosage form is preferably a combination of magnesium and aluminum salts. This combination is preferred as it provides an antacid with the properties of both metals. Gel-forming swelling agents used with the antacids described above are pharmaceutically acceptable high molecular weight substances that swell to form a gel upon contact with water. Such gel-forming swelling agents include various rubbers, polysaccharides, cellulose derivatives, and the like. Particular examples of gums are gum acacia, gum tragacanth, gum guarana and gum xanthan. Examples of polysaccharides include carrageenans and alginic acid and its derivatives such as sodium alginate and propylene glycol alginate. Suitable cellulose derivatives are methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium carboxymethylcellulose.
Of the materials mentioned above, sodium carboxymethylcellulose is particularly suitable for use in the present invention. Water-insoluble lipid materials used in combination with gel-forming swelling agents are hydrophobic metal salts of fatty acids such as stearic acid, palmitic acid, oleic acid and lauric acid. Metals that can be used to form the above salts are magnesium, calcium and aluminum. Of these materials, magnesium and calcium stearate are preferred. Dosage forms according to the invention are preferably formulated from granules containing an antacid and a sweetening excipient.
A gel-forming swelling agent and a water-insoluble lipid material are added to the granules, which may contain additional materials such as gelatin or starch. If desired, a portion of the gel-forming swelling agent may be dissolved and incorporated into the granules. Other materials such as talc, fragrances, pigments, etc. may be added to the granules before compressing the mixture into lozenges. Since the product is intended to dissolve slowly in the mouth, it is important that the lozenge contain large amounts of palatable excipients. Suitable palatable sweetening excipients include the sugar alcohols mannitol, sorbitol and xylitol. Sugar alcohols are particularly suitable for use in the present invention because they provide lozenges that are "sugar-free" and therefore non-carcinogenic. Of the sugar alcohols mentioned above, mannitol is the most suitable since it is less soluble than sorbitol. It gives a slightly sweet product with a particularly refreshing taste due to its negative heat of solution. Furthermore, the products produced using it have excellent shelf life because mannitol, unlike sorbitol, is not hygroscopic. When the sweetening excipient is an alcoholic sugar, it may be necessary to add an artificial sweetener to obtain a lozenge with a usable taste. Mannitol is preferred, but may be substituted with or used in combination with other sugar alcohols. If a candy-like lozenge is desired, sucrose or glucose may be used in place of the sugar alcohol. Since these sugars are more soluble than mannitol, the amount of gel-forming swelling agent and the amount of water-insoluble lipid material must be increased to provide lozenges with comparable dissolution times. The antacid is provided in an amount sufficient to effect neutralization of the acid over a selected period of time. When used according to the invention, the period is between 15 and 60 minutes, preferably
30-60 minutes. For this, each lozenge is made from 15 to
An antacid with 40 meq, preferably 20-30 meq. The amount of sweetening excipient is selected to impart a desirable sweetness to the lozenge. For this purpose,
The sweetening excipient is 25-60% by weight of the lozenge, preferably
Make up 35-50. When the excipient is mannitol, it is most preferably present in an amount of about 30-55%. The amount of gel-forming swelling agent and the amount of water-insoluble lipid material will vary depending on the particular agent selected. However, it should be present in combination in sufficient quantities so that the lozenge gradually dissolves over the required period of time to provide the antacid. Since the patient usually handles the lozenge with his tongue and teeth, there is continuous destruction of the lozenge, so that the dissolution time in vivo is much shorter than in vitro, even with good agitation. The gel-forming swelling agent forms a film barrier through which the hydrated antacid is gradually diffused. If no water-insoluble lipid material is added, satisfactory lozenges cannot be produced. That is, when enough gel-forming swelling agent is added to control release time, the lozenge has a muddy, off-tasting mouth feel. On the other hand, if no gel-forming swelling agent is added, the chilly feel and astringent taste of the antacid is exposed. By providing the proper balance of the drugs, it is possible to obtain a controlled antacid delivery system with good taste. When the gel-forming swelling agent is medium viscosity grade sodium carboxymethylcellulose,
Preferably, it is present in an amount of about 3-10% by weight. If larger amounts are used, for example 15-20%, the lozenges will have an undesirable rubbery feel. If the amount is less than 3%, it will not slowly dissolve sufficiently,
Amounts exceeding 10% produce a cool, squishy feel. When the water-insoluble lipid material is calcium or magnesium stearate, it is suitably present in an amount of about 1-5% by weight. Amounts less than 1% do not provide sufficient slow dissolution, and amounts greater than 5% may interfere with the acid in the stomach. the compressive force that produces the lozenge, as well as the surface area;
Shape therefore also has an important effect on elution time. Lozenges according to the invention have a hardness of at least 15 Kg/in ² as measured using a modified Herberlein hardness tester.
It has a hardness of As modified, one of the test jaws has a V-shaped indentation to closely match the corresponding V-shaped protrusion on the other jaw.
Such lozenges have a deep concave surface 5/
It can be made into pieces weighing 1-3 grams on a Stokes tablet press using an 8 inch punch at a pressure of about 7 tons. Similar tablets can be made using a Carver laboratory press at a pressure of 3600 psi. Although the aforementioned manufacturing methods are effective, they are merely illustrative. The controlled antacid delivery forms of the present invention may also contain other excipients or therapeutic substances. The formulations of the invention are particularly useful in antacid therapy because the gradual release of antacid counteracts the effects of gastric emptying and the continuous secretion of acid. When the lozenge contains a mixture of antacids with different reactivities, the present invention provides for substantially complete utilization of all of the antacid components. It is also useful in the treatment of reflux esophagitis and heartburn. The following examples illustrate the invention: Example 1 Wet granules having the composition shown in Table 1 were prepared as follows: mannitol, aluminum hydroxide-magnesium carbonate coprecipitate and magnesium carbonate in a twin barrel blender. Mixed for 5 minutes. The blend described above and the gelatin solution were mixed in a Simpson Mix Miller to form wet granules. The wet granules were spread on a plate and dried at 60°C for 8 hours.
The dried granules were then passed through an Elueca granulator to reduce the dry material to a particle size of 18 mesh or finer. This dry material is called coarse granules. Table 1 Crude Granules Particle component % Mannitol powder 48.17 Aluminum hydroxide-magnesium carbonate co-precipitate
25.74 Magnesium carbonate 21.76 Gelatin solution, 10 w/w% 4.33 100.00 Lozenges with the composition shown in Table 2 were prepared as follows: coarse granules, sodium carboxymethylcellulose, calcium stearate, talc and fragrance in a twin barrel blender for 15 minutes. Mixed. The mixture was then formed into lozenges at a pressure of 7 tons on a Stokes RD-3 tablet press with a 5/8 inch die and deep concave punches. Table 2 Lozenge prescription ingredients % Coarse granules 91.33 Sodium carboxymethylcellulose ⁽¹⁾ 5.00 Calcium stearate 1.00 Talc 1.00 Fragrance 1.67 100.00 (1) Medium viscosity grade The lozenges produced by this example were very hard;
It was above the normal scale range for Phizer, Eruueka, or Herbel line. The average time to dissolve the lozenge in the mouth was approximately 50 minutes. They are,
It had a sweet, pleasant taste without an unpalatable muddy or runny mouth feel. These lozenges had an antacid neutralizing capacity of 18meq. Reference Example 1 Coarse granules having the composition shown in Table 3 were prepared according to the procedure of Example 1, except that calcium carbonate was used as the antacid ingredient and starch paste was used as the auxiliary binder. This wet granule was heated at 60℃.
and dried for 24 hours. Table 3 Crude Granules Granular Ingredients % Mannitol Powder 19.63 Calcium Carbonate 76.45 Starch Paste, 10w/w% 3.92 100.00 A lozenge having a slow-dissolving layer and a fast-dissolving layer having the compositions shown in Tables 4 and 5, respectively, was prepared using a slow-dissolving and fast-dissolving mixture. Prepared as in Example 1 except loaded into a Manestay double layer tablet press with a 5/8 inch die and deep concave punches. The machine was adjusted so that the slowly dissolving layer weighed 1.8 g and the fast dissolving layer weighed 0.8 g. Table 4 Slow dissolution Layer component % Coarse granules 54.5 Sodium carboxymethyl cellulose 4.0 Calcium stearate 1.1 Granular sorbitol 39.6 Fragrance 0.8 100.00 Table 5 Slow dissolution Layer component % Coarse granules 42.00 Granular sorbitol 52.66 Calcium stearate 0.10 Talc 0.40 Colorant 0 .30 Primogel 4.00 Fragrance 0.54 100.00 The lozenges produced according to this example were very hard. The fast-dissolving layer dissolved within 5 minutes. Elution time for the full double layer lozenge in the mouth was 20 minutes.
The lozenge had a pleasant taste without an unpalatable muddy or runny mouth feel. Example 2 Coarse granules having the composition shown in Table 6 were prepared according to the procedure of Example 1, except that calcium carbonate was included as part of the antacid ingredient and starch paste was used as a co-binder. Prepared. Table 6 Crude Granules Particle component % Mannitol powder 53.87 Aluminum hydroxide-magnesium carbonate co-precipitate
9.43 Magnesium Carbonate 13.47 Calcium Carbonate 18.52 Starch Paste, 10w/w% 4.71 100.00 Table 7 Lozenge Prescription Ingredients % Coarse Granules 93.34 Sodium Carboxymethyl Cellulose 3.00 Calcium Stearate 1.00 Talc 1.00 Fragrance 1.66 100.00 This lozenge is hard, gradually dissolves and 24meq
It had the ability to neutralize antacids. They had a sweet pleasant taste without an unpalatable muddy or runny mouth feel. They weigh 2g
and had an elution time of 47 minutes. Example 3 Coarse granules having the composition shown in Table 8 were prepared according to the procedure of Example 1, except that magnesium carbonate was replaced with magnesium hydroxide and a portion of mannitol was replaced with sorbitol. Table 8 Crude granule Component % Mannitol powder 31.53 Sorbitol solution, 10w/w% ⁽¹⁾ 4.74 Aluminum hydroxide-magnesium carbonate co-precipitate
14.24 Magnesium hydroxide 42.37 Gelatin solution, 15w/w% ⁽¹⁾ 7.12 100.00 (1) 10w/w% in sorbitol and in gelatin
Added as a 15% w/w sorbitol and gelatin solution. Lozenges having the composition shown in Table 9 were prepared according to the procedure of Example 1. Table 9 Lozenge prescription ingredients % Coarse granules 90.34 Sodium carboxymethyl cellulose 5.00 Calcium stearate 2.00 Talc 1.00 Fragrance 1.66 100.00 This lozenge had an acid neutralizing ability of 33 meq and required an average time of 50 minutes to dissolve in the mouth. Example 4 Coarse granules having the composition shown in Table 10 were prepared according to the procedure of Example 1, except that powdered sugar was substituted for mannitol powder. Table 10 Crude Granules Powdered Sugar 49.17 Aluminum hydroxide-magnesium carbonate coprecipitate
26.26 Magnesium carbonate 22.19 Gelatin solution, 10% w/w 2.38 100.00 Lozenges having the composition shown in Table 11 were prepared according to the procedure of Example 1. These lozenges weighed 2 grams and dissolved in approximately 30 minutes. Table 11 Lozenge prescription ingredients % Coarse granules 91.49 Sodium carboxymethylcellulose 5.00 Calcium stearate 1.00 Talc 1.00 Aromatics 1.51 100.00 Example 5 Table 12 was prepared according to the procedure of Example 3, except that some of the mannitol was replaced with sorbitol. Coarse granules were prepared with the composition shown. Table 12 Crude Granules Particle component % Mannitol powder 47.88 Sorbitol solution, 10w/w% 4.40 Aluminum hydroxide-magnesium carbonate co-precipitate
13.57 Magnesium carbonate 27.55 Gelatin solution, 15% w/w 6.60 100.00 Lozenges having the composition shown in Table 13 were prepared according to the procedure of Example 1, except that the sodium carboxymethylcellulose was replaced with xane gum. Table 13 Lozenge Prescription Ingredients % Coarse Granules 93.59 Xanthan Gum 3.00 Calcium Stearate 1.00 Talc 1.00 Fragrance 1.41 100.00 As in all previous cases, this lozenge has a sweet pleasant taste, with no off-flavored muddy or tangy taste. I couldn't feel the sensation in my mouth. They dissolved in the mouth in about 33 minutes. Reference Example 2 Coarse granules having the composition shown in Table 14 were prepared according to the procedure of Example 1, except that calcium carbonate was used as the antacid component. Table 14 Crude granule component % Mannitol powder 51.80 Calcium carbonate 46.04 Gelatin solution, 10w/w% 2.16 100.00 A lozenge having a slowly dissolving layer and a fast dissolving layer having the compositions shown in Tables 15 and 16, respectively, was subjected to the operation of Reference Example 1. thus prepared. Table 15 Slow dissolution Layer component % coarse granules 90.82 Sodium carboxymethyl cellulose 6.00 Calcium stearate 1.00 Talc 1.00 Sodium hexametaphosphate 0.52 Fragrance 0.66 100.00Table 16 Rapid dissolution Layer component % Coarse granules 96.60 Calcium stearate 1.00 Talc 1.00 Hexa Sodium metaphosphate 0.52 Air freshener 0.58 Colorant 0.30 100.00 This lozenge has a pleasant taste, with no off-flavor muddy or watery mouth feel. Example 6 To compare the lozenges of the invention prepared in Example 1 and Reference Example 2 with conventional antacids, a cross-over study was conducted as follows: 10 humans participated in each of the four groups. did. Group Human: MAALOX (trademark) 30c.c. (72meq); Group: MAALOX (trademark) 60c.c. (144meq); Group: Lozenge 1 (18meq) prepared according to Example 1; Lozenge 1 (20meq) prepared according to Reference Example 2
was administered. Marlox is a commercially available antacid containing a magnesium antacid salt and an aluminum antacid salt. Prior to administering antacids, a siliconized gastroesophageal tube was inserted into the gastric paddle. Once the tube was in place, a sample of gastric fluid was taken and the PH was then recorded and returned later. This was done 30 minutes, 15 minutes and immediately before antacid administration to provide three control points. The humans in groups and groups then ingested the amounts of Maalok shown above, and the humans in groups and
and the lozenge of Reference Example 2 was inhaled. The pH of 2 ml of gastric fluid was read from time to time and then returned to the stomach. The effect of the antacid was considered to have ended when the PH decreased below 3.5. The results are shown in Figure 1. Groups are represented by black triangles, groups by white circles, groups by white squares, and groups by white triangles.
Table 17 shows that the new antacid delivery form of the present invention maintains gastric contents above PH 3.5 twice as long as Maalox with 1/8th the acid neutralizing capacity.

[Table] From the above, it can be seen that the present dosage form neutralizes stomach acid for a significantly longer period of time with a much smaller amount of antacid compared to the conventional dosage form. Example 7 This example shows that the magnesium component of an antacid containing a combination of magnesium and aluminum is reacted first. As shown in Table 17,
When the antacid is in excess, the aluminum is virtually unreactive. However, when the antacid is treated sequentially in accordance with the present invention, both metal components are utilized. In Tests 1-4, Maalox tablets were ground to a powder that passed through a 30 mesh sieve. This powder was suspended in water and the amount of acid shown in Table 17 was added. The solution was filtered and the liquid containing the reacted antacid was analyzed for magnesium and aluminum content. As shown in Table 17, aluminum did not substantially react. Tests 5-10 were carried out similarly except that in test 5, 5 ml of Maalox liquid was used instead of the powdered Maalox tablets. In Tests 6-10, MYLANTA™ tablets were used in place of Maalox tablets. In addition,
Mylanta is a commonly formulated over-the-counter antacid containing magnesium antacid salts and aluminum antacid salts. In Tests 11-14, lozenges made according to Example 1 were ground to a powder that passed through a 35 mesh sieve. In tests 11-12, the powdered lozenges were dissolved in water and the amounts of acid shown in Table 17 were added. On the other hand, in Tests 13-14, the antacid was suspended in a small amount of water and the acid was added at the same time. Table 17
As shown in Tests 13-14, both the magnesium and aluminum components of the antacid are utilized. These studies simulate the in vivo benefits obtained with the controlled antacid delivery form of the present invention. In view of the above, it can be seen that several objects of the invention are achieved and other advantages are obtained. It is intended that all matter contained in the above description be construed as illustrative and not in a limiting sense, as various changes may be made to the above methods and products without departing from the scope of the invention. .

【table】 [Brief explanation of the drawing]

FIG. 1 is a diagram showing the results of a cross-sectional study conducted to compare the lozenges prepared in Example 1 and Reference Example 2 with a commonly used antacid (Example 6). The horizontal axis represents time (minutes), the vertical axis represents PH, black triangles represent groups, white circles represent groups, white squares represent groups, and white triangles represent groups.

Claims (1)

[Claims] 1. Consists of a mixture of a magnesium antacid salt and an aluminum antacid salt, which salt has a reaction rate different from that of hydrochloric acid, and is selected from the group consisting of mannitol, sodium carboxymethyl cellulose and xanthan gum. mannitol in combination with a selected gel-forming swelling agent and a hydrophobic magnesium, calcium or aluminum salt of a fatty acid selected from the group consisting of stearic acid, palmitic acid, oleic acid and lauric acid; The gel-forming agent is present in an amount of 3 to 10% by weight, and the hydrophobic magnesium, calcium or aluminum salts of fatty acids are present in an amount of 1 to 60% by weight.
Present in an amount of ~5% by weight and approximately 15-60% in the user's mouth
to obtain lozenges that dissolve in minutes, and each of the lozenges dissolves in minutes.
It has a neutralizing ability of 15 to 40 meq and reduces the PH of the user's gastric juice.
A non-carcinogenic controlled antacid delivery composition compressed into a lozenge having a hardness of at least 15 Kg/in ² containing an effective amount of antacid salt to maintain the antacid salt above 3.5. 2. The antacid delivery composition of claim 1, wherein the lozenge weighs between 1 and 3 grams. 3 the lozenge consists of at least two layers;
3. The antacid delivery compositions of claim 2, each having a different dissolution rate.