WO2015176848A1

WO2015176848A1 - Self-drying dosage form with controllable drying time and drying rate

Info

Publication number: WO2015176848A1
Application number: PCT/EP2015/056079
Authority: WO
Inventors: K. H. Bauer
Original assignee: Bauer K H
Priority date: 2014-05-21
Filing date: 2015-03-23
Publication date: 2015-11-26

Abstract

A self-drying pharmaceutical dosage form and a process for its manufacture are provided. The process involves the binding of water provided by a syrup of one or more pharmaceutically acceptable sugar(s), sugar alcohol(s) or salt(s), or mixtures thereof used for formulation by a suitable water-acceptor, selected from CaO and/or MgO that form a stable hydrate at room temperature. The inventive process allows to directly form ready-to-use castings without involving any physical drying, tableting or extrusion steps. The process further allows for industrial scale application, since the drying time and drying rate can be controlled and fine tuned by varying choice or ratio of the water-acceptor and by optionally further adding a pharmaceutically acceptable acid.

Description

SELF-DRYING DOSAGE FORM WITH CONTROLLABLE

DRYING TIME AND DRYING RATE

FIELD OF THE INVENTION

The present invention relates to a self -drying pharmaceutical dosage form or food product , and a process for preparing a pharmaceutical dosage form or food product, which are able to dry in situ and do not require any drying measures such as heating and which allow controlling of both the drying time and the drying rate .

BACKGROUND OF THE INVENTION

Conventional methods for preparing a pharmaceutical dosage form comprise we mixing or wet granulation of the ac ive pharmaceutical ingredient ( s) with suitable pharmaceutical excipients and thereafter bringing the dosage form into its desired physical shape , e.g. by compression in the case of a tablet . Subsequen ly, the thus obtained mixed and wet granulated intermediate pharmaceutical dosage forms are subjec ed to physical drying, usually by heating and/or by evaporation, in order to remove excess water from the intermediate as well as from the final dosage form.

Subsequently the dried and tableted dosage form is put into primary packages such as blisters or the like . These steps are time-consuming and cost- intensive .

It is therefore an object of the present inven ion to provide a process for preparing a pharmaceutical dosage form or food product, which is faster and more economical in that it requires (a) neither physical drying nor compressing steps to bring the dosage form into the desired form and (b) further allows controlling both drying time and drying rate . The control of the drying time and the drying rate ( = reaction rate) of a pharmaceutical dosage form is important for

industrial application in order to assure that the dosage form is pourable or kneadable during the entire dosing of the single dosage forms into moulds or packaging. The chemical drying reaction has to be delayed until the dosing step has been completed. In a subsequent step, the single dosage forms are then allowed to chemically dry in situ without any further external influence .

SUMMARY OF THE INVENTION

Accordingly, the present invention provides in a first aspect a process for preparing a pharmaceutical dosage form

comprising the steps of (a) preparing a pourable or kneadable mass comprising (i) at least one active pharmaceu ical ingredient , (ii) at least one pharmaceutically acceptable water- donor selected from a syrup of one or more

pharmaceutically acceptable sugar ( s ) , sugar alcohol ( s) or salt (s) , or mixtures thereof , (iii) optionally one or more pharmaceutically acceptable acid(s) , and ( iv) at least one pharmaceutically acceptable earth alkaline metal oxide selected from CaO and/or MgO as water- acceptor , (b) dosing the pourable o kneadable mass into moulds or packaging, and (c) allowing the mass to dry in situ by means of water- binding chemical reactions after completion of the dos ng step (b) .

Such a process allows the producing of dosage forms without any physical drying step such as heating and/or evaporation or the like . The process further allows adj sting the reaction time of the drying reaction depending (a) on the choice of the water-acceptor or the ratio of CaO and MgO used as water -acceptor, (b) on the choice of the water-donor and/or (c) the addition of one or more pharmaceutically acceptable acid(s) .

According to the present inven ion, the water-binding chemical reaction allowing the mass to dry in situ is conducted with at least one pharmaceutically acceptable earth alkaline metal oxide selected from CaO and/or MgO, preferably a mixture of CaO and MgO, that orms , upon being contacted with water, the solid hydroxides Ca (OH) ₂ and/or Mg (OH) ₂ · While the reaction of CaO with water to Ca (OH) ₂ is a very rapid and exothermic reaction, the reaction of MgO to Mg (OH) 2 is much slower due to the ormation of a Mg (OH) 2 protective layer on the surface of the MgO, which, as a consequence significantly prolongs the complete conversion of MgO to Mg (OH) 2■ Removal of the protective layer allowing for a complete conversion of MgO to Mg (OH) 2 ₍ can be achieved by the addition of one or more pharmaceutic l acceptable acid (s) .

The choice of water- cceptor , the ratio of CaO and MgO, as well as the choice of acid (s) used to accelerate the rate of conversion, has surprisingly been found to be a suitable means to fine tune both the drying time and drying rate . If e.g. an acid is chosen which is able to convert free water used for the preparation of the formulation, the free water is converted into tightly bound crystal water of the

respective hydrate , which accelerates the chemical drying react on and thus drying time . The water binding effect is increasing with the number of the molecules of crystalline hydrate water that are stably bound. Magnesium citrate for example is able to bind high amounts of crystal water (14 mol) and thus represents a fa orable salt to optimize the chemical drying step . It can be formed in si u by reaction of MgO and citric acid in the presence of a water donor

according to the present invention.

It has fur her been found that the choice of acid used to increase the conversion of MgO to Mg (OH) ₂ is suitable to influence the dissolution profile of the final dosage form due to the different solubility properties of the resulting salts . Magnesium citrate for exam le has surprisingly been found to exhibit a higher dissolution in water than Calcium citrate .

In a second aspect , the present invention provides a solid, non-porous pharmaceutical dosage form, which is a cas ing comprising (a) at least one ac ive pharmaceutical ingredient , (b) at least one pharmaceutically acceptable excipient selected from Ca (OH) ₂ and Mg (OH) ₂ , a hydrated metal salt of Ca and/or Mg of a pharmaceutically acceptable acid, or a mixture thereof and (c) at least one pharmaceutically acceptable excipient selected from one or more

pharmaceutically acceptable sugar ( s) , sugar alcohol { s) or salt (s) , or mixtures thereof .

The amount of water in the casting suspension is preferably in the range of 10 to 25% w/w, and more preferably in the range of 15 to 20% w/w, based on the total dosage form. The amount of free or immobile water which is contained in the final pharmaceutical dosage form after the chemical drying reaction is between 0 and 5% w/w, preferably 1 -4% , more preferably 2-3% w/w.

In further preferred embodiments, the molar ratio of the water acceptors used in the inventive formulations and the water content of the water-donor (s) is between 2 : 1 and 1:4, more preferably between 1:2 and 1:1.

A casting according to the second aspect of the invention is obtainable by a process according to the present invention, including any preferred embodiment thereof as set forth in the appending claims . In a particular embodiment of the present invention the casting is obtained by using a process according to the present invention. In this case , a casting suspension still containing unreacted CaO and/or MgO and syrup is poured or cast into appropriate cavities , such as moulds or the cavities of a blister pack and allowed to slowly dry so as to form the corresponding hydroxides and/or hydrated salts . The main part of this drying process occurs after the casting process , e.g. by standing over night . the final (dried) casting will therefore contain

at least one earth alkaline metal hydroxide selected from Ca (OH) 2 and/or Mg (OH) ₂ , and/or the hydrated earth alkaline metal salt (s) of Ca and/or Mg of a pharmaceu ically

acceptable acid which are the reaction product (s) of a chemical drying reaction as described above , wherein the drying agent is the water-acceptor selected from at least one pharmaceutically acceptable earth alkaline metal oxide selected from CaO and/or MgO.

In a third aspect the present inven ion provides the use of at least one pharmaceutically acceptable water-acceptor selected from CaO and/or MgO for preparing a self -drying pharmaceutical dosage form or food product , allowing

controlling both the drying time and drying rate by varying the type and amount the of water-acceptor, the ratio of CaO and MgO and the acid used to accelerate the conversion of MgO to Mg (OH} 2. Preferably, the present invention provides the use of at least one pharmaceutically acceptable water- acceptor, more preferably a mixture of CaO and MgO, and one or more pharmaceutically acceptable waterdonor selected from a syrup of one or more pharmaceutically acceptable sugar (s) , sugar alcohol (s) or salt (s ) , or mixtures thereof , and optionally one or more pharmaceutically acceptable acid ( s) for preparing a self -drying dosage form, which can be a pharmaceutical dosage form or a food product . The dosage form can be a casting as described herein.

DETAILED DESCRIPTION OF THE INVENTION

A) Definitions

The present inven ion is directed to a process for preparing a pharmaceutical dosage form, which does not require and preferably does not involve any physical drying ste .

Instead, the drying is conducted in situ, i.e. the dosage for dries by itself , by means of a water-binding chemical reaction ("chemical drying" ) . In other words , all or at least a substan ial part (preferably at least 75 wt.%, more preferably at least 85% , even more pre erably at least 95 wt.%) of the water contained in the water-donor reacts with the water- acceptor to form either a hydroxide or a hydrate of the water- acceptor . In contrast, by "physical drying" in the sense of this description a process is meant wherein excess liquid

{particularly water) contained in a pharmaceutical

composition is removed by physical means such as e.g. heating or applying reduced pressure (evaporation) , centrifugal forces or other drying technologies known to the skilled person . The present invention aims to avoid such physical drying processes .

A "pharmaceutical dosage form" according to the present invention is a dosage form for the treatment and prevention of diseases in humans or animals . The inventive

pharmaceutical dosage forms may thus be used in human and/or veterinary medicine .

A "food product" according to the present invention must be solid, edible and approvable for human and.or animal

consumption. The term food product particularly includes swee s , for example lollipops or candies . Food products are distinguished from pharmaceu ical dosage forms in that, they do not contain an active pharmaceutical ingredient ' drug) . They can be prepared by the same inven ive processes as pharmaceutical dosage forms, except that the active

pharmaceutical ingredient is omitted. Any references to pharmaceutical dosage forms in this application can therefore be readily transferred to food products , if only the active pharmaceutical ingredient is omitted. For example, the present invention also includes in one of its aspects a process for preparing a pharmaceutical dosage form comprising the steps of

a. preparing a pourable or kneadable mass comprising (i) at least one pharmaceutically acceptable water-donor selected from a syrup of one or more pharmaceutically acceptable sugar ( s) , sugar alcohol (s) or salt (s) , or mixtures thereof , , (ii) optionally further pharmaceutically acceptable excipients, and (iii)at least one

pharmaceutically acceptable earth alkaline metal oxide selected from CaO and/or MgO as water-acceptor to form said pourable or kneadable mass,

b. dosing the pourable or kneadable mass into moulds or

packaging, and

c. allowing the mass to dry in situ by means of water-binding chemical reactions after completion of the dosing step b .

The present invention also includes food products having the same composition as described in appending claims 11 - 15 , except that they do not contain an active pharmaceutical ingredient .

The term "dosage form" as used herein is supposed to embrace both pharmaceutical dosage forms and food products that prepared according to the present inventio .

A "water-binding chemical reaction" within the meaning of the invention is a chemical drying process wherein one or several pharmaceutically acceptable excipients acting as water- acceptors chemically react with and bind water . Preferably, this process takes place in situ and at room temperature when the water-binding drying agent is contacted with the water- donor .

A "chemical reaction" as used herein includes the formation of a (normally stable, crystalline) hydrate of a previously anhydrous or less strongly hydra ed form of a chemical substance .

The term "pharmaceutically acceptable" , as used herein, has the ordinary meaning and particularly includes the aspects that the excipient should be suff ciently acceptable in taste , stable under the conditions in which the use of the dosage form is intended and not cause undesirable adverse effects . Preferably, the excipient should be one that has been approved for pharmaceutical uses . The expression

"pharmaceutically acceptable" in the context of an excipient characterizes a property of the excipient (i.e. the excipient must be suitable for pharmaceutical uses) , but should not be misunderstood as actually requiring such a pharmaceutical use in each and every case . For example, a pharmaceutically acceptable excipient may also be used in the preparation of a food product , such as a candy .

The "pharmaceutical acceptable a id" according to the present invention is an acid which has been approved for

pharmaceutical use and which is preferably a water- free, to avoid undesired prolongation of the chemical drying reaction. In a preferred embodiment the "pharmaceutical acceptable acid" is an organic acid, more preferably a fruit acid and in the most preferred embodiment citric acid . The process according to the present invention as well as the casting obtained by the process of the present invention may also contain more than one "pharmaceutical acceptable acid".

The "water-donor" according to the present invention is a syrup of a pharmaceutically acceptable excipient . A syrup according to the present invention is a highly concentrated aqueous solution, which is both still fluid and contains relatively little water, and is highly water-soluble . The use of syrup is superior over the use of pure water, which does not allow controlling the drying time and affords a longer drying time . The excipient used to form the water-donor is a pharmaceutically acceptable sugar , sugar alcohol , salt or a mixture thereof. Useful examples of suitable excipients are sorbitol , saccharose , fructose , xylitol , glucose , fructose or mixtures thereof . Sorbitol and saccharose or a mixture thereof is particularly pre erred.

The "control of drying rate and drying time" according to the present invention describes the possibility to fine tune the reaction time of the chemical in situ drying reaction by varying several parameters , ( 1 ) the choice of water- acceptor, i.e. either CaO or MgO or a mixture thereof , (2) the ratio of CaO and MgO if used in a mixture , (3 ) the type and amount of one or more pharmaceutically acceptable acid, and (4 ) the type and amount of the syru . In the presence of water CaO and MgO are converted to Ca (OH) ₂ and Mg{OH)₂, respectively. While CaO reacts to Ca (OH) ₂ in a fast and exothermic

reaction, MgO reacts muc more slowly due to the forma ion of a protective layer on the MgO surface . The mixture and choice of ratio of CaO and MgO as water-acce tor thus allows controlling the drying time and drying rate . The drying time and drying rate is further influenced by the addition of an acid, which is able to destroy the Mg (OH) 2 protective layer, which has been formed on the surface of MgO, slowing down the reaction time. The amount of added acid and the choice of acid represent a further tool to control the drying rate and drying time .

"Highly soluble" within the meaning of the present invention refers to a water solubility of at least 400 g per litre of water at 20°C.

A "casting", as used herein, is a moulded, solid

pharmaceut ical dosage form obtained by filling a pourable or kneadable wet mass into a suitable mould, e.g. the cavities of a blister pack, and allowing it to dry . This filling process can be carried out by using appropriate dose

dispensers .

The casting according to the present invention is non-porous . i.e. is substantially free of any void spaces and has a homogenous structure when observed by a microscope, in contrast to common tablets or granulates where particular structures can still be observed. The casting according to the present invention is generally prepared by a casting process wherein the homogeneous liquid or kneadable masses as described above are dispensed into moulds or blister packs , followed by chemical drying in situ .

Porosi y can be measured by several methods known in the art . In principle porosity can either be measured by determining the pore volume by using e.g. mercury intrusion porosimetry or fluid saturation methods or by determining the grain volume e.g. by gas expansion methods (Boyle's law porosimeter) . By "non-porous", a porosity of less than 5%, preferably 3% or less, more preferably 1% or less, still more preferably 0.5% or less , and most preferably 0% is meant, as measured by mercury porosimetry.

The "water-acceptor", "drying agent" or "hydraulic binding agent", which terms can be used interchangeably in the context of this invention is at least one pharmaceutically acceptable earth alkaline metal oxides selected from CaO and/or MgO that is able to chemically bind water and to thus allow for the in situ drying of the freshly prepared casting . In a preferred embodiment a mixture of CaO and MgO is used as water -accepto . The water-acceptor should be used in the process according to the present invention in an amount that is sufficient to bind at least 90 wt . - % , more preferably at least 95 wt . -%, and most preferably at least 98 wt . - % of the free water contained in the dosage form . Other earth alkaline metals such as Sr might be used for special applications , but only in limited and non- toxic amounts. They are generally less suitable for the purposes of the present invention .

By "free water" the water is meant that can be readily

removed by physical drying, e.g. by heating the

pharmaceutical dosage form at 50 °C until its weight remains constant. Crystal water (hydrate water) is not "free water" within the meaning of the present invention, but is "bound water" and therefore remains in the pharmaceutical dosage form also after the chemical drying in situ of the dosage form. "Bound water" also includes molecularly bound water: for example, Magnesium hydroxide (Mg (OH) 25 contains one molecule of molecularly bound water . Bound water cannot be removed under ordinary physical drying conditions such as by heating at 50°C . The term "at least one" as used in this application includes one, two, three , four and more, preferably one or two . For example, one or two excipients are used to form the water- donor and/or the water-acceptor. Even more preferably, just one sugar, sugar alcohol or salt is combined wi h water to form a homogenous syrup {water-donor) . The water-acceptor is CaO, MgO, or a mixture of these species .

The term "comprising" is used herein in its ordina y sense, and includes , as a special case, "consisting of". For instance , the process according to the invention may

prefe bly consist of the steps a, b and c as recited in claim 1, and the pourable or kneadable mass used therein may preferably consist only of the components (i) - ( iv) as recited in claim 1. Likewise , the casting according to the present invention may just consist of the components (a) , (b) and (c) as recited in the claims , but may also contain further components, for example a further pharmaceutically acceptable excipient such as at least one flavouring or colouring agent , a sweetener , an antifoaming agent , a dispersing agent or a diluent .

B) Pre erred Aspects and Embodiments of the Invention Bl) Principles

Water-binding chemical drying reactions are known per se and have been used e.g. in the building industry for centuries : By using 1 part of slaked lime (CaO) and 4 parts of water, a solidifying mortar is mixed. The corresponding hydroxides are thereby formed . They gradually convert into the respective carbonates under uptake of C0₂ from the air .

In the building industry, reagents such as CaO that readily bind water are commonly referred to as hydraulic binding agents . In one of its aspects the present invention provides the use of at least one pharmaceutically acceptable hydraulic binding agents for preparing a self-drying pharmaceutical dosage form or food product selected from CaO and/or MgO, and preferably a mixture of CaO and MgO.

The water-binding chemical drying reaction of a water- containing pharmaceutical dosage form according to the present invention is based on the same hydraulic binding reaction: A pharmaceutically acceptable water-acceptor or a mixture of such excipients as defined above that is able to bind water is added to an aqueous pharmaceutical composition, and then the mass is allowed to dry in situ by means of water-binding chemical reactions . The further conversion of the hydroxides into the corresponding carbonates by CO2 uptake is not necessary according to this invention, but is not excluded and may be a further possible embodiment of the invention.

In a further embodiment of the present invention, the pourable or kneadable wet mass is dosed and brought into its desired shape before drying. This can easily be accomplished, for example, by casting the wet mass into suitable moulds such as the cavities (wells) of a blister packaging.

Expensive tablet compression and melt-extrusion granulation as well as drying steps can thus be avoided and the entire manufacturing process be simplified.

In further embodiment the drying time and drying rate of the single dosage form is such that the chemical drying starts only after completion of the dosing step, allowing to use the advantage process of the present inven ion in an industrial scale , affording dosing times of 10 hours and more . The drying time and drying rate can be controlled and optimized by varying the water-acceptor, i.e. either using CaO, MgO or a mixture of these two, and by opt onally adding an acid, which depending on the kind of acid and amount added can further influence the drying time and drying reaction. B2 ) Process Aspects - Hydration Reaction

One embodiment of the present invention is therefore a process wherein a pharmaceutical dosage form is dried in situ based on a water-binding reaction by using a pharmaceutically acceptable water-acceptor selected from at least one

pharmaceutically acceptable alkaline earth metal oxides CaO and MgO, and preferably a mixture of CaO and MgO.

The amount of pharmaceutically acceptable water-acceptor that is able to bind water is added in an amount so that most of the free water (at least 90 wt.-%, preferably at least 95 wt . - % , more preferably at least 98 w . -%) present in the formulation is absorbed and transformed into molecular water or into crystal water of the pharmaceutically acceptable alkaline earth metal hydroxides and hydrates of Ca and/or Mg . The free water present in the formulation may stem from the water-donor used for formulation as defined above or may be formed during e.g. the neutralisation of an earth alkaline oxide or hydroxide with a solid pharmaceutically acid, if such acid is also used for the formulation .

The at least one pharmaceutically acceptable alkaline earth metal oxide is CaO and/or Mg-GaO, and preferably a mixture thereof . The oxide (s) should ideally be in a state that allows them to readily react with water to form the

corresponding hydroxides and hydrates . Therefore, over-burned CaO or MgO should be avoided.

A pharmaceutically acceptable acid, in particular a water- free acid, can be used in the present invention to form the pourable or kneadable mass th t is then allowed to dry in situ. The use of such a pharmaceutically acceptable acid is particularly advantageous if MgO is used as a drying agent alone or in a mixture with CaO, since magnesium oxide forms a protecting layer of Mg (OH) ₂ upon contact with water. Using an acid helps to destroy this protecting layer and to enable the reaction of MgO with water to continue . Without the use of an acid the chemical drying reaction would take much longer.

The pharmaceutically acceptable acid is preferably water-free and can mainly be selected e.g. from citric acid, glacial acetic acid, phosphoric acid, tartaric acid, malic acid, fumaric acid, adipinic acid, ascorbinic acid and raaleic acid or mixtures thereof . In a preferred embodiment the

pharmaceutically acceptable acid is one or more water- free fruit acid, preferably anhydrous citric acid.

The amount (s) of MgO and/or CaO, water-donor as defined above and pharmaceutically acceptable acid or mixture of

pharmaceutically acceptable acids, are preferably adjusted so that a substantial portion (e.g. at least 90 wt . - % ,

preferably at least 95 wt . -%, most preferably at least 98 wt . - % of the water used or formulation and the water formed by the neutralisation of the oxide is absorbed and

transformed into molecular water or into crystal water of a pharmaceutically acceptable alkaline earth metal salt of Ca and/or Mg .

The hydrated product obtained from the drying reaction is C (OH) 2 and/or Mg(OH)₂ or a hydrated alkaline earth metal salt of Ca and/or Mg of a pharmaceutically acceptable acid.

The self -drying reaction using e.g. MgO as the excipient in the presence of water- free citric acid may be represented as follows :

MgO + H₂0 - Mg (OH) ₂

3 Mg(OH)₂ + 2 (C₆Hg0₇) + 8 H₂0 → Mg₃(C_sH₅0₇)₂ ^" 14 H₂0*

H₂0*= crystal water

Therefore, if it is desired to convert the entire magnesium oxide into magnesium citrate 14 -hydrate, the molar ratio of MgO and citric acid used should be 3:2. In most cases, however, it will not be necessary to convert the entire MgO to g citrate and it will be acceptable that the final formulation still contains some unreacted earth alkaline me al hydroxide . Therefore, higher molar ratios of MgO and citric acid than 3:2 may also be used, such as e.g. 4:2 or 3:1.

It is also possible to add an alkaline metal carbonate or an earth alkaline metal carbonate to the formulations of the present invention, but these carbonates do not act as water- accepting agents, but as disintegration enhancers in the acidic stomach j uices .

B3 ) Process Aspects - Forming solid dosage forms

Conventional methods for the preparation of tablets or granules usually requi e a compressing or extrusion step after formulation in order to obtain the final dosage form. The inventor considered that, it would be advantageous to be able to dispense with this step without compromising the quality of the obtained dosage forms . It is therefore a further object of the present invention to avoid such a compressing or extrusion step and to instead prepare a pourable or kneadable mass comprising at least one

pharmaceutically acceptable water-acceptor selected from CaO and/ or MgO, and pre erably a mixture of CaO and MgO, in an amount that is sufficient to bind at least 90 wt . % of the free water contained in the pourable or kneadable dosage form. This mass can then be directly dosed into moulds or packagings and is then allowed to dry in situ using the hydration reaction aspects described above .

A pourable or kneadable mass of the self-drying dosage form according to the present invention contains a syrup of one or more pharmaceutically acceptable water-donor (s) , selected from sugars, sugar alcohols or salts , or mixtures thereof . The sugars , sugar alcohols and salts have a water solubility of at least 50%, which means that at least 50 g of the sugar, sugar alcohols or salts or mixtures thereof are soluble in

100 mL of water.

In a preferred embodiment the water-donor as used in the present invention has a ratio of excipient to water at the processing temperature of at least 60:40, preferably from 70:30 up to 90:10, more preferably between 75 : 25 and 85 : 15 and most preferably around 80:20 (± 3 parts by weight) .

Saccharose for example forms an aqueous solution in water at 20 °C that contains 66.7 parts by weight of saccharose in 33 . 3 parts by weight of water. Sorbitol , which forms a 82:18 solution in water at 35°C and a 66.7:33.3 solution in water at 25 °C is even more preferred. Such weight ratios generally afford sufficiently viscous , but not too viscous solutions with which sufficient amounts of water can be introduced so that a pourable or kneadable wet mass can be formed that can then be illed into suitable moulds and chemically dried to obtain a solid casting within short time .

Mixtures of several sugars and/or sugar alcohols may also be used in the present invention . In a preferred embodiment, such mixtures have a higher solubility in water that either of their components alone . For example, inverted sugar syrup has a higher solubility in water that either glucose or fructose and may therefore be preferred ever at least glucose . Other useful mixtures include hydrogenated starch hydrolysates containing a mixture of sugar alcohols such as maltitol and sorbitol .

In another preferred embodiment the commercially available syrup Karion^® 70 is used, consisting of 70 g of sorbitol and 30 g of water. If Karion^® 70 is used as a wa er-donor and CaO and/or MgO as a water-acceptor, a ratio of 40-100 parts by weight of Karion^® 70 to 8-30 parts by weight of CaO and/or MgO, preferably a ratio of 60-80 parts by weight of Karion^® 70 to 15-20 parts by weight CaO and/or MgO, is particularly usef l . By using, according to a preferred inventive embodiment , a highly concentrated syrup , which is both still fluid and contains relatively little water, the time for the self - drying in situ can be fine-tuned and is thus superior over the use of pure water. The dehydrat on can thus be adjusted to the required speed of the dosing of the kneadable or pourable pharmaceu ical dosage form into the moulds or packaging. This allows for exam le to even dose bigger charges into moulds or packaging without being at the risk of an untimely and complete self-drying prior to the completion of the dosing .

The process for preparing a self -drying dosage form thus comprises the following steps of:

1. preparing a pourable or kneadable mass comprising (i) at least one pharmaceutically acceptable water- donor (s) selected from a syrup of one or more pharmaceutically acceptable sugar ( s) , sugar

alcohol ( s) or salt (s) , or mixtures thereof , (ii) at least one pharmaceutically acceptable water-acceptor selected from CaO and/or MgO, preferably a mixture thereof , and ( ii) optionally at least one

pharmaceutically acceptable acid,

2. dosing the pourable or kneadable mass into moulds or packaging without physically drying it, and

3. allowing the mass to dry in situ by means of water- binding chemical reactions .

In this process , the drying in situ mainly takes place after the completion of the dosing step (2) .

If the dosage form is for pharmaceu ical use, it will further contain at least one active pharmaceutical ingredient . It may also contain other pharmaceutically acceptable excipients , such as inert fillers, etc .

The surface of the moulds into which the pourable or

kneadable mass is dosed is optionally pre- treated with a release or antisticking agent . The release agent is

preferably a pharmaceutically acceptable oil , fat or wax . Example for release agents which may be used in the present invention are : Melissa oil , Eucalyptus oil , Miglyol^®

(caprylic/capric triglycerides = Neutralol EuAB) , castor oil, hydrated castor oil , bee wax, hard fat EuAB (adeps solidus) or mixtures thereo . In a preferred embodiment a mixture of 3 parts (by weight) of the wa -like hydrated castor oil , and 6 parts (by weight) of a spreading oils such as Miglyol^® is used as a mould release agent . The releasing agents may be liquefied prior to application by heating or by dissolving in a suitable organic solvent such as ethyl acetate .

After the pourable or kneadable mass has been dosed or dispensed into the moulds or packaging, the moulds or packagings are normally immediately closed or sealed to avoid contamination . In the case of a blister, paper or plastic foils are normally used for sealing. In the case of moisture - tight blisters an aluminium foil is used.

B4) Formulation Aspects

In a further embodiment , the present invention is directed to a solid pharmaceutical dosage form, which is a non-porous casting, comprising at least one active pharmaceutical ingredient and at least one hydrated pharmaceutically acceptable excipient . The hydrated pharmaceu ically

acceptable excipient comprises an alkaline earth metal hydroxide selected from Ca (OH) 2 and/or Mg (OH ) 2 or a hydrated alkaline earth metal salt of Ca and/or Mg of a

pharmaceutically acceptable acid . The hydrated

pharmaceutically acceptable excipient is the reaction product of water and the wate -acceptor used to form the self-drying dosage form according to the present invention.

The pharmaceutical ingredient (i) present in the

pharmaceutical dosage form according to the present invention (but not in the food product according to the present invention) may be any organic or inorganic, preferably organic active pharmaceutical ingredient (API) or a

pharmaceutically acceptable salt thereof or a mixture of several active ingredients or salts thereof . There are no particular limitations with regard to the type and amount of the active pharmaceutical ingredient (s) to be used, except of course that they should remain stable in the formulation environment according to the present inventio . Where incompatibi1ities of API and formulation excipients are observed or are to be feared, the API can be suitably pre- treated to avoid such incompatibilities , e.g. by coating .

When acidic APIs such as ibuprofen or diclofenac are used in their free acid form, the amounts of CaO and/or MgO should be adjusted accordingly, since the acid groups of such APIs will also react with the water-acceptor .

The solid self-drying pharmaceutical dosage form of the present invention may further comprise one or more additional pharmaceutically acceptable exci ients such as e.g. diluents, binding agents, absorption enhancers , buffers , acids, coatings , disintegrants (such as carbonates or hydrogen carbonates, e.g. sodium carbonate) , surfactants , moisturizing agents , structural builders (e.g. calcium phosphates or calcium sulphates) , sweeteners , and flavorings etc .

Preferably, the solid self-drying pharmaceutical dosage form of the present invention contains a pharmaceutically

acceptable acid in an amount that supports the drying reaction. Suitable amounts of acid range from 0 to 20 wt.%, preferably 0 to 15 wt . % , more preferably 0.1 to 15 wt.%, even more preferably 0.2 to 10 wt.%, still more preferably 1 to 5 wt.%, and most preferably 1.5 to 2.5 wt . ¾ based on the total weight of the dosage form . Preferred acids for such use are citric acid (preferably anhydrous citric acid) , glacial acetic acid, tartaric acid, but other pharmaceutically acceptable acids as mentioned above may also be used. In a preferred embodiment, the solid pharmaceutical dosage form of the present inven ion is for oral administration.

In a preferred embodiment, the solid non- orous

pharmaceutical dosage form of the present invention is a casting in a blister pack .

As mentioned above, the final dosage forms according to the present invention do not exhibit porous structures like they exist in conventional tablets or granulates, but have a very homogenous structure consisting of sugars or sugar alcohols and hydrated salts/hydroxides which are fused together . The castings can have a soft caramel-like to hard glassy

consistency. Unlike common tablets , they also do not

disintegrate in water, but dissolve when being sucked in the mouth, or when placed into stom ch acid within about 5-10 minutes .

Preferably, the final dosage forms according to the present invention are free from non-biodegradable polymers such as polyethylene oxides or PVP . Preferred dosage forms of the present invention do also not contain a wax or polymer matrix in which the active ingredient is embedded .

In a further preferred aspect , the present final dosage forms contain 80% or more, more preferably 90% or more, and most preferably 95% or more (based on the total weight of the final dosage form) of ( i ) sugars and/or sugar alcohols and ( ii) hydrated salts and/or hydroxides .

EXAMPLES

The invention is illustrated by the following examples , wherein all percentages are by weight unless indicated otherwise . Example Is Acetylsalicylic Acid Castings

0.1 g Poloxamer 188 , 0.4 g aspartame, and 30.0 g mannitol are homogenously suspended in 90.0 g of a 70% aqueous sorbitol syrup (Karion 70 ) while gently heated. After cooling down to room temperature, 100.0 g of acetylsalicylic acid (ASS ) are added to the obtained mixture . Subsequently, 28,5 g of finely ground CaO is added followed by the addition of 1.0 g of glacial acetic acid. Finally, 0.5 g of Melissa oil is added to and homogenously distributed w thin said mass . The homogeneous mass is dosed in single dosages having a weight of 250 mg per dosage unit and cast into the cavities of a blister packaging that has been pretreated with silicone oil as a mould- release agent . Each casting contains 100 mg of the ac ive ingredient ASS . The blister packaging is sealed with standard aluminium foil for blisters and the sealed dosage form is allowed to dry in situ by storing at room

temperature . After 2 to 3 days the castings have become solid.

Example 2 s Loperamid Castings

23.98 g of mannitol, 0.01 g of aspartame, 0.01 g of menthol , 1.0 g of sodium carbonate and 4.0 g of Loperamid-HC1 are suspended in 50.0 g of a warm, aqueous 70% sucrose syrup . Subsequently, 10.0 g CaO, 5.0 g MgO and finally 2.0 g citric acid are added to the mixture and are homogenised. Single dosages having a weight of 48 mg are dispensed into silicone oil -pretreated blister cavities using a suitable dosage device to obtain dosage forms containing 2.0 mg of the active ingredient . The further processing is as in example 1.

Example 3 : Diclofenac Castings

0.05 g Poloxamer 188 , 0.15 g aspartame, 0.2 g acesulfame and 25.6 g mannitol are homogenously suspended in 50 g of a warm solution of a 70% sorbitol syrup in water. To this suspension 10.0 g diclofenac lysinate and 2.0 g peppermint oil are added . Subsequently, 10.0 g MgO is added. Finally, 2.0 g tartaric acid is added .

After sufficient homogenisation, the mass is dispensed into blister cavities in single dosages of each 100 mg total weight by using a suitable dosage device . The obtained dosage form contains 10 mg of the active ingredient . The blister is sealed with aluminium foil and stored at room temperature , while the mass is allowed to dry in situ.

Example : Eucalyptus Oil Castings

10.0 kg of warmed and highly concentrated 70% saccharose syrup are mixed with 5.0 kg of icing sugar. Subsequently, the mass is intimately mixed with 1.5 kg of finely powdered MgO and 1.5 kg of finely powdered CaO . Afterwards, 3.0 kg of citric acid, 0.05 kg of Poloxamer 188 and 0.05 kg of

eucalyptus oil are homogenously incorporated. The single dosages of each 500 mg are filled into blister cavities using a suitable dosage device . The blister has been pretreated wi h a suitable mould release agent . After 2 - 3 days the castings have become solid and can easily be removed f om the blister packaging .

Example 5: Tadalafil Castings

0.2 g Poloxamer 188 , 0.4 g of aspartame , 13.4 g of manni ol , 4.0 g of Tadalafil , 10 g of finely ground CaO, 2.0 g of MgO and 10.0 g of co fee powder are added to 40.0 g of a 70% aqueous warm saccharose syrup until the mass is evenly coloured.

The obtained mass is cast into blister cavities in single dosages of each 0.2 g by using a suitable dosage device . Each casting contains 10 mg of Tadalafil . Example 6 : Vardenafil Castings

20.0 g of a 75% aqueous sorbitol syrup are mixed and

vigorously stirred with the following components , which are added in the indicated order : 0.1 g Sorbitan 20, 0.001 g sodium saccharine, 5.699 g mannitol , 4.2 g Vardenafil HCl , 6.0 g of finely ground MgO and in a last s ep 6.0 g of anhydrous citric acid. The obtained mass is cast in single dosages of each 0.42 g into blister cavities by using a suitable dosage device , following the procedure of Exam le 1. Each casting contains 20 mg of Vardenafil .

Claims

1. A process for preparing a pharmaceutical dosage form

comprising the steps of

a. preparing a pourable o kneadable mass comprising (i) at least one active pharmaceutical ingredient , ( x) at least one pharmaceutically acceptable water-donor selected from a syrup of one or more pharmaceutically acceptable sugar ( s ) , sugar alcohol (s) or salt (s) , or mixtures thereof , ( iii) optionally one or more

pharmaceu ically acceptable acid ! s) , and ( iv) at least one pharmaceutically acceptable earth alkaline metal oxide selected from CaO and/or MgO as water-acceptor, b. dosing the pourable or kneadable mass into moulds or packaging , and

c . allowing the mass to dry in situ by means of water- binding chemical reactions .

2. The process according to claim 1, wherein the drying in situ takes place after com le ion of the dosing step (b) .

3. The process according to claim 1 or 2 , wherein the water acceptor is a mixture of CaO and MgO .

4. The process according to any of the preceding claims,

wherein one or more pharmaceutically acid (s) is added, which is free of water.

5. The process according to claim 4, wherein the water- free acid is citric acid, glacial acetic acid, phosphoric acid, tartaric acid, malic acid, fumaric acid, adipic acid, ascorbic acid and maleic acid or mixtures thereof .

6. The process according to claim 5 , wherein the

pharmaceutically acceptable acid is citric acid .

7. The process according to any of the preceding claims , wherein the water-donor is an aqueous syrup of sorbitol and/or saccharose .

8. The process according to any of the preceding claims comprising the following steps :

a) Providing a syrup of at least one pharmaceutically acceptable sugar, sugar alcohol , salt , or a mixture thereof (water-donor) ,

b) Mixing said water-donor with at least one active pharmaceutical ingredient , one or several water- acceptor (s) selected from MgO and/or CaO, and

optionally one or more pharmaceutically acceptable acid (s) and further pharmaceutically acceptable excipients, so as to form a pourable or kneadable mass ,

c) Pouring the pourable or kneadable mass form into moulds or packaging

d) Allowing the mass to self-dry in situ.

9. The process according to claim 8, wherein an aqueous

syrup of sorbitol and/or saccharose is provided in step {a) , and mixed in step (b) with a mixture of MgO and CaO, and water-free pharmaceutically acceptable citric acid so as to form a pourable or kneadable mass .

10. The process according to claims 8 or 9, wherein the

surface of the moulds has been pre-treated with a mould release agent, preferably a pharmaceutically acceptable oil , f t or wax .

11. A solid, non-porous oral pharmaceutical dosage form, which is a casting comprising (a) at least one active pharmaceutical ingredien , (b) at least one earth alkaline metal hydroxide selected from Ca (OH) ₂ and/or Mg (OH) 2 and optionally a hydrated earth alkaline metal salt of Ca and/or Mg of a pharmaceutica11y acceptable acid, and (c) at least one highly water soluble sugar, sugar alcohol , salt or a mixture thereof .

12. The solid, non-porous pharmaceutical dosage form

according to claim 11 wherein the amount of bound water is in the range of 10-25 % by weight of the total composition and/or wherein the amount of free and immobile water is between 0 and 5% w/'w.

13. The solid, non-porous pharmaceutical dosage form

according to any of claims 11 or 12 , wherein the highly water soluble sugar or sugar alcohol have a solubility in water of at least 500 g / 1 water at 20 °C.

14. The solid, non-porous pharmaceutical dosage form

according to claim 13 , wherein the sugar or sugar alcohol is selected from sorbitol , saccharose , inverted sugar syru , fruc ose, xylitol and hydrogenated starch and glucose hydrolysates .

15. The solid, non-porous pharmaceutical dosage form

according to any of claims 11 - 14 , wherein the earth alkaline metal hydroxide or hydrated earth alkaline metal salt of a pharmaceutical y acceptable acid are selected from calcium hydroxide , magnesium hydroxide , calcium citrate , magnesium citrate, the tartrates , malonates, maleates, malates , fumarates, adipates , ascorbates of calcium and magnesium or mixtures of any of the

foregoing, preferably from a mixture of calcium

hydroxide , and magnesium citrate .