WO2011024208A1

WO2011024208A1 - Combination dosage form with acetylsalicylic acid, calcitriol and calcium

Info

Publication number: WO2011024208A1
Application number: PCT/IS2010/000011
Authority: WO
Inventors: Torfi E. Kristjansson
Original assignee: Colotech AS
Current assignee: Colotech AS
Priority date: 2009-08-24
Filing date: 2010-08-24
Publication date: 2011-03-03
Anticipated expiration: 2012-02-24

Abstract

The invention provides a stable pharmaceutical composition comprising acetylsalicylic acid (ASA), 1,25 dihydroxycholecalciferol (calcitriol) and calcium, providing all the three active ingredients in a single dosage form but such that the ingredients are chemically substantially separated. The invention also relates to process for the preparation of such compositions. The dosage forms of the invention include layered tablets including inlay tablets and compression coated tablets, capsules with different granules with respective ingredients, capsules with an inner capsule and capsule containing an inner tablet with ASA and a matrix comprising calcitriol and calcium.

Description

Combination dosage form with acetylsalicylic acid, calcitriol and calcium

FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical composition suitable for administration to mammals comprising acetylsalicylic acid (ASA), 1,25 dihydroxycholecalciferol (calcitriol) and calcium. The invention also relates to a process for the preparation of such compositions and their use.

BACKGROUND OF THE INVENTION

It is known from EP1220676 that a combination of ASA, calcitriol and calcium can prevent and/or reduce the progression of colorectal cancer in humans. Clinical tests are ongoing to further assess the utility of this promising invention.

It is however very challenging to develop and produce a dosage form with all of these three active ingredients combined, as they are essentially not chemically compatible with each other. Calcitriol is known to be extremely sensitive to oxidation, and acetylsalicylic acid is very sensitive to humidity and hydrolytic degradation to salicylic acid and acetic acid. EP1220676 does not disclose or suggest any suitable particular compositions and appears to suggest that the ingredients can be provided as individual doses, to be administered simultaneously.

It is generally often non-trivial to develop formulations with combination of chemically different active ingredients, each active ingredient will have its own optimal matrix conditions that affect stability, dissolution and absorption characteristics. This can be difficult with two active ingredients and even more so with three active ingredients.

It would be much appreciated to be able to administer one dosage form with all of the three active ingredients together, instead of a combination of two or three dosages taken together. Any combination of the three ingredients is further complicated by the very different suitable amounts of the compounds, as taught by EP 1220676, as the proposed amount of calcitriol is on the order of ten million times less than the proposed amount of calcium.

As described in more detail below, the inventors have managed to develop stable pharmaceutical compositions comprising ASA, calcitriol and calcium, together in a single dosage form.

SUMMARY OF THE INVENTION

The present invention relates to a stable pharmaceutical composition comprising acetylsalicylic acid (ASA), 1,25 dihydroxycholecalciferol (calcitriol) and calcium, all in a single dosage form, such as but not limited to a pill or capsule. The invention also relates to a process for the preparation of such compositions and their use. The compositions and dosage forms of the invention exhibit excellent stability, shelf-life and dissolution characteristics. DEETAILED DESCRIPTION

As mention above, EP1220676 discloses the general clinical benefits of the combination of the three active ingredients of the present invention, calcitriol, acetylsalicylic acid (ASA) and calcium. This document is incorporated by reference in its entirety.

It is a demanding challenge to combine the mentioned three active ingredients in a single dosage form as the compounds are not compatible with each other, i.e. they have destabilising effects on each other. The present inventors have managed to develop pharmaceutical compositions that show excellent stability and disintegrate readily such that the active compounds are biologically accessible.

The present invention provides a pharmaceutical composition comprising in a single dosage form calcitriol, acetylsalicylic acid or a salt thereof and calcium, wherein the calcitriol has been solubilised in a lipophilic carrier and the acetylsalicylic acid is separated from the calcitriol and preferably also separated from the calcium.

By the term "separated" as used in this context is meant that compounds that are separated are not homogeneously mixed and have substantially less chemical contact than if they would be homogeneously mixed together in liquid or fine powder form. Thus, "separated" encompasses as a non-limiting example when two compounds are granulated separately, those granulates can then be mixed but the respective compounds are accordingly in limited contact (only through surface- surface contact of the different granules) and thus have a degree of separation, i.e. they are "separated" according to the convention used herein. Preferably however such limited contact is further limited, e.g. by coating such granules or mixing the granules in a third excipient to thereby limit contact between the different granules. Accordingly, for "separating" two compounds A and B according to the present meaning of the term, compound A can be granulated whereas compound B is not granulated, and preferably the granules of A are coated, subsequently the granules are mixed with compound B and optionally and typically further excipients.

In accordance with the invention, the calcitriol is solubilised in a lipophilic carrier. The lipophilic carrier may be selected from suitable low viscosity di- or triglycerides, such as di- and/or triglycerides comprising substantially C8 and/or ClO fatty acids, or mixtures of triglycerides of C8, ClO fatty acids and linoleic acid. Suitable lipophilic carriers include fractionated triglycerides sold under the trade name Miglyol® (Sasol, Germany) such as Miglyol 810, Miglyol 812 and Miglyol 818. Miglyol 840 is a diglyceride (glycol diester) with C8 and ClO fatty acids, such diglycerides are also contemplated as a useful lipophilic carrier. Miglyol 810 and Miglyol 812 are particularly preferred. Other lipophilic carriers include dimethyl sulphoxide and suitable lipophilic alcohols, including isopropyl alcohol, ethylene glycol, propylene glycol or glycerol; or a mixture of any of those.

The dosage form of the invention comprises preferably the calcitriol component in the amount of about 0.1 μg (microgram) to about 2 μg, including about 1 μg or 1.2 μg, more preferably in the range of about 0.1 to about 0.5 μg, including about 0.25 μg and about 0.35 μg. This small amount makes stringent requirements on the process for preparing the composition, in order to ensure uniformity of the calcitriol amount between individual dosage forms.

In accordance with applicable pharmaceutical standards, in preferred embodiments calcitriol can be added in the manufacturing process in 20-60% overage, which means that in the manufacturing process 120 - 160% is added of the intended amount, to allow for certain degradation, in particular during the processing, which is hard to fully prevent. In preferred embodiments calcitriol is added in 20-30% overage. Preferably, calcitriol is added in overage such that the tablets right after manufacturing comprise 90-130% measured amount of the target amount of calcitriol.

The calcium is most preferably in the form of calcium carbonate. In other embodiments of the invention other calcium salts are used such as calcium phosphate, calcium chloride, calcium phosphate and calcium sulphate. Typically, the dosage form of the invention will comprise in the range of about 200 mg to 3000 mg calcium carbonate, more preferably in the range of about 300 mg to 2000 mg, and even more preferably in the range of about 500 mg to 1000 mg, including about 500 mg, about 625 mg, about 650 mg or about 750 mg.

Acetyl salicylic acid (ASA) is generally in the dosage form in the amount of about 20 mg to about 500 mg, or in the range of about 25 mg to about 400 mg, more preferred in the range of about 25 to 300 mg, including the range of about 50 to 150 mg, or the range of about 25 mg to 100 mg, and including about 25 mg, 37 mg and about 50 mg.

As mentioned above, the pharmaceutical composition of the invention comprises the above mentioned three ingredients in a single dosage form, where the ASA is chemically separated from the calcitriol and calcium. Several embodiments of this inventive new concept have been developed and are encompassed by this invention, and will be further described herein.

In preferred non-limiting embodiments, the dosage form of the invention are instant release tablets, i.e. tablets that dissolve and/or disintegrate readily after intake so as to allow rapid adsorption of the active compounds. Preferably the disintegration is less than 30 min and more preferably less than 15 min, yet more preferably less than 10 min, as measured by standards protocols described in Ph. Eur. Dissolution of the active components is preferably within similar ranges of time.

In one embodiment, the dosage form of the invention is an inlay tablet comprising an inner tablet which comprises the ASA, and one or more outer tablet layer which comprises the calcitriol and the calcium. The inner tablet will generally be coated, preferably film coated, in order to provide the desirable separation of the ASA from the other active ingredients. The term "inlay tablet" is used herein in the conventional meaning, referring to a tablet having an inner tablet which is generally not fully enclosed by an outer layer, but rather the inner tablet sits embedded in the top (or bottom) surface of the compressed outer tablet. Also preferred embodiments include compression coated tablets. The term "compression coated tablet" refers herein to a tablet comprising an inner layer/tablet, fully surrounded by an outer layer, referred to as a "mantle layer". In the compression coated tablet of the invention, the ASA is suitably compressed in an inner tablet as further described herein, and the calcitriol component and calcium components are placed in one or more outer layer, preferably such that the calcitriol and calcium are separated.

Tablets according to the invention have good friability and desired hardness, as illustrated in the accompanying Examples. Preferably the hardness is in the range of about 20-200 N, more preferably in the range 30-150 N, and even more preferably in the range 40-90 N, wherein hardness is measured by a method as describred in Ph. Eur.

A moisture barrier coating is preferred, such as for example polyvinylalcohol based coatings, including a polyvinyl alcohol-based coating with lecithin, such as Opadry AMB (Colorcon, USA) (See US patent No. 5,885,617). For a tablet core (i.e. uncoated tablet) of the inner tablet in the range of 50-100 mg, the coating will generally add about 1-8 mg to the tablet core, corresponding to a weight increase of about 2-8%. In preferred aspect the moisture barring coat is from 3-7% and most preferably it is about 6%. A moisture barrier coat in this invention may also be based on other ingredients such as but not limited to hydroxypropyl methylcellulose and polyvinyl pyrrolidone (PVP) or polyvinyl alcohol (PVA).

The inner tablet preferably comprises suitable pharmaceutical excipients compatible with ASA, such as a carrier/diluent which in some embodiments is selected from microcrystallised cellulose, dextrose, mannitol, sorbitol, corn starch, modified corn starch or mixtures of two or more thereof. The amount of carrier/diluent can be in the range of about 10-75 wt% of the uncoated core of the inner tablet, such as in the range of about 20-65 wt%, including the range of about 25-50 wt%.

It is preferable to include in the inner tablet a disintegrant, such as but not limited to

croscarmelose, crospovidone, and sodium starch glycolate. The disintegrant is preferably included in the inner tablet in an amount in the range of about 5-25% based on weight of the uncoated inner tablet, such as in the range of 10-20%, including about 10%, about 15% and about 18%.

A lubricant is preferably added to the inner tablet, which is in certain embodiments is one or more of magnesium stearate, sodium stearyl fumarate, stearic acid, colloidal anhydrous silica, synthetic aluminum silicate, magnesium oxide, calcium stearate, talc, hydrogenated castor oil, glyceryl dibehenate and mixtures thereof. Lubricant will generally be present in the amount in the range from about 0.1% to about 4% by weight of the uncoated tablet, preferably from about 0.5 % to about 2% by weight. In preferred embodiments, magnesium stearate or stearic acid is selected as the most preferred lubricant.

As the dosage amounts of the calcium and ASA are substantial amounts as indicated above, it is preferred to not add too much of inert excipients to the dosage form, so as to not making the dosage form too large and difficult to ingest orally. Accordingly, in one embodiment of the composition, the total weight of the active ingredients (i.e. calcitriol, ASA, and calcium, including their salts if applicable) is 60% or more of the total weight of the dosage form. More preferably the active ingredients comprise at least 70% of the total weight of the dosage form.

For providing the outer layer of an inlay or compression coated tablet according to the invention, the calcitriol and calcium can be mixed to form a suitable homogeneous mix as will be further described herein. Alternatively, the calcitriol and calcium can be added in separate layers.

Calcitriol component

Preferably, calcitriol is solubilised in a lipophilic carrier such one or more of those mentioned above. A further lipid compound is added in some embodiments, such as but not limited to hydrogenated vegetable oil (e.g. as sold under the trade name Lubritab (JRS), or Sterotex® (ABITEC) which is hydrogenated cottonseed oil, or castor wax, which is hydrogenated castor oil), or glycerol behenate (e.g. Compritol® (Gatte Fosse)).

Additionally, an antioxidant may be added to the calcitriol mix, preferably BHA (tert-butyl-4- hydroxyanisole) or BHT (butylated hydroxytoluene).

A suitable uniform mix with calcitriol and calcium suitably separated from each other can be made by first solubilising calcitriol in the lipophilic carrier, optionally with the added antioxidant. If a further lipid component is used, this component is suitably dissolved in another portion of the lipophilic carrier, heated as needed to dissolve the lipid compound, and the two portions are combined.

A calcitriol lipid solution as described is in certain embodiments Filled in small capsules (such s size 5 capsules, according to standardized sizes well known to the skilled person). Preferably, the lipid solution is kept at a temperature in the range of about 40-45⁰C to maintain homogeneous pouring solution.

In order to make calcitriol granules, the dissolved calcitriol with the optional antioxidant and/or further lipid component, such as those mentioned, is mixed with a suitable carrier, such as but not limited to dextrose, mannitol, sorbitol, lactose or microcrystalline cellulose, which is preferred. This resulting mixture is well mixed, such as in a high shear mixer, and dried. The calcitriol solution and carrier can be mixed in a suitable ratio such as in the range of about 1:8 to about 1:20, e.g. about 1: 10 or 1: 12.

The obtained calcitriol granules according to the above procedure are found to be stable. These granules can be combined with a calcium carbonate component.

Calcium component

The calcium carbonate is preferably pre-mixed with a disintegrant, such as preferably

croscarmelose, crospovidone, or sodium starch glycolate, which can be mixed with the calcium carbonate in a weight ratio of about 1: 10 to about 1:20, such as about 10, 12 or 15% of the disintegrant. In order to compress the calcium component, the calcium carbonate or calcium carbonate disintegrant premix can be compacted with roller compaction. In some embodiments, it is useful to add to the calcium carbonate mix a surfactant, such as a poloxamer copolymer (triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol), e.g. Poloxamer 407, such as Pluronic F127 (BASF, Germany).

Calcium carbonate component and calcitriol granules as described above are mixed together in one embodiment. Preferably, a lubricant is added, such as one of those mentioned above with respect to the inner ASA tablet.

For the purpose of illustration a few specific preferred embodiments are described in more detail below:

(i) Inlay tablet

The calcitriol-calcium mix can be suitable compressed on to an inner tablet with the ASA as described above. The obtained inlay tablet with inner ASA tablet and outer inlay layer with calcitriol and calcium can be suitably coated, such as with a coating as mentioned above.

(ii) Compression coated tablet

A similar embodiment to the above described involves the initial preparation of ASA inner tablets as just described, preferably film coated, which are fed into a suitable modified compression machine in which calcitriol granules such as described above and the calcium component are fed. Thus, a tablet is provided with a surrounding mantle around the inner ASA tablet, wherein the surrounding mantle comprises the calcitriol and calcium. In an alternative of this embodiment, the inner tablet is first partially compressed, e.g. at a pressure in the range from 0.5-5 tons, to form a partially- compressed core. This partial compression holds the components of the core together, but is not compressed to its final hardness/thickness. The final tablets may be formed by a process wherein both the core and mantle blends are placed onto the two sides of a single machine (e.g. a Manesty Dry-Cota tablet press). The core blend is again partially compressed (compressed, but not to its final hardness/thickness, only sufficient to hold together until it is transferred) on the core side of the press and then transferred to the mantle side of the press where it is sandwiched in the mantle blend. This core/mantle blend is then compressed into the final, compression-coated tablet.

(iii) Tablet with separated granules

The ASA can also be granulated in granules which are suitably coated, preferably with a suitable film coating material such as but not limited to HPMC based coatings, Kollidon (copovidone) or the like. Calcitriol is provided in granule form preferably as described above and the two respective types of granules are mixed with the calcium component. The resulting mix is subsequently compressed into tablets, which may be further coated, for enhanced stability and/or aesthetic appeal.

(iv) Capsule with separated granules

Similar components as described and used in alternative (iii) are used in an embodiment wherein the mix of ASA granules, calcitriol granules and calcium component is placed in a suitable capsule.

(v) Double Capsule

As described above, the solubilised calcitriol with the optional stabilising antioxidant(s) and/or further lipid component can be added to small capsules. In a useful embodiment, an inner tablet with ASA, a small capsule with calcitriol solution and calcium component as described above are placed in a sufficiently large capsule. Such capsule is preferably packed in Alu-alu blister packaging, to give long-term stability. It is found that large such large capsule dosage forms including all three active ingredients readily dissolve to release all ingredients as clinically desired.

(vi) Capsule with inner tablet

An inner tablet with ASA can be prepared as described above and used in illustration (i), this inner tablet is one embodiment film coated as described above and placed in a capsule together with calcitriol granules such as described above, and the calcium component.

The term potency as used herein referring to calcitriol refers to the measured amount of calcitriol and the active derivative pre-calcitriol, as measured by established assay. The following method to measure calcitriol can be used. A column such as Tracer Inertsphere, ODS, 5μ, 250mm x 4.6 mm or equivalent at 25°C, having the detection set at UV at 265 nm, injecting 200μL samples, using the mobile phase Water: Acetonitrile: Methanol in the following ratio 30:45:25 (v/v/v) at flow rate of 1.5 mlVmin.

In another embodiment of the invention the size of the pharmaceutical dosage form can optionally be further decreased by roller compacting or other techniques of one or more of the active ingredients with or without additional excipients. In particular it may be advantageous to roller compact calcium prior to making the final dosage form.

It is noted that it is beneficial to package the dosage form in stabilising packaging material especially chosen to protect the dosage form from moisture, including Duma containers, preferably with desiccant. In a preferred embodiment of the invention, the dosage form is provided in aluminium blister packaging (alu-alu).

As appears from above, the pharmaceutical composition and dosage form of the invention is useful for prevention and/or treatment of colon cancer in mammals, in particular in humans. However, the composition and dosage forms are also useful in the prevention of epithelial cancer such as lung, bladder, prostate or gynaecological cancer or the initiation and/or progression of epithelial cancer such as lung, bladder, prostate or gynaecological cancer in a human. The pharmaceutical composition can further be used to treat conditions such as the treatment of swelling, osteoporosis, headache and calcium deficiency in mammals such as humans.. In preferred embodiment of the invention the mammal is a human.

EXAMPLES

Example 1: Inner tablet with ASA

An ASA tablet was prepared by combining the following ingredients, mixing them in a drum mixer and pressing them together in a tablet press using 6 mm punches. For optimal results the tablets were then coated with about 6 wt% PVA based coating (Opadry AMB).

Table 1

Example 2: Calcitriol granules

Calcitriol granules were created by using the following ingredients and techniques. Butylated hydroxyanisole (BHA) was dissolved in isopropyl alcohol. Calcitriol was dissolved in the BHA - isopropyl alcohol solution, and sterotex is melted and added to the mix. The resulting mixture was then mixed with mannitol in high shear mixer and dried in fluidised bed processor at 40⁰C.

Table 2

Example 3: Calcium carbonate component mixture

Calcium carbonate component was created by combining calcium carbonate with crosslinked povidone.

Table 3

Example 4: Inlet tablet with inner ASA tablet overlaid with calcitriol and calcium

Calcitriol granules and calcium carbonate from examples 2 and 3 were mixed along with sodium stearyl fumarate. They were then compressed into a tablet over the ASA tablet from example 1 thus creating an inlay tablet. The tablets can then optionally be coated. The tablets were then packed into aluminum blisters.

Table 4

The tablets had measured hardness 49-75 N, friability of 0.1% and disintergation time 8 min 20 sek (measured dissolution of calcium).

Example 5: Inner tablet with ASA

ASA tablet was created by combining the following ingredients, mixing them in a drum mixer and pressing them together in a tablet press using 6 mm punches. For optimal results the tablets were then coated with 6% PVA based coating (Opadry AMB).

Table 5

Example 6: Calcitriol solution component

Butylated hydroxyl anisole and butylated hydroxyl toluene were dissolved in miglyol. Calcitriol in solid form is then added to the solution which was heated to 40-45⁰C to get a clear solution. Lubritab was then melted at 50-70⁰C and allowed to cool until 40-45⁰C before adding it to the Miglyol solution. The above solution was then added to small capsules. A 40-45⁰C temperature was maintained while filling the capsules.

Table 6

Example 7: Calcium carbonate component mix

Calcium carbonate, starch and poloxamer were sifted and mixed together. Optionally a part of the magnesium stearate can be added. The blend was then roller compacted and sieved to reduce its volume. Magnesium stearate was then added to the blend as lubricant followed by a short mixing.

Table 7

Dissolution of the prepared component was assayed with standard methods, after 30 min in 900 mL 0.1N HCL dissolution was 95.8%.

Example 8: Capsule with calcitriol in inner capsule

Coated ASA tablet from example 5, calcitriol capsule from example 6 and the calcium carbonate from example 7 were put into a single large capsule in a capsule filling machine. The capsules were then packed into aluminum blisters. Example 9: Analysis of calcitriol stability

Calcitriol potency is measured in samples according to the following HPLC procedure. The potency of calcitriol is defined as the assayed combined amount of calcitriol and the active derivative pre- calcitriol.

Column: Tracer Inertsphere, ODS, 5μ, 250mm x 4.6 mm or equivalent

Column temperature: 25°C

Detection: UV at 265 nm

Injection volume: 200 μL

Mobile phase Water: Acetonitrile: Methanol = 30:45:25 (v/v/v)

Flow rate: 1,5 mL/min

Example 10: Stability of dosaαe forms

Potency of calcitriol in percentages in two types of dosage forms tested under different stability conditions. Both types of dosage forms were packed in alu-alu blister packaging.

Table 8

RH: relative humidity

The results show good stability of the tested dosage forms of the invention.

Claims

1. A pharmaceutical composition comprising in a single dosage form calcitriol, acetylsalicylic acid or a salt thereof, and calcium, wherein said calcitriol has been solubilised in a lipophilic carrier, and said acetylsalicylic acid is separated from the calcitriol.

2. The pharmaceutical composition according to claim 1, wherein said acetylsalicylic acid is separated from said calcium.

3. The pharmaceutical composition according to claim 1 or 2, wherein the calcium is in a form selected from calcium carbonate, calcium phosphate, and calcium sulfate.

4. The pharmaceutical composition according to claim 1 or 2, wherein said lipophilic carrier comprises tri- and/or diglycerides of C8 and ClO fatty acids.

5. The pharmaceutical composition according to claim 1 or 2, wherein said lipophilic carrier comprises a solvent selected from the group consisting of isopropyl alcohol, dimethyl sulphoxide , ethylene glycol, propylene glycol, glycerol, and a mixture of any of those.

6. The pharmaceutical composition according to claim 1 or 2, wherein the calcitriol is

solubilised in a lipophilic carrier which comprises a further lipid component selected from hydrogenated vegetable oil, including hydrogenated cottonseed oil, and hydrogenated castor oil, and glycerol behenate.

7. The pharmaceutical composition according to claim 1 or 2, wherein an antioxidant is added to the calcitriol and lipophilic carrier.

8. The pharmaceutical composition according to claim 7, wherein said antioxidant is selected from BHA, BHT, and a mixture thereof.

9. The pharmaceutical composition according to claim 1 or 2, wherein the calcitriol solubilised in lipophilic carrier is mixed with a pharmaceutically acceptable solid carrier, and said mix is dried and granulated.

10. The pharmaceutical composition according to any of claims 1-9, wherein said dosage form is in the form of an inlay or compression coated tablet, wherein ASA is comprised in an inner tablet, and calcitriol and calcium are comprised in one or more outer layer of said inlet tablet.

11. The pharmaceutical composition according to claim 9 10, wherein calcitriol is formulated in granules as described in claim 9, which granules are mixed with a solid matrix comprising calcium, said mix compressed in an outer layer at least partially surrounding said inner tablet.

12. The pharmaceutical composition according to claim 10, wherein said dosage form is in the form of a compression coated tablet, with the ASA comprised in an inner tablet and said calcitriol and calcium comprised in mantle layer surrounding said inner tablet.

13. The pharmaceutical composition according to any of claims 1-9, wherein said dosage form is in the form of a capsule.

14. The pharmaceutical composition according to claim 13, wherein the calcitriol is comprised in an inner capsule.

15. The pharmaceutical composition according to claim 12, wherein the calcitriol is comprised in granules.

16. The pharmaceutical composition according to any of claims 12-15, wherein ASA is

comprised in an inner tablet placed inside said capsule.

17. The pharmaceutical composition according to any of the aforementioned claims, wherein the dosage form is packaged moisture limiting packaging selected from Duma containers and aluminium-aluminium blisters packaging.

18. A process for preparing a pharmaceutical dosage form comprising in a single dosage form calcitriol, acetylsalicylic acid or a salt thereof and calcium, said process comprising

dissolving calcitriol in a suitable lipophilic carrier, mixing with a carrier and drying to obtain calcitriol granules,

compressing ASA in a tablet or granulating ASA, optionally with a suitable excipient, to obtain an ASA component,

optionally coating said ASA component in the form of a tablet or granules, combining said ASA component and calcitriol component with a calcium component to obtain said pharmaceutical dosage form.

19. The process according to claim 18, wherein said lipophilic carrier comprises tri- and/or diglycerides of C8 and ClO fatty acids.

20. The process according to claim 18 or 19, wherein said lipophilic carrier comprises a solvent selected from isopropyl alcohol, dimethyl sulphoxide , ethylene glycol, propylene glycol, glycerol, and a mixture of any of those.

21. The process according to any of claims 18 to 20, wherein the calcitriol is solubilised in a lipophilic carrier which comprises a further lipid component selected from hydrogenated vegetable oil, including hydrogenated cottonseed oil, and hydrogenated castor oil, and glycerol behenate.

22. The process according to claim 18, wherein said ASA is compacted to a tablet, which is optionally coated.

23. The process according to claim 22, wherein said calcitriol is formulated as a granulate component and is mixed with said calcium component and the obtained mix compressed in a layer on or around said ASA tablet to form a layered tablet, which can be an inlay tablet or a compression coated tablet.

24. The process according to claim 22, wherein said ASA tablet is placed in a capsule together with said calcitriol granulate component and said calcium component.

25. The process according to claim 21, wherein said calcitriol is put in an inner capsule, which inner capsule is placed inside said capsule.

26. The process of any of claims 18-25, wherein said calcium component is roller-compacted to reduce its volume.