HK1162354B - Improved dissolution stability of calcium carbonate tablets - Google Patents

Description

Improved dissolution stability of calcium carbonate tablets

Technical Field

The present invention relates to a process for the preparation of calcium carbonate tablets, which process results in tablets with improved storage stability in terms of dissolution characteristics. The process involves the use of sugar alcohols with binding properties, in particular sorbitol and/or isomalt; the use of sugar alcohols not having binding properties, in particular selected from mannitol, maltitol or xylitol; and externally applying a lubricant to the punches and dies of the tablet press. In the case where the concentration of sorbitol does not exceed 10% w/w, the lubricant may also be mixed into a mixture containing: i) calcium carbonate, ii) sugar alcohols having binding properties, and iii) sugar alcohols having no binding properties. If, in the latter case, alkaline earth metal stearates are used, the concentration should be relatively low, e.g. not exceeding 0.35% w/w (based on the final powder mixture to be compressed into tablets).

Thus, the present invention also provides an alternative method for preparing calcium carbonate tablets having the above advantages in terms of dissolution stability. This alternative involves the use of an internally applied lubricant, but requires the use of a sugar alcohol with adhesive properties, and another sugar alcohol that does not have significant adhesive properties. Moreover, the concentration of the sugar alcohol having adhesiveness must not exceed 10% of the whole composition.

The invention also relates to tablets obtained by the process of the invention.

Background

Calcium is essential for many important functions in the body, both as ionic calcium and complex calcium (Campell AK. Clin Sci 1987; 72: 1-10). Both cell behavior and growth are regulated by calcium. In combination with troponin, calcium controls contraction and relaxation of muscle (Ebashi S.Proc RSoc Lond 1980; 207: 259-86).

Selective calcium channels are a common feature of cell membranes, and electrical activity of neural tissue and release of neurosecretory granules are both a function of the balance between intracellular and extracellular calcium levels (Burgoyne RD. Biochim Biophys Acta 1984; 779: 201-16). The secretion of hormones and the activity of important enzymes and proteins are dependent on calcium. Finally, calcium as a calcium phosphate complex imparts bone stiffness and strength (Boskey AL. Springer, 1988: 171-26). Since bone contains more than 99% calcium throughout the body, bone calcium can also serve as the primary long-term calcium reservoir.

Calcium salts such as calcium carbonate may be used as a source of calcium, particularly for patients suffering from or at risk of osteoporosis. Furthermore, calcium carbonate may be used as an acid neutralizing agent in antacid tablets.

Calcium salts such as calcium carbonate are used in tablets and, due to the high calcium dose required, such tablets are often in the form of chewable tablets. It is a challenge to formulate chewable tablets containing calcium salts, and which tablets have a palatable taste and an acceptable mouthfeel, without the dominant taste or sensation characteristic of chalk.

Furthermore, i) high doses of calcium carbonate (normally 300-. Adequate taste masking is another major challenge when making chewable tablets.

As described in WO2005/117829, the applicant has found a simple process: tablets containing physiologically tolerable calcium-containing compounds are produced by using granules containing agglomerates (agglomerates) of the calcium-containing compounds. The granules are obtained without the use of any solvent (e.g. water), but rather involve techniques of rolling the calcium-containing compound to form agglomerates having suitable characteristics for further processing into solid dosage forms such as tablets.

Calcium carbonate tablets are well described in the patent literature, see for example WO2005/117829, WO 2005/115342, WO 00/028973. From WO2005/117829, calcium carbonate tablets containing sorbitol and maltitol are also known.

However, it has recently been found that when calcium carbonate tablets are manufactured for swallowing, the dissolution profile obtained during or immediately after tablet production may change over time. In other words, the tablet is unstable with respect to dissolution. The tablets are acceptable as long as the change is within acceptable limits (typically ± 10%). However, the inventors have observed conditions in which there is a sharp decrease in the dissolution profile, i.e. the release of calcium is i) much slower, and/or ii) incomplete. The present inventors have addressed this problem and have provided a solution thereto.

Detailed disclosure of the invention

Accordingly, the present invention provides a method for preparing a calcium carbonate-containing tablet having a desired stability in terms of dissolution. Furthermore, the present invention relates to novel calcium carbonate tablets which are stable with respect to dissolution behaviour.

If the dissolution profile changes over time, this is typically seen during the first 14 days after manufacture.

Herein, the change in dissolution profile is determined by plotting the dissolution profile at time t0 for 10 min, 20 min, 30 min, and 60 min at specific time points. In order for this profile to be acceptable, the total amount of calcium carbonate released after 20, 30, and 60 minutes must exceed 80%. After about 14 days, such dissolution profiles are plotted according to repeated dissolution tests at that time point. If the values at 20, 30, and 60 min exceed 80%, the test tablets are stable with respect to the dissolution profile, provided that the test tablets are stored in open petri dishes (petri dish) at 25 ℃ and 60% relative humidity. Typically, the test is performed immediately after tablet production, or at least within the first week after tablet production.

The dissolution profile was obtained according to pharmacopoeia specifications. Thus, the release of calcium was tested using the european pharmacopoeia apparatus 2(ph. eur. appaatus 2) (leaf), a 70rpm spin, 1000ml of HCl 0.1N, and a dissolution test at 37 ℃, measured on 3 tablets. The test was performed initially, and after 14 days of storage in open petri dishes at 25 ℃ and 60% Relative Humidity (RH). This test is generally applicable in order to test whether the composition is stable with respect to dissolution profile.

In accordance with the above, the present invention provides a process for the preparation of a tablet comprising at least 50% w/w calcium carbonate, said process comprising

i) Providing a particulate composition (particulate composition) comprising: a) calcium carbonate, b) a binding sugar alcohol selected from sorbitol or isomalt, or a combination thereof, c) a non-binding sugar alcohol selected from mannitol, maltitol or xylitol, or a combination thereof, and

ii) compressing the composition using a tablet press equipped with at least one pair of punches and dies, wherein the punch and die pair is sprayed with a lubricant selected from magnesium stearate, calcium stearate or stearic acid, or a combination thereof, prior to filling the particulate composition into the dies.

Herein, the term "sugar alcohol having binding properties" or "binding sugar alcohol" refers to a sugar alcohol having a crushing strength of 20N or more when compressed into tablets using a compaction force of 5kN as described in example 1 herein, and/or having a crushing strength of 60N or more when compressed into tablets using a compaction force of 10kN as described in example 1 herein. Sorbitol and isomalt are examples of such sugar alcohols.

When compaction is used to prepare the tablets of the invention, the sugar alcohols used which have binding properties typically have an average particle size of at most about 150 μm, for example at most about 110 μm, at most about 100 μm, at most about 90 μm, at most about 80 μm, at most about 70 μm, at most about 60 μm, at most about 50 μm, at most about 40 μm, at most about 30 μm, at most about 20 μm or 10 μm. Thus, the particle size may have an average particle size in the range of about 5 to about 150 μm, for example about 5 to about 110 μm, or about 5 to about 80 μm.

In particular, suitable sorbitols for use in the embodiments herein have an average particle size in the range of about 25 to about 50 μm, for example about 35 to about 45 μm, or about 30 to about 45 μm. Another suitable sorbitol for use in embodiments herein has an average particle size in the range of about 50 to about 150 μm, for example about 75 to about 125 μm, or about 100 to about 120 μm, or 110 μm.

Isomaltulose of suitable properties with respect to particle size is isomalt having an average particle size in the range of about 20 to about 50 μm, for example about 25 to about 35 μm, or about 20 to about 35 μm. Another suitable property of isomalt has an average particle size in the range of about 50 to about 150 μm, for example about 75 to about 125 μm, or about 100 to about 120 μm, or 110 μm.

Also, herein, the term "sugar alcohol having no adhesiveness", "sugar alcohol having no significant adhesiveness", or "non-adhesive sugar alcohol" refers to a sugar alcohol having a crushing strength of 20N or less when compressed into a tablet with a compaction force of 5kN as described above, and/or having a crushing strength of 60N or less when compressed into a tablet with a compaction force of 10kN as described above. Mannitol, maltitol, and xylitol are examples of such sugar alcohols.

It is contemplated that other sugar alcohols with or without binding properties may also be used in accordance with the present invention. Such sugar alcohols are typically selected from mannitol, xylitol, maltitol, inositol, and lactitol, and mixtures thereof. Examples are Sorbitol, Neosorb P100T, Sorbidex P1666B0, and Sorbogel fine Crystalline Sorbitol (Sorbogel Fine Crystalline Sorbotol) from the company Roquette freses, Cerestar, and SPIPolyols, respectively. Maltosorb P90 (maltitol) available from Roquette fres; xylitol CM50, fructifin CM (fructose), and lactitol CM50 available from Danisco sweenters; isomalt ST-PF, isomalt DCl00, Gaio tagatose, and Manitol, available from Palatinit, Arla Foods, and Roquette, freses, respectively. Other examples of suitable sugar-based binders/sweeteners include sucrose, dextrose.

Suitable tableting machines that can be used to test the sugar alcohol binding properties are equipped at the very least with data acquisition to measure the applied pressure.

As seen in example 1 herein, the crushing strength can be suitably measured by using Schleuniger-2E of dr.

For the preparation of tablets, it is often necessary to add one or more pharmaceutically acceptable excipients (e.g. lubricants) to avoid sticking and/or to increase the flowability of the resulting granules. Thus, the method may further comprise the step of mixing the resulting granules with one or more pharmaceutically acceptable excipients. As discussed below, the present inventors have observed that in order to obtain suitable dissolution stability, it may in some cases be advantageous to add the lubricant from the outside, i.e. by spraying directly onto the punches and dies of the tablet press, i.e. when the calcium carbonate tablets contain a binding sugar alcohol such as sorbitol and/or isomalt (note: the lubricant may be added internally provided sorbitol is used in a relatively low concentration).

Externally applied lubricants such as magnesium stearate, calcium stearate, or stearic acid are important features of one aspect of the invention. As seen from the examples herein, if a lubricant is added to the granules before compression, the resulting dissolution profile will change over time (during the first 14 days after manufacture). However, the present inventors found that the desired stability in terms of dissolution was obtained if the lubricant was sprayed on the die and punch by using compressed air before tableting.

The process of the invention typically comprises agglomerating the calcium carbonate using rolling, especially in the presence of one or more sugar alcohols. The applicant has previously found that rolling calcium carbonate together with e.g. sorbitol results in agglomerates which can be easily tabletted. However, it is contemplated that other related methods besides rolling may also produce suitable results, such as pounding (slugging).

Thus, in the process according to the invention, the particulate composition in step i) above is prepared by the following steps:

i) rolling calcium carbonate and a binding sugar alcohol selected from sorbitol or isomalt, or a combination thereof, and a non-binding sugar alcohol selected from mannitol, maltitol or xylitol, or a combination thereof, to obtain rolled granules, and

ii) if appropriate, mixing one or more of said pharmaceutically acceptable excipients in a mixer.

Depending on the concentration of sorbitol in the final powder mixture, a lubricant may be added to the particulate composition obtained by rolling or related processes (e.g., if the concentration of sorbitol does not exceed 10% w/w), or externally to the tableting equipment (regardless of the concentration of sorbitol).

The rolling process enables the powder material to build up cohesive forces between the individual particles, i.e. an increase in the average particle size is observed. When preparing tablets, the establishment of granules (or agglomerates) is important in order to ensure proper flowability and fixation (agglomeration) in the granules (or agglomerates) of the components that make up the tablet. If this is not the case, there is a significant risk of component split during manufacture, which often leads to unsatisfactory characteristics in terms of pharmacopoeial regulations with respect to quality variations and dose variations.

As mentioned before, the process of rolling the powder can be used as an alternative to the known granulation or agglomeration methods, i.e. wet granulation or-when tablets are prepared-direct compression using dry binders. The inventors have found that the rolling process does not destroy the possibility of obtaining a product with an acceptable mouthfeel, while not having a dominant chalky taste or sensation. Typically, rolling is used to increase the bulk density of the particulate matter or composition, for example to convert bulk material into a less bulky material which is readily used in the manufacture of pharmaceutical compositions, which is not the primary purpose where the goal is primarily to agglomerate the material.

Calcium carbonate is administered in relatively high amounts, and therefore it is important that the drug load (drug load) is relatively high to avoid too large a tablet size. This is usually of greatest significance if the tablet is intended for swallowing, but even in the case of chewable tablets, patients prefer tablets of a less large size. Thus, in order to be able to produce tablets, the excipients used should generally be kept at relatively low concentrations.

The sugar alcohol is present in the tablet composition in a total concentration of about 15% to 35% w/w, for example about 20% to about 25% w/w. Such a concentration makes it possible to produce calcium carbonate tablets having a calcium carbonate concentration of at least 50% w/w. As seen from the examples herein, much higher drug loadings are possible, for example at least 60% w/w, at least 65% w/w, or at least 70% w/w.

In addition to the binding sugar alcohol, the examples herein show that blending a non-binding sugar alcohol with a binding sugar alcohol results in desirable dissolution stability. The total concentration of non-binding sugar alcohols in the tablets of the invention is at least 1% w/w, such as at least 2% w/w, at least 3% w/w, or at least 4% w/w. As seen from the examples herein, suitable combinations of binding sugar alcohols and non-binding sugar alcohols are typically:

by applying the above method, using an externally applied lubricant, tablets having the following composition were obtained:

it is important to emphasize that if the sorbitol content in the calcium tablet does not exceed 10% w/w, a lubricant such as an alkaline earth stearate may be used at a total concentration of about 0.26% w/w-0.44% w/w, e.g. about 0.3% w/w-0.4% w/w. In a preferred embodiment, the alkaline earth stearate is used at a concentration of about 0.35% w/w. The very low concentrations mentioned hereinafter correspond to the amount of lubricant applied during pressing by spraying the pressing tool with a dispersion/solution containing the lubricant. However, it will be understood by those skilled in the art in light of this disclosure that if the concentration of sorbitol is low, then it is also-or might be-possible to mix the lubricant into the particulate material prior to compression, but the concentration should be lower than that normally used, i.e. lower than 5% w/w. In the examples herein, concentrations of up to 0.35% w/w are shown to give suitable results.

A calcium carbonate tablet comprising:

70-75% w/w calcium carbonate,

4-25% w/w of one or more binding sugar alcohols,

4-25% w/w of one or more non-binding sugar alcohols,

2-10% w/w of one or more pharmaceutically acceptable excipients (e.g. binders, fillers, additives etc. -other than lubricants such as magnesium stearate, calcium stearate or stearic acid),

0-2% w/w of one or more flavouring agents, artificial sweeteners, etc.,

0.001-0.01% w/w magnesium stearate, calcium stearate or stearic acid,

provided that the total amount corresponds to 100% w/w.

A calcium carbonate tablet comprising:

70-75% w/w calcium carbonate,

4-25% w/w sorbitol,

4-25% w/w of one or more of mannitol, maltitol, or xylitol,

2-10% w/w of one or more pharmaceutically acceptable excipients (e.g. binders, fillers, additives etc. -other than lubricants such as magnesium stearate, calcium stearate or stearic acid),

0-2% w/w of one or more flavouring agents, artificial sweeteners, etc.,

0.001-0.01% w/w magnesium stearate, calcium stearate or stearic acid,

provided that the total amount corresponds to 100% w/w.

A calcium carbonate tablet comprising:

70-75% w/w calcium carbonate,

4-25% w/w isomalt,

4-25% w/w of one or more of mannitol, maltitol, or xylitol,

2-10% w/w of one or more pharmaceutically acceptable excipients (e.g. binders, fillers, additives etc. -other than lubricants such as magnesium stearate, calcium stearate or stearic acid),

0-2% w/w of one or more flavouring agents, artificial sweeteners, etc., and

0.001-0.01% w/w magnesium stearate, calcium stearate or stearic acid,

provided that the total amount corresponds to 100% w/w.

A calcium carbonate tablet comprising:

70-75% w/w calcium carbonate,

10-25% w/w of one or more binding sugar alcohols,

4-15% w/w of one or more non-binding sugar alcohols,

2-10% w/w of one or more pharmaceutically acceptable excipients (e.g. binders, fillers, additives etc. -other than lubricants such as magnesium stearate, calcium stearate or stearic acid),

0-2% w/w of one or more flavouring agents, artificial sweeteners, etc.,

0.001-0.01% w/w magnesium stearate, calcium stearate or stearic acid,

provided that the total amount corresponds to 100% w/w.

Furthermore, the inventors have observed that a suitable stability in terms of dissolution may also be obtained by a process for preparing tablets comprising at least 70% w/w calcium carbonate, said process comprising

i) Rolling a) calcium carbonate, b) a binding sugar alcohol selected from sorbitol or isomalt, or a combination thereof, and c) a non-binding sugar alcohol selected from mannitol, maltitol or xylitol, or a combination thereof, to obtain rolled granules,

ii) mixing the lubricant with optionally one or more of said pharmaceutically acceptable excipients in a mixer, and

iii) compressing the composition using a tablet press,

provided that the concentration of sorbitol in the tablet composition does not exceed 10% w/w.

Thus, in this case, the lubricant is already added internally to the granules before compression. Details regarding dissolution stability, concentration of isomalt (if present), concentration of non-binding sugar, and the like when the lubricant is applied from the outside are the same as those described above. The only difference is with respect to the maximum content of sorbitol present in the tablet and the concentration of lubricant, which in this case is slightly higher than in tablets prepared by external application of a lubricant. As seen from the examples herein, a suitable lubricant is magnesium stearate (based on the total weight of the tablet) used at a concentration of 0.35% w/w. Magnesium stearate used at a concentration of 0.45% w/w results in tablets with an unsatisfactory dissolution profile (calcium release is too slow) and when magnesium stearate is used at a concentration of 0.25% w/w, adhesion to the punch and die is observed.

Suitable tablets prepared by internal application of a lubricant are:

a calcium carbonate tablet comprising:

70-75% w/w calcium carbonate,

2-10% w/w of one or more binding sugar alcohols,

4-25% w/w of one or more non-binding sugar alcohols,

2-10% w/w of one or more pharmaceutically acceptable excipients (e.g. binders, fillers, additives etc. -other than lubricants such as magnesium stearate, calcium stearate or stearic acid),

0-2% w/w of one or more flavouring agents, artificial sweeteners, etc.,

0.26-0.44% w/w magnesium stearate, calcium stearate or stearic acid,

provided that the total amount corresponds to 100% w/w.

A calcium carbonate tablet comprising:

70-75% w/w calcium carbonate,

2-10% w/w of one or more binding sugar alcohols,

4-25% w/w of one or more non-binding sugar alcohols,

2-10% w/w of one or more pharmaceutically acceptable excipients (e.g. binders, fillers, additives etc. -other than lubricants such as magnesium stearate, calcium stearate or stearic acid),

0-2% w/w of one or more flavouring agents, artificial sweeteners, etc.,

0.3-0.4% w/w magnesium stearate, calcium stearate or stearic acid,

provided that the total amount corresponds to 100% w/w.

A calcium carbonate tablet comprising:

70-75% w/w calcium carbonate,

2-10% w/w of one or more binding sugar alcohols,

4-25% w/w of one or more non-binding sugar alcohols,

2-10% w/w of one or more pharmaceutically acceptable excipients (e.g. binders, fillers, additives etc. -other than lubricants such as magnesium stearate, calcium stearate or stearic acid),

0-2% w/w of one or more flavouring agents, artificial sweeteners, etc.,

0.35% w/w magnesium stearate, calcium stearate or stearic acid,

provided that the total amount corresponds to 100% w/w.

Calcium carbonate

As mentioned previously, calcium has a number of important functions in the mammalian body, particularly in the human body.

Calcium salts such as calcium carbonate are used in tablets and, due to the high calcium dose required, such tablets are often in the form of chewable tablets. It is a challenge to make chewable tablets, e.g. containing calcium salts, which tablets have a palatable taste and an acceptable mouthfeel, without the dominant taste or sensation characteristic of chalk.

Calcium carbonate is used as the active substance in the present invention. It may be used in combination with other calcium salts, provided that the resulting tablet has desirable characteristics in terms of dissolution stability.

Suitable other calcium salts for use in combination with calcium carbonate may be bisglycinate (bisglycinate), calcium acetate, calcium carbonate, calcium chloride, calcium citrate-malate, calcium corn oleate (calcium cornate), calcium fluoride, calcium glubionate, calcium gluconate, calcium glycerophosphate, calcium hydrogen phosphate, calcium hydroxyapatite, calcium lactate, calcium lactobionate, calcium lactogluconate (calcium lactogluconate), calcium phosphate, calcium oxyprolinate, calcium stearate, and tricalcium phosphate.

Typically, tablets made according to the invention contain an amount of the calcium-containing compound equivalent to about 100 to about 1000mg Ca, for example about 150 to about 800mg, about 200 to about 700mg, about 200 to about 600mg, or about 200 to about 500mg Ca.

Calcium carbonate can be in three different crystal structures: calcite, aragonite, and vaterite. Mineralogically, these are special mineral phases that involve different arrangements of calcium, carbon, and oxygen atoms in the crystal structure. These different phases affect the shape and symmetry of the crystalline form. For example, calcite can be obtained in four different shapes: scalenohedral, prismatic, spherical, and rhombohedral, and aragonite crystals may be obtained as discrete or clustered needles, for example. Other shapes, such as cubic (Soralite from Scora) are also available.

As shown in the examples herein, a calcium carbonate of particularly suitable properties is a calcium carbonate having an average particle size of 60 μm or less, for example 50 μm or less or 40 μm or less.

Furthermore, calcium carbonate has an interesting property of having a bulk density below 2 g/mL.

Calcium carbonate 2064Merck (obtained from Merck, Darmstadt, Germany) having an average particle size of 10-30 μm, an apparent bulk density of 0.4 to 0.7g/mL, and 0.3m²Specific surface area per gram;

calcium carbonate 2069Merck (available from Merck, Darmstadt, Germany) having an average particle size of about 3.9 μm, an apparent bulk density of 0.4 to 0.7 g/mL;

scoralite 1A (obtained from Scora Watrigant SA, France) having an average particle size of 5-20 μm, an apparent bulk density of 0.7 to 1.0g/mL, and 0.6m²Specific surface area per gram;

scoralite 1B (obtained from Scora Watrigant SA, France) having an average particle size of 10-25 μm, an apparent bulk density of 0.9 to 1.2g/mL, and 0.4 to 0.6m²Specific surface area per gram;

scoralite 1A + B (obtained from Scora Watrigant SA, France) having an average particle size of 7-25 μm, an apparent bulk density of 0.7 to 1.2g/mL, and 0.35 to 0.8m²Specific surface area per gram;

pharmacarb LL (from Chr. Hansen, Mahawah, N.J.) L, with an average particle size of 12-16 μm, an apparent bulk density of 1.0 to 1.5g/mL, and 0.7m²Specific surface area per gram;

sturcal H has an average particle size of about 4 μm, an apparent bulk density of 0.48 to 0.61 g/mL;

sturcal F has an average particle size of about 2.5 μm, an apparent bulk density of 0.32 to 0.43 g/mL;

sturcal M has an average particle size of 7 μ M, an apparent volume density of 0.7 to 1.0g/mLDegree, and 1.0m²Specific surface area per gram;

mikhart 10, SPL, 15, 40, and 65 (obtained from Provencale, france);

mikhart 10 has an average particle size of 10 μm,

mikhart SPL had an average particle size of 20 μm,

mikhart 15 has an average particle size of 17 μm,

mikhart 40 has an average particle size of 30 μm, an apparent bulk density of 1.1 to 1.5 g/mL;

mikhart 65 has an average particle size of 60 μm, an apparent bulk density of 1.25 to 1.7 g/mL;

omyapure 35 (from Omya S.A.S., Paris, France), having an average particle size of 5-30 μm, and 2.9m²Specific surface area per gram;

socal P2PHV (from Solvay, Brussels, Belgium) having an average particle size of 1.5 μm, an apparent bulk density of 0.28g/mL, and 7.0m²Specific surface area per gram;

calci Pure 250 Heavy, Calci Pure 250 Extra Heavy, and Calci Pure GCC HD 212 have a mean particle size of 10-30 μm, an apparent bulk density of 0.9-1.2g/mL, and an apparent volume density of 0.7m²Specific surface area per gram (obtained from Particle Dynamic, St. Louis, Montana).

The content of the calcium-containing compound in the tablets manufactured according to the invention is in the range of about 50% to about 90% w/w, such as about 55% to about 90% w/w, about 60% to about 85% w/w, about 65% to about 80% w/w, or about 70% to about 75% w/w.

Typically, the dose of calcium for therapeutic or prophylactic purposes is from about 350mg (e.g. neonatal) to about 1200mg (lactating women) per day. The amount of the calcium-containing compound in the tablet can be adjusted such that the tablet is suitable for administration 1-4 times daily, preferably once or twice daily.

Those skilled in the art will know how to adjust the composition and various process parameters in order to obtain the desired calcium-containing product.

Where it is desired to include an additional active substance other than the calcium-containing compound, the method may further comprise the step of adding one or more therapeutically, prophylactically, and/or diagnostically active substances to the resulting granules.

Such materials include one or more nutrients, such as one or more vitamins or minerals. In a particular embodiment, the other active substance is vitamin D, such as vitamin D₃Vitamin D₂Or a derivative thereof.

Vitamin D or other active substances

The granular material as well as the tablets obtained according to the invention may comprise other therapeutically and/or prophylactically active substances. Of particular interest are one or more vitamin D compounds. Non-limiting examples are dry vitamin D3, 100CWS obtained from DSM, and dry vitamin D3100 GFP obtained from BASF.

The granular material or tablet manufactured according to the invention may comprise other therapeutically and/or prophylactically active substances, or it may contain one or more nutrients, for example one or more vitamins or minerals. Of particular interest are, for example, vitamin B, vitamin C, vitamin D, and/or vitamin K, as well as minerals such as zinc, magnesium, selenium, and the like.

Of particular interest are one or more vitamin D compounds, e.g., vitamin D₂(ergocalciferol) and vitamin D₃(cholecalciferol) comprising dried vitamin D obtained from DSM₃100CWS, and dried vitamin D from BASF₃100GFP。

In addition to its role in calcium and bone homeostasis, vitamin D is involved in the regulation of several major systems in the body. By 1, 25- (OH) produced mainly in the kidney₂The complex formed between vitamin D and Vitamin D Receptor (VDR) exerts the action of vitamin D (mediator) on the genome. The vitamin D receptor is widely distributed in many cell types. The 1, 25- (OH)₂The vitamin D/VDR complex has important regulatory roles in cell differentiation and the immune system. Some of these effects may depend on local production of 1, 25- (OH) by certain tissues other than the kidney₂Vitamin D is capable and plays a role in paracrine (Adams JS et al Endocrinology 1996; 137: 4514-7).

In humans, vitamin D deficiency can lead to rickets in children and osteomalacia in adults. The fundamental abnormality is a delay in the rate of mineralization of the osteoid as it is produced by osteoblasts (Peacock M. London Livingstone, 1993: 83-118). It is not clear whether this delay is due to 1, 25- (OH) dependence in osteoblasts₂The failure of vitamin D mechanisms is again due to a decrease in calcium and phosphate supply secondary to malabsorption, or a combination of both. Associated with delayed mineralization are reduced calcium and phosphate supply, severe secondary hyperparathyroidism with hypocalcemia and hypophosphatemia, and increased bone turnover.

Vitamin D insufficiency is a preclinical phase of vitamin D deficiency and also causes a decrease in calcium supply and secondary hyperparathyroidism, although to a lesser extent than that found in deficiency. If this condition is maintained for a long period of time, it may lead to osteopenia. The biochemical process that causes the calcium deficiency state may be due to 1, 25- (OH)₂Substrate 25 for vitamin D-1, 25- (OH) by reduction of OHD₂Vitamin D levels are inappropriate (Francis RM et al Eur J Clin Invest 1983; 13: 391-6). Vitamin D deficient states are most commonly found in the elderly. With age, this results in a reduction in serum 25-OH vitamin D due to reduced exposure to sunlight, and possibly due to reduced skin synthesis. Furthermore, in the elderly, a reduction in calcium intake and conversely a reduction in calcium absorption exacerbates the condition. Kidney 1, 25- (OH) caused by decrease in renal function with age₂The reduction in vitamin D production may be a contributing factor. There have been many studies on the effects of vitamin D supplementation on bone loss in the elderly. Some people do not supplement calcium, others supplement calcium. From studies it has been shown that although vitamin D supplementation is necessary to reverse deficiencies and deficits, it is more important in terms of bone to provide calcium supplementation because the major skeletal defect is calcium deficiency. In the literature based on clinical trials, recent findings have shown a trend towards higher vitamin D doses for elderly patients (Compston JE. BMJ1998; 317: 1466-67). An open-semi-random study (quasi-randomised study) with annual injections of 150.000-300.000IU of vitamin D (corresponding to approximately 400-800 IU/day) showed that the total fracture rate was significantly reduced in the treated patients, but not the hip fracture rate (Heikinheimo RJ et al, Calcif Tissue Int 1992; 51: 105-110).

As indicated above, the combination of calcium with vitamin D is of interest. Calcium and vitamin D₃The Recommended Daily Allowance (RDA) of (European commission. report on osteoporosis in the European community. preventive action. lucensburg 1998(European commission. report on osteoporosis in the European community. action for prevention. office for office publication of the European community of the future of the public society of the European community of 1998)):

^*the RDA of calcium varies from country to country and is being reevaluated in many countries.

Pharmaceutically acceptable excipients

In the present context, the term "pharmaceutically acceptable excipient" refers to any material which is inert in the sense of not having substantially any therapeutic and/or prophylactic effect per se. In order to make it possible to obtain pharmaceutical compositions having acceptable technical characteristics, pharmaceutically acceptable excipients may be added to the active pharmaceutical substance. Although pharmaceutically acceptable excipients may have some effect on the release of the active drug substance, materials used to achieve the release modification are not included in this definition.

The calcium-containing compound (herein: calcium carbonate) and the sugar alcohol may be mixed with one or more pharmaceutically acceptable excipients before or after rolling. Such excipients include those commonly used in the formulation of solid dosage forms, such as fillers, binders, disintegrants, lubricants, flavoring agents, coloring agents, including sweetening agents, pH adjusting agents, stabilizing agents, and the like.

Typically, the disintegrant is selected from: sodium croscarmellose (a cross-linked polymer of sodium carboxymethylcellulose), crospovidone, starch NF; polacrilin sodium or potassium (sodium or potassium), and carboxymethyl starch sodium. Those skilled in the art will appreciate that it is desirable for a compressed tablet to disintegrate within 30 minutes, more desirably within 10 minutes, and most desirably within 5 minutes; thus, the disintegrant used preferably results in disintegration of the tablet within 30 minutes, more preferably within 10 minutes, most preferably within 5 minutes.

Examples of useful disintegrants are, for example, cellulose derivatives including microcrystalline cellulose, low substituted hydroxypropylcellulose (e.g. LH22, LH21, LH20, LH32, LH31, LH 30); starches, including potato starch; croscarmellose sodium (i.e., croscarmellose sodium salt; e.g., Ac-Di-Sol)) (ii) a Alginic acid or alginates; insoluble polyvinylpyrrolidones (e.g. povidone)CL(PolyvidonCL) povidoneCL-M, KolieCL(KollidonCL), crospovidoneXL(PolyplasdoneXL), crospovidoneXL-10); sodium carboxymethyl starch (e.g. Primogel)And Explotab)。

Fillers/diluents/binders, such as polyols, sucrose, sorbitol, mannitol, erythritol can be incorporatedTagatoseLactose (e.g. spray-dried lactose, alpha-lactose, beta-lactose, Tabletose)Various grades of medicinal lactose(Pharmatose) Micro-emulsified sugar (Microtose) or Fast-Floc) Microcrystalline cellulose (e.g., various grades of Avicel)For example AvicelPH101、AvicelPH102, or AvicelPH105、ElcemaP100、EmcocelVivacelMing TaiAnd Solka-Floc) Hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted) (e.g. L-HPC-CH31, L-HPC-LH11, LH22, LH21, LH20, LH32, LH31, LH30), dextrin, maltodextrin (e.g. Lodex @)5 and Lodex10) Starch or modified starch (including potato starch, corn starch, and rice starch), sodium chloride, sodium phosphate, calcium sulfate, calcium carbonate.

In the pharmaceutical compositions manufactured according to the invention, microcrystalline cellulose, L-hydroxypropyl cellulose, dextrin, maltodextrin, starch, and modified starch have proved to be very suitable, inter alia.

In a particular embodiment of the invention, the calcium-containing compound may be rolled together with one or more pharmaceutically acceptable binders, or the binder may be added after rolling. Suitable binders include those commonly used in the pharmaceutical arts, but binders commonly used in wet granulation processes are unlikely to function to the same extent, since substantially no liquid is present during agglomeration.

More specifically, examples include

Cellulose derivatives including methyl cellulose, hydroxypropyl cellulose (HPC, L-HPC), hydroxypropyl methyl cellulose (HPMC), microcrystalline cellulose (MCC), sodium carboxymethyl cellulose (Na-CMC), etc.;

mono-, di-, oligo-, polysaccharides including dextrose, fructose, glucose, isomalt, lactose, maltose, sucrose, tagatose, trehalose, inulin, and maltodextrin;

polyols including sugar alcohols such as lactitol, maltitol, mannitol, sorbitol, xylitol, and inositol;

polyvinylpyrrolidone including Colidyne K30, Colidyne 90F, or Colidyne VA64, and

proteins, including casein.

Surfactants such as nonionic (e.g., polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glycerol monooleate, and polyvinyl alcohol (polyvinyl alcohol)), anionic (e.g., sodium docusate and sodium lauryl sulfate), and cationic (e.g., benzalkonium chloride, benzethonium chloride, and cetrimide), or mixtures thereof, may be used.

Other suitable pharmaceutically acceptable excipients may include coloring agents, flavoring agents, and buffering agents.

The tablet may comprise a sweetener selected from the group consisting of: dextrose, fructose, glycerol, glucose, lactitol, lactose, maltose, sucrose, tagatose, trehalose, alitame, aspartame, acesulfame potassium, cyclamic acid salts (e.g., calcium cyclamate, sodium cyclamate), sucralose, neohesperidin dihydrochalcone (neohesperidinihydrochalcone), thaumatin, saccharin salts (e.g., ammonium saccharin, calcium saccharin, potassium saccharin, sodium saccharin), and mixtures thereof.

The tablets obtained by the process of the invention may be provided with a coating, provided that the coating does not substantially delay the release of the active drug substance from the composition. Typically, a film coating may be used.

If desired, known flavoring agents and known FD & C coloring agents may be added to the composition.

The present invention is illustrated in the following examples without limiting the invention thereto.

Examples

EXAMPLE 1 (REFERENCE)

Compactibility testing of different sugar alcohols

Tablets containing neosorb P100T, Sorbidex P1666BO, Isomalt ST-PF, polysorb P90, Mannitol 60, or Xylitol CM50 were compressed on an instrumented Fette exact 1/F single punch press, and only the maximum compression force on the upper punch was recorded.

The punch tip and die bore (die bore) were lubricated with a 5% suspension of magnesium stearate in acetone before each tablet was compressed. The acetone was allowed to evaporate prior to compression of the tablets.

The sugar alcohols were weighed and transferred to the mould holes and then pressed, see table 1. The tablets were tested for crushing strength immediately after demolding.

TABLE 1

The crushing strength of the resulting tablets of sugar alcohol is assumed to be independent of particle size and to have two different average particle sizes: this was tested with sorbitol 38 μm and 110 μm. It can be seen from fig. 1 (each point is the average of three measurements) that the assumption is correct. Therefore, the particle size test is not repeated for other sugar alcohols.

From FIG. 1 it can be seen that sorbitol has the best compactibility, which leads to the steepest slope of the correlation (correlation) between compaction force and crushing strength. Sorbitol is followed by isomalt. Maltitol, mannitol, and xylitol have very poor compactability.

At the very least, data acquisition is provided on the tablet press used to measure the compaction force applied. However, any tablet press machine may be used as long as the applied compaction force can be measured.

The crushing strength was measured by using Schleuniger-2E of dr. Schleuniger corporation and determined as the average of the measurements of the crushing strength of 10 individual tablets.

Example 2

Effect on dissolution stability of binding and non-binding sugar alcohol mixtures in combination with internal or external lubrication

In this example, sorbitol was selected as the binding sugar alcohol and maltitol as the non-binding sugar alcohol.

Table 2: composition of tablet [% ]

Tablets according to table 3 were manufactured in the following way, based on a batch scale of about 20 kg:

sorbitol and mannitol were milled using a Quadro comil. These materials were then mixed with calcium carbonate using a roller mixer. A Gerteis 3W-Polygran roller press was used, based on the following parameters: the mixture was rolled with a gap size (gap size) of about 3.5mm, a compaction force (fixed) of 12kN/cm, a roll speed of 5rpm and a mesh opening size of 1.5 mm. The remaining excipients were mixed into the granules thus obtained using a drum mixer. The final blend was compressed into tablets using a Fette 2090 rotary tablet press, capsule punch design (18.9mm x 9.4mm), compression force targeting a crush strength of 11kP, tablet mass 1728 mg. Magnesium stearate was added externally by using a PKB2 magnesium stearate spray system that sprayed magnesium stearate onto the tablet punches.

Calcium release was tested by dissolution testing using european pharmacopoeia (ph. eur.) device 2 (leaf), rotation 70rpm, HCl 0.1N, and 37 ℃, testing 3 tablets. This has been done initially, and after 14 days of storage in open petri dishes at 25 ℃ and 60% Relative Humidity (RH). This test is generally applicable in order to test whether the composition is stable with respect to dissolution profile.

The results of the dissolution test are shown in figure 2

From this figure it can be seen that for the external addition of magnesium stearate the dissolution was not affected by the tested relation between sorbitol/maltitol upon storage.

Example 3

Effect on dissolution stability of binding and non-binding sugar alcohol mixtures in combination with internal or external lubrication

In this example, sorbitol was chosen as the binding sugar alcohol and mannitol as the non-binding sugar alcohol.

Table 3: composition of tablet [% ]

Based on the compositions in table 3, tablets were produced according to example 2.

However, for the tablets in experiments 1-5, magnesium stearate had been added internally, resulting in a tablet mass of 1728 mg; whereas for experiments 6-10, magnesium stearate was externally added by using a PKB2 magnesium stearate spray system that sprayed magnesium stearate onto the tablet punches, resulting in a tablet mass of 1722 mg.

In experiments 1-5, the amount of magnesium stearate was about 6mg per tablet, corresponding to about 0.35% w/w. In experiments 6-10, about 30-50 μ g of magnesium stearate was deposited on the surface of the tablets during compression.

Dissolution testing was performed according to example 2.

The resulting dissolution profiles can be seen in figures 3 and 4.

As can be seen from these figures, the dissolution profile, fig. 2, was not initially affected by the amount of sorbitol in the formulation when magnesium stearate was added internally (in the tablet formulation). However, the amount of sorbitol after 14 days appears to be critical leading to unsatisfactory dissolution profiles for experiments 1-3. However, if magnesium stearate was externally added, the amount of sorbitol had no effect on the stability of dissolution, fig. 3.

Examples 2 and 3 illustrate that if magnesium stearate is added internally, the dissolution profile, even if initially acceptable, will be affected by the relationship between the binding and non-binding sugar alcohols upon storage. This relationship has no effect on dissolution from the tablet after storage if magnesium stearate is added from the outside.

Example 4

Effect on dissolution stability of two binding sugar alcohol mixtures in combination with an internal or external lubricant

In this example, sorbitol and isomalt were selected as binding sugar alcohols.

Table 4: composition of tablet [% ]

Based on the compositions in table 4, tablets were produced according to example 2.

However, for the tablets in experiments 11-16, magnesium stearate had been added internally, resulting in a tablet mass of 1728 mg; for experiments 17-22, magnesium stearate was externally added by using a PKB2 magnesium stearate spray system that sprayed magnesium stearate onto the tablet punches, resulting in a tablet mass of 1722 mg.

Dissolution testing was performed according to example 2. The resulting dissolution profiles can be seen in figures 5 and 6.

From these figures it can be seen that the dissolution profile, fig. 5, when magnesium stearate is added internally (in the tablet formulation) is not initially affected by the ratio between sorbitol and isomalt in the formulation. However, after 14 days of storage in open petri dishes at 25 ℃ and 60% RH, the amount of sorbitol appeared to be critical leading to an unsatisfactory dissolution profile for all experiments. Furthermore, even if sorbitol is completely removed from the formulation, storage results in an suboptimal dissolution profile, although reducing the amount of sorbitol does reduce the effect.

In contrast to what is seen in example 3, only low amounts of sorbitol for the external addition of magnesium stearate gave dissolution profiles which were not affected by storage of the tablets in open petri dishes at 25 ℃ and 60RH, fig. 6.

Claims (14)

1. A process for preparing a tablet comprising at least 50% w/w calcium carbonate, the process comprising

i) Providing a particulate composition comprising: a)70-75% w/w calcium carbonate, b)4-25% w/w of a cohesive sugar alcohol selected from sorbitol or isomalt, or a combination thereof, c)4-25% w/w of a non-cohesive sugar alcohol selected from mannitol, maltitol or xylitol, or a combination thereof, and d)2-10% w/w of one or more pharmaceutically acceptable excipients other than magnesium stearate, calcium stearate or stearic acid; and

ii) compressing the composition using a tablet press equipped with at least one pair of punches and dies, wherein the punch and die pair is sprayed with a composition comprising a lubricant selected from magnesium stearate, calcium stearate or stearic acid, or a combination thereof, prior to filling the dies with the particulate composition,

wherein the total concentration of magnesium stearate, calcium stearate or stearic acid present only on the outermost surface of the tablet is from 0.001 to 0.01% w/w, provided that the total amount of the tablet composition corresponds to 100% w/w.

2. The method according to claim 1, wherein the particle composition is prepared by the steps of:

i) rolling the calcium carbonate and the binding sugar alcohol and the non-binding sugar alcohol to obtain rolled granules, and

ii) mixing one or more of said pharmaceutically acceptable excipients in a mixer.

3. A process according to any one of claims 1-2, wherein the total concentration of sugar alcohols present in the tablet composition is from 15% w/w to 35% w/w.

4. A process according to any one of claims 1-2, wherein the total concentration of sugar alcohols present in the tablet composition is from 20% w/w to 25% w/w.

5. Calcium carbonate tablet obtainable by the process according to any one of claims 1-2.

6. A calcium carbonate tablet comprising:

70-75% w/w calcium carbonate,

4-25% w/w of one or more binding sugar alcohols selected from sorbitol or isomalt or a combination thereof,

4-25% w/w of one or more non-binding sugar alcohols selected from mannitol, maltitol or xylitol or a combination thereof,

2-10% w/w of one or more pharmaceutically acceptable excipients, wherein the excipient is not a lubricant,

0-2% w/w of one or more flavouring agents,

0.001-0.01% w/w magnesium stearate, calcium stearate or stearic acid,

with the proviso that the total amount corresponds to 100% w/w and wherein the content of magnesium stearate, calcium stearate or stearic acid is present only on the outermost surface of the tablet.

7. A calcium carbonate tablet comprising:

70-75% w/w calcium carbonate,

4-25% w/w sorbitol,

4-25% w/w of one or more of mannitol, maltitol or xylitol,

2-10% w/w of one or more pharmaceutically acceptable excipients, wherein the excipient is not a lubricant,

0-2% w/w of one or more flavouring agents,

0.001-0.01% w/w magnesium stearate, calcium stearate or stearic acid,

with the proviso that the total amount corresponds to 100% w/w and wherein the content of magnesium stearate, calcium stearate or stearic acid is present only on the outermost surface of the tablet.

8. A calcium carbonate tablet comprising:

70-75% w/w calcium carbonate,

4-25% w/w isomalt,

4-25% w/w of one or more of mannitol, maltitol or xylitol,

2-10% w/w of one or more pharmaceutically acceptable excipients, wherein the excipient is not a lubricant,

0-2% w/w of one or more flavouring agents, and

0.001-0.01% w/w magnesium stearate, calcium stearate or stearic acid,

with the proviso that the total amount corresponds to 100% w/w and wherein the content of magnesium stearate, calcium stearate or stearic acid is present only on the outermost surface of the tablet.

9. A calcium carbonate tablet comprising:

70-75% w/w calcium carbonate,

10-25% w/w of one or more binding sugar alcohols selected from sorbitol or isomalt or a combination thereof,

4-15% w/w of one or more non-binding sugar alcohols selected from mannitol, maltitol or xylitol or a combination thereof,

2-10% w/w of one or more pharmaceutically acceptable excipients, wherein the excipient is not a lubricant,

0-2% w/w of one or more flavouring agents,

0.001-0.01% w/w magnesium stearate, calcium stearate or stearic acid,

with the proviso that the total amount corresponds to 100% w/w and wherein the content of magnesium stearate, calcium stearate or stearic acid is present only on the outermost surface of the tablet.

10. The calcium carbonate tablet according to any one of claims 6 to 9, which is prepared by the process as described in any one of claims 1 to 4.

11. A process for preparing a tablet comprising 70-75% w/w calcium carbonate, the process comprising

i) Rolling a)70-75% w/w calcium carbonate, b)2-10% w/w of a binding sugar alcohol selected from sorbitol or isomalt, and c)4-25% w/w of a non-binding sugar alcohol selected from mannitol, maltitol or xylitol, to obtain rolled granules,

ii) mixing 0.35% w/w magnesium stearate, calcium stearate or stearic acid, and optionally 2-10% w/w of one or more pharmaceutically acceptable excipients, wherein the excipient is not a lubricant, in a mixer, and

iii) compressing the composition using a tablet press,

provided that the concentration of sorbitol in the tablet composition does not exceed 10% w/w and provided that the total amount of the tablet composition corresponds to 100% w/w.

12. Calcium carbonate tablets obtainable by the process according to claim 11.

13. A calcium carbonate tablet comprising:

70-75% w/w calcium carbonate,

2-10% w/w of one or more binding sugar alcohols selected from sorbitol or isomalt,

4-25% w/w of one or more non-binding sugar alcohols selected from mannitol, maltitol or xylitol or a combination thereof,

2-10% w/w of one or more pharmaceutically acceptable excipients, wherein the excipient is not a lubricant,

0-2% w/w of one or more flavouring agents,

0.35% w/w magnesium stearate, calcium stearate or stearic acid,

provided that the total amount corresponds to 100% w/w.

14. The calcium carbonate tablet according to any one of claims 6-9 and 13, wherein the flavoring agent is an artificial sweetener.