JPH01500434A - Pharmaceutical formulation - 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] Preparation agent location field of invention The present invention relates to a novel pharmaceutical composition and a method for producing the same, and in particular, the present invention relates to a novel pharmaceutical composition and a method for producing the same. Concerning gin-containing suspensions.

Background of the invention Cimetidine is used in duodenal and benign gastric ulcers, recurrent and stomatal ulcers, and esophageal reflux disease. patients and where reducing stomach acid with cimetidine has proven beneficial, e.g. For example, for many years to treat other conditions such as persistent dyspepsia with or without ulcers. It is a used histamine H7-antagonist. Stable, ga, acceptable shimechi Considerable technical expertise is involved in producing pharmaceutical compositions, particularly solution and suspension compositions. It is widely recognized that difficulties exist. First, polymorphic dislocations and crystal growth There are polymorphic difficulties that pose problems. Cimetidine has at least five different The scales present in polymorphic forms and these polymorphic forms depend on crystal properties and crystallization characteristics. This means that they differ in their properties, thermodynamic stability, and water solubility and dissolution rate. is generally recognized. Polymorph A is used almost exclusively in the composition. It is generally recognized that , Journal on Pharmaceutical and Biomedical A Narisis (B, Heged'js and S, Gi5r5g.

J, Pharmaceutical & Biomedical Anal ysis), 3(4), 303-313 (1985)]. Second, Shimechi The problem is that gin has a very bitter taste and palatability is a key requirement for oral compositions. There is a problem.

There is a need for liquid-based and palatable cimetidine compositions. That is clear. Cimetidine is mostly absorbed in the small intestine, and , liquid base compositions may be used in tablet compositions, especially coatings to minimize unpleasant taste. It offers the possibility that it can be absorbed more quickly and effectively than tablet compositions that are Ru. However, the unpleasant bitterness is particularly problematic with cimetidine solutions. . A suspension of cimetidine could, in principle, offer the advantage of being more palatable, but Until recently, no stable acid form of cimetidine has been described or marketed. go Some companies are developing simethi in drug bags that can be mixed with water on the spot to produce suspension compositions. By selling gin powder or granules, we are addressing the obvious need for such products. Attempting to meet the requirements.

EPAO 138540-A describes suspensions containing cimetidine, preferred examples is a highly viscous buffer. Due to their high viscosity, such suspensions flow easily from the bottle. Therefore, it is prescribed in a medicine bag.

Aqueous suspensions of cimetidine polymorph A are thermodynamically unstable and have relatively low If many such suspensions are prepared that exhibit viscosity, polymorphism changes when subjected to temperature fluctuations. It has been found that body B can undergo polymorphic rearrangements. This polymorphic dislocation form polymorph B of very long needle-like crystals in the field, which makes the suspension lumpy and non-uniform. quality, resulting in inaccurate dosing and an unpleasant oral sensation.

Disclosure of invention The object of the invention is to provide stable and, in particular, easy-flowing bottles, and can be easily administered using devices that can precisely and accurately measure various doses. The present invention provides a suspension of cimetidine that has relatively low viscosity. and control Forms a stable composition to which other ingredients such as acids or alginates can be added This is also an object of the present invention.

The present inventors have now discovered that by preparing a suspension from cimetidine polymorph B, We found that the problems of shape dislocations and in-situ growth of long needles can be avoided. .

The present invention provides a suspension of particulate cimetidine in an aqueous phase having a pH of at least 7 and and suspending agent and, optionally, any other pharmaceutical excipients, present in the system. A safe drug suitable for oral administration characterized in that substantially all of the methidine is in polymorphic form B. The present invention provides a stable pharmaceutical composition.

Preferably at least 90%, particularly preferably at least 95% exists in polymorphic form B. Preferably, substantially no polymorph A is present.

By "stable" we mean a long period of time, e.g. at least 6 months, preferably at least Can be maintained in a pharmaceutically acceptable condition for one year, most preferably three years or more! Represents a cloudy liquid. Thus, there was no significant crystal growth and any precipitates that formed can be resuspended by only gentle agitation, i.e. the precipitate can be easily resuspended. No “cake”: The cake does not take the form of lumps, preferably no precipitate is formed. do not.

Usually, the p of the suspension is 7 to 9.5, preferably 7.4 to 8.4, especially 7.8 ~8.2. As can be seen, the suspension may be buffered or unbuffered. Teshiizumi 1 is also fine.

The invention! ! l! The turbid liquid is below +500 mPa, s, but above 200 mPa, s above, for example, having a viscosity within the range of 1200 mPa, s to 500 mPa, s is preferable. As is clear to those skilled in the art, the viscosity value obtained for a given system depends on the temperature. depending on degree, shear rate and shear history. The above values are 0 at approximately 25°C. For the freshly shaken and effluent suspension subjected to a shear rate of 75 ec-' .

of suspensions with a viscosity in the range of 200 III Pa, s to I 500 mPa, s The advantage is that they can be easily drained. This is usually done to keep it stable. i.e. high viscosity is required to minimize polymorphic interconversion; prepared from nomethinone polymorph A with a viscosity such that they cannot easily flow out. @In contrast to a suspension.

``Easily spillable'' means that they are easily spilled out of suitable containers such as bottles. It means scales. Obviously, if the composition is a reversible gel, It may be necessary to shake the container before washing to break up the gel structure.

If the suspension contains alginate, the thickening effect of the alginate The viscosity of the liquid is usually higher than the range of 200 to 1500 mPa, s, which is typical. in the range of 2500 to 5000 mPa, s, for example, about 3500 nPa, s. produces the result that there is.

Examples of suspending agents are xanthan gum, hydroxypropyl methylcellulose, methyl Cellulose, carrageenan, carboxymethylcellulose, sodium and calcium Ruboxymethyl cellulose sodium/microcrystalline cellulose mixtures, especially carboxymethyl cellulose Includes sodium dimethylcellulose/microcrystalline cellulose mixture. preferable Suspending agents include xanthan gum, carrageenan and carboxymethyl cellulose It is a dixotropic @turbidity agent such as thorium/microcrystalline cellulose mixture, and has special properties. A preferred suspending agent is avicel RC591.

They are Avicel RC581 and Avicel CL611. Avisel is FMC code R, C591, RC581 and CL611 are trademarks of Borayon. It is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose. Existence The amount of suspending agent present will depend on the particular suspending agent used and its ability to act as a suspending agent. or the presence or absence of other ingredients that make a significant contribution to the viscosity of the composition. It changes depending on the situation. However, usually the amount of suspending agent will be 0.05% of the total weight of the composition. C in the range of 1 to 15% pickles 1 When the suspension agent is xanthus gum, the total weight It exists in a considerable amount between 01 and 05% of Typical amounts are in the range from 0.6 to 15%, especially about 1.2% W/★. Kara If ginan is used, it constitutes from 0.5 to 1% 1 of the composition. Serious Alginate-containing compositions that exhibit thickening effects typically contain lower IT suspension agents. 17. Avoiding the problem of viscosity becoming so high that the composition cannot flow out.

The suspension may contain ingredients that improve its taste, such as sweetening agents, sodium chloride, etc. Bitter masking agent and contramarum-like flavor Masking flavours, flavor entrainers such as monosodium glutamate It may contain enhancers and flavoring agents.

Examples of sweeteners are sucrose, hydrogenated glucose syrup, and the sugar alcohol sorbitol. and bulk sweeteners such as xylitol and sodium cyclamate, Like cullin sodium, aspartame and glycyrrhizin ammonium sweeteners.

The bulk sweetener is usually in an amount corresponding to about 15-70% W/W of the total weight of the suspension. and the amount of other ingredients having a thickening effect on the composition, such as It depends in part on whether ruginate is present or not. For example, sorbitol is used as one bulk sweetener and a thickening agent (e.g. alginate) If absent, the dry weight of sorbitol present typically exceeds the dry weight of the suspension. The concentration is within the range of 35-55% W/W of dry weight, for example about 45% W/W.

Hydrogenated glucose syrup (approximately 74% solids content) as the sole bulk sweetener When used, it typically comprises 55-70% w/w of the suspension, such as about 65% w/w of the suspension. % W/W (equivalent to 49% solids). Bulk sweetness as evident combinations of agents, such as sorbitol and hydrogenated glucose blocks or sucrose and sorbitol can be used.

Other excipients that can be used are propylene glycol and glycerol. and colorants such as titanium oxide.

Typically, the total amount of wetting agent present is within the range of 0 to 10% W/W. Shifni Thus, for example, propylene glycol and glycerol each contain about 4% May be present in amounts up to V.

Preferably, the suspension contains a preservative to prevent microbial contamination.

Examples of preservatives are alkylparabens, especially propylparaben and butylparaben. It's Ben. Parabens tend to be unstable at high pH values, so if p)l is 8. It is most stably used when it is 2 or less.

Preferably, the suspension contains 140-4.5% &/W simethinone.

In one preferred embodiment of the invention, 15-3.5% W/W cimetidine, 3 5-45% ☆/- water, 35-55% W/★ sorbitol, 0-10% ★/unit Propylene dipropylene glycol is a humectant that is glycerol, 0.6-1. 5% W/★ of carboquine methylcellulose sodium and microcrystalline cellulose Compositions containing mixtures and, optionally, other pharmaceutical excipients are provided.

Compositions of the invention may optionally contain antacids. Antacids neutralize stomach acid It is a pharmaceutically acceptable basic substance that has sufficient neutralizing ability to of antacids Examples are aluminum hydroxide, magnesium hydroxide, magnesium carbonate, calcium carbonate. aluminum and co-dried gels, e.g. aluminum hydroxide-magnesium carbonate co-dried There is dried keel.

Preferably, the amount of antacid is such that a unit dose contains 10 to 30 milliequivalents. It is.

In another embodiment of the invention, the cimetidine polyester further comprises alginate. A suspension of Form B is provided.

The purpose of the alginate is to form a voluminous slurry that floats above the contents of the stomach and thus preventing gastroesophageal reflux (GORD) or alleviating its symptoms. It is. Potassium bicarbonate or a carbonate such as sodium bicarbonate is usually added. I can do it. The reaction of the carbonate with acidic gastric fluid generates carbon dioxide and the alginate suspension aerate and reduce its density, thereby making it more easily suspended in the gastric soil. can be done.

If bicarbonate is present, maintain the suspension at a pH of 75 or higher to Prevents premature decomposition and carbon dioxide generation. Typically, the p) (is, for example, Maintained within the range of 78-8.4 by using a buffer such as phosphate buffer do.

To avoid too large an increase in the viscosity of the suspension, use a low viscosity grade of alginic acid. Low viscosity grades of alginates suitable for use in the compositions of the present invention using salts include: Usually, it has a viscosity of 4 to 1° mPa,s in a 1% aqueous solution at 20°C. alginate Salts are polymers consisting of mannuronic acid and guluronic acid monomer units.

The ratio of mannuronic acid and guluronic acid determines the float-forming properties of the alginate. , typically with a high guluronic mannuronic ratio (e.g. 70% guluronic acid) phosphates form the strongest floaters. Containing such high concentration C) guluronic acid Preferably, one such alginate is used in the composition of the invention. The alginate is Protanal LF R5/60 .

Nitrification of alginate optimizes the float-forming ability of the 9m liquid, while reducing the viscosity. In order not to adversely affect the fluidity of the suspension by constantly increasing it greatly. See choice 5.

In practice, the concentration of alginate (★/dip) is typically relative to the total weight of the suspension. In comparison, it is less than 10%. Preferably, the alginate is present at a concentration of about 5%. Exists.

The alginate is usually prepared as an alkali metal salt such as sodium alginate. exist.

A problem encountered in the preparation of cimetidine/alginate suspensions is that the cimetidine can be oxidized to its sulfoxide.

Nmedidine sulfoxide is a known metabolite of cimetidine, and its presence in the suspension is Currently, the sulfoxide does not pose a toxicity problem, but the sulfoxide has virtually no role as an H3-antagonist. It is inactive and therefore oxidation of cimetidine may result in a decrease in the efficacy of the composition. Ru.

The mechanism of sulfoxide formation is unknown. Propyl gallate and sodium sulfite Addition of standard antioxidants such as aluminum does not suppress the formation of the sulfoxide.

Additionally, certain chelates such as polyphosphates and trisodium citrate Addition of additives has been found to be ineffective in inhibiting oxidation. but However, this time, surprisingly, ethylenediaminetetraacetic acid (EDTA) It was found that the addition of sulfoxide and its salts significantly inhibited sulfoxide formation. .

Therefore, in a preferred embodiment of the invention, cimetidine polymorph B and further to provide the aforementioned pharmaceutical suspension consisting of alginate and EDTA or a salt thereof. do. Typically, the EDTA is about 0.05% (w/w) of the total weight of the suspension. It is present in an amount of ˜0.25% (v/W), particularly about 0.1% (W/W).

The EDTA is usually added as a salt, especially the disodium salt.

In the compositions of the invention, typically the particle size of the cimetidine is within the final suspension. In a liquid, 80% by weight of the particles have a size of 20θμ or less but greater than about 5μ It's a big size. The size mentioned is the Malvern 3600E-The Pa -Ticle Sizer (Malvern3600 E La5er Parti cle S 1zer) [Malvern Instruments Limited, SP Ring Lane, Worcester, UK (Malvern I instruments) Limlted, Spring Lane, Worcester.

The apparent diameter is the diameter when measured by U, ni, )].

The composition of the present invention comprises cimetidine polymorph B and a suspending agent and any other substances contained therein. It can be prepared by mixing the ingredients of and forming a suspension.

The cimetidine polymorph B is an isopropanol aqueous solution (10% isopropanol) Form a solution of methionone acetate in the solution, clarify by filtration, and refer to Reference Example 1. It can be prepared by making it basic with aqueous ammonia (10% excess) as described. Wear. The mixture is then stirred to completely crystallize polymorph B, and then the raw The product is isolated by filtration, washed thoroughly with water and dried to constant weight.

cold carp Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto. It's not.

In addition, in the examples, all indications for cimetidine refer to the applicable cimetidine unless otherwise specified. Concerning polymorph B.

Example 1 Cimetidine suspension (10m (medium 200 z9) * sorbitol 3460g, water 1 480g method Avicel was dispersed in demineralized water using a low shear propeller mixer and the resulting dispersion at high speed with a 25μ gap using a Premier colloid mill. oid m1ll) [Premier Colloid Mills Limited, Wal) N - On Thames, Surrey, UK (Preraier Collo Colloid L td, Walton-on Thames, S urrey, U , , ). The Avicel high shear dispersion and 3.6 kg of Sorbitol 7 0% solution in glycerol and then propylene glycol. Add a solution of parabens. Next, stir the flavor and titanium oxide paste. Add with stirring to obtain a homogeneous mixture. Then, after adding cimetidine, the sorbitol Add the remainder of the toll for a total volume of 612.

The batch is then processed in such a way that the grinding process causes the temperature of the ground material to exceed 35°C. Pass it through a colloid mill set at the lowest possible gap (approximately 25μ) at low speed to avoid . The I)H of the resulting f2 suspension is approximately 7.8.

Example 2 Cimetidine Suspension (5m (!2001) This doubles the amount of cimetidine The composition was the same as that of Example 1 except for this.

Example 3 Cimetidine Suspension in Hydrogenated Glucose Tube This is a 70% substitute for sorbitol. Using an equivalent volume of hydrogenated glucose syrup (74% solids) as the vehicle, The outside has a composition similar to that of Example 2 above.

Example 4 Measurement of the viscosity of the formulations of Examples 1-3.6 and 8 Compositions of Examples 1-3.6 and 8 The viscosity of the material is supplied by Contraves of Switzerland. Measurements were made using a Rheomat 30 rheometer. The measurement is It was carried out at 27°C.

The results are shown in Table 2.

Example 5 Comparative stability of suspension containing polymorph A and @ suspension containing polymorph B 1) Comparative stability of suspension containing polymorph A and suspension containing polymorph B 1) The composition was subjected to thermostatic storage for one year at temperatures of 4°, 22°, 30° and 40°C. Ta. Microscopic examination after this period showed that no crystal growth had occurred.

The composition of Example I was also subjected to 50 thermal cycles between 10 and 30°C.

No crystal growth was observed after this test.

11) The above procedure except that cimetidine polymorph A is used instead of cimetidine polymorph B. Compositions similar to those of Example 1 were also subjected to stability testing. Freshly prepared suspension The median particle size in the suspension was approximately 40μ.

After 5 months at room temperature, filaments with a length of 750 μ were observed during microscopic examination. .

With filamentary clusters up to 1 mm long, up to 2°5 mm in length. Filaments were observed.

When stored at 30°C for 3 days, filaments up to 2.5 mm in length When observed and stored at 40°C for 3 days, large filamentous aggregates with a total length of 4 mm were observed. A merger was detected.

After 9 cycles of thermal cycling at 10-30℃, up to 800μ length and 200μ width Many feather-like clusters were formed. One feather-like aggregate with a length of 1.8 mm was detected. It was done.

Example 6 +00+yinmethidine/sodium alginate suspension method Dissolve the hydroxybenzoate in warm propylene glycol and add glue to the resulting solution. Add lyserole and boil for 1 hour. After cooling the solution to room temperature, cimetidine was added with stirring. In addition, a homogeneous slurry was obtained. Dissolve edetate disodium in demineralized water and then Disperse the sodium alginate in the solution using a high shear homogenizer. A sodium alginate mixture was prepared.

The shimedigin slurry, sorbitol solution, hydrogenated glucose syrup and alcohol Add the sodium ginate mixture to the dispersion of Avicel in demineralized water and the resulting mixture was stirred until homogeneous. Add remaining ingredients and, if necessary, add demineralized water. to ensure accurate capacity. Finally, set the suspension at low speed as in Example 1 above. It was passed through a colloid mill.

Example 7 200π9/5 mQ cimetidine/magnesium hydroxide/aluminum hydroxide @3 Turbid liquid Example 8 100*915iI2 cimetidine/magnesium hydroxide/aluminum hydroxide suspension cloudy liquid Example 9 10Oz915inometidine/calcium carbonate suspension Example 1O Shimedizine/calcium carbonate/magnesium hydroxide suspension solution reference example 1 Preparation of cimetidine polymorph B Cimetidine polymorph A252 in 20Q water and 250mQ isopropanol Add a solution containing 60 g of acetic acid in 125 m of water to 1 g of the stirred PFIA solution. The mixture was stirred and the resulting solution was clarified by filtration.

While stirring, add 125 mL of water (68 mL containing concentrated ammonia) to the resulting clear solution. solution (27% V/W) was added. After precipitation of cimetidine base, the mixture was It was heated to 45°C and maintained there for 24 hours. Appropriate manufacturing process checks after this time. * indicates that the national polity is completely in form "B". cooling the mixture; The product was isolated by filtration and thoroughly washed with water. Dry the solid at 60°C, Obtained 240 g (95%) of crystalline cimetidine with a melting point of 124.5-144 °C. Ta.

*A suitable process check is to obtain an infrared spectrum of the product, 1004 and 99 The purpose is to calculate the ratio of the peak heights of the absorption bands at 3 cm-'. Accordingly, polymorphism The concentration of Form C was expressed as the peak ratio for various standard mixtures of Form C and Form B. The calibration curve obtained by plotting is used as a standard.

The method for producing the above-mentioned cimetidine polymorph B is disclosed by Mako, with priority on August 10, 1986. Co-pending European patents derived from UK Patent Application No. 8618846 Disclosed and claimed in the application. Polymorphs used above B'' includes reference to crystalline cimetidine prepared by the method. .

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Claims (10)

[Claims] (1) Suspension and suspension of particulate cimetidine in an aqueous phase having a pH of at least 7. a clouding agent and, optionally, further pharmaceutical excipients, to remove any cimetidine present. A stable pharmaceutical composition suitable for oral administration, characterized in that it is qualitatively entirely polymorphic Form B. thing. (2) The group according to item (1) above, wherein at least 95% of cimetidine is polymorphic form B. A product. (3) of the suspension when measured at 25°C and a shear rate of 0.7 sec-1. Viscosity is 200mPa. s~1500mPa. Paragraph (1) above or within the scope of s. or the composition of item (2). (4) The viscosity is 500 mPa. s~1200mPa. In paragraph (3) above, which is s. Composition. (5) The suspending agent is sodium carboxymethylcellulose and microcrystalline cellulose. and the mixture is in the range of 0.6 to 1.5% w/w of the total weight of the composition. The composition of any one of paragraphs (1) to (4) above, present in an amount of: (6) at least 80% of the cimetidine particles have an apparent size within the range of 5μ to 200μ; The composition of any one of paragraphs (1) to (5) above, having a diameter. (7) The composition according to any one of items (1) to (6) above, containing an antacid. (8) 1.5-3.5% w/w cimetidine, 35-45% w/w water, 35- 55% w/w sorbitol, 0-10% w/w propylene glycol and Wetting agent which is/or glycerol, 0.6-1.5% w/w carboxymethylene mixture of cellulose sodium and microcrystalline cellulose and optionally , and other pharmaceutical excipients. (9) The composition according to any one of items (1) to (6) above, containing an alginate. . (10) ED in an amount of about 0.05% w/w to about 0.1% w/w of the total weight of the composition. The composition according to item (9) above, containing TA or a salt thereof.