WO2023228167A2

WO2023228167A2 - Solid food or pharmaceutical formulation, methods for obtaining and drying it and its uses in pharmaceutical, nutraceutical or veterinary products

Info

Publication number: WO2023228167A2
Application number: PCT/IB2023/058726
Authority: WO
Inventors: Carlo De Angelis
Original assignee: Carlo De Angelis
Priority date: 2023-09-04
Filing date: 2023-09-04
Publication date: 2023-11-30
Also published as: WO2023228167A3

Abstract

Food or pharmaceutical formulation, solid, for oral use, comprising ademetionine or a salt thereof in an amount equal to or greater than 80% in weight, and at least one edible or pharmaceutically acceptable fatty matter, in an amount comprised between 0, 1% and 20% in weight. Said at least one fatty matter has a melting point comprised between +30°C and +65°C, and preferably between +30 °C and +60°C.

Description

SOLID FOOD OR PHARMACEUTICAL FORMULATION, METHODS FOR OBTAINING AND

DRYING IT AND ITS USES IN PHARMACEUTICAL, NUTRACEUTICAL OR VETERINARY

PRODUCTS

TECHNICAL FIELD

The invention relates to a pharmaceutical solid formulation of ademetionine and pharmaceutical, nutraceutical and veterinary products which contain it . Furthermore, the invention relates to a method for preparing said food or pharmaceutical formulation, comprising ademetionine . Finally, the invention relates to a method for drying ademetionine-based granulates . STATE OF THE ART

Ademetionine (S, S-adenosyl-L-methionine) , marketed as Samyr®, is a drug for disorders of the central nervous system and particularly depressive states; it is also used in the treatment of inflammatory diseases, e . g . , in osteoarthritis . Ademetionine is also available in nutritional supplements, both for humans and animals .

The S, S-adenosyl-L-methionine molecule is an ion characterised by strong chemical instability, only its salts with strong acids are stable . The mixed sulfate/ptoluenesulf onate salt is commercially available, in which 50-55% is ademetionine ion, while 45-50% consists of the two acids .

Ademetionine is strongly hygroscopic and deliquescent, which causes a problem in the industrial processing, which must be carried out in a highly dehumidified environment, typically with a relative humidity (RH) of less than 20%; this obviously entails additional costs . In addition, the final pharmaceutical form is not stable in ordinary packaging, e . g . , in plastic containers, but has to be stored in moisture-proof packaging, e . g . , in alu/alu blisters, which further increases the costs .

In order to improve the stability of ademetionine it is possible to use excipients : e . g . , in EP1446107 and EP2170920 inorganic dehydrants such as calcium or magnesium oxides, or salts thereof are used. In addition to these, inositol can be used, which enhances the dehydrating effect, as taught in PCT/EP2006/068533 . Among the dehydrants, magnesium oxide in particular gives the preparations an acceptable taste and it is therefore suitable for orodispersible formulations, as taught in EP2393475. In the case of film-coated tablets, stability can be improved by using special compositions of the coating film, as taught in PCT/EP2006/068533 . A coated granulate can be prepared by drying, using a fluidised bed apparatus, an aqueous solution of ademetionine in the presence of coating agents and technological excipients, as taught in EP1325740. However, the ademetionine content of products thus prepared is not more than 60% in weight .

For the capsule formulation a special material was developed suitable for containing strongly hydroscopic substances in liquid form, as described in US20170239187 . This solution seems particularly suitable for ademetionine, possibly accompanied by other active principles and excipients, including lipid substances such as soybean oil . However, the low ademetionine content and high cost of the special capsules and the associated filling process with liquid compositions are unavoidable drawbacks with this technology . An ulterior ademetionine formulation in a lipid matrix is described in Amasya et al . , Chemistry and Physic of Lipids, 237, 105086 (2021) ; it is a nanoparticle formulation which contains only 6% ademetionine aiming to improve enteric absorption . US2002164369 teaches the manufacture of a soft ademetionine capsule, in a way that counteracts its strong hygroscopicity . In addition, US '369 teaches how to dilute granulated ademetionine (ademetionine disulfate tosylate as active principle) with oily excipients in order to obtain a soft tablet containing, due to dilution, a 200 mg dosage of active principle (ademetionine expressed as ion) ; however, to obtain such a dosage, 425-440 mg of ademetionine disulfate tosylate salt are required, obtaining a soft capsule with a total weight of 1100-1300 mg.

CN 114 306 266 discloses an enteric adenine butanedisulfonate tablet film-coated twice . Said tablet is obtained by a process consisting of : a) dry granulation, b) tableting, c) drying of the tablet at +45°C, d) first wet coating of the tablet with a gastro-resistant film, e) second coating of the tablet, also wet, with a gastro-resistant film. However, the process disclosed by CN ' 266 counteracts only partially the natural hygroscopicity of the active principle, since ademetionine containing tablets are still stored in double aluminium blister .

TECHNICAL PROBLEM

As described above, there is currently a lack of a technical solution for the ademetionine formulation which allows to limit drawbacks caused by the strong acidity and hygroscopicity of ademetionine and that would also be applicable for formulations other than capsules; in particular, there is a lack of tablet formulation that is inexpensive, easy to formulate and high in ademetionine content . SUMMARY DESCRIPTION OF THE INVENTION

A first object of the present invention is to provide a food or pharmaceutical formulation, solid, for oral use, comprising ademetionine or a salt thereof which overcomes the above-mentioned drawbacks and allows to overcome the technical difficulties of preparing the common pharmaceutical forms such as tablets, capsules and orodispersible granulates, and at the same time improves ademetionine stability . This object is achieved by the defined characteristics in claim 1 .

A second object of the present invention is to propose a method for preparing an ademetionine-based food or pharmaceutical formulation which overcomes the above-mentioned drawbacks . This second object is achieved by the defined characteristics in claim 12 .

A third object of the present invention is to propose a method for drying ademetionine or salts thereof, which overcomes the above- mentioned drawbacks . This third object is achieved by the defined characteristics in claim 14 .

Subordinate claims describe preferential characteristics of the invention .

According to the present invention a solid, stable ademetionine formulation can be obtained by mixing an ademetionine salt with at least one fatty matter characterised by a low melting point, comprised between +30°C and +80 °C, preferably between +30°C and +65°C, and even more preferably between +30 °C and +60 °C . Such a formulation surprisingly overcomes the technical preparation difficulties described above of common pharmaceutical forms such as tablets, capsules and orodispersible granulates, and at the same time improves conservation stability of ademetionine . In addition, the formulation of the invention presents the additional advantage of being low in hygroscopicity and non deliquescent .

DETAILED DESCRIPTION OF THE INVENTION

The present invention resolves problems related to ademetionine stability, allowing it to be formulated both in capsules and tablets and other pharmaceutical forms without any particular protection . In addition, it also resolves the problem of ademetionine' s hygroscopicity and allows subsequent processing even in non-dehumidif led environments . Furthermore, the obtained preparation can be stored for a long time in simple plastic containers, thus reducing the cost of the final formulation . In addition, the preparation contains few excipients, it doesn' t contain dehydrants, it has a high content of ademetionine and allows therefore, the preparation of relatively small tablets using the same dose .

In its preferred embodiment, the invention consists of a food or pharmaceutical formulation, solid, for oral use, having:

- a high content of active principle (ademetionine) , of at least 80% of total weight; and - a low content of fat, included within a range of about 0, 1% and 20% of total weight .

Advantageously, the formulation can also include other components such as phospholipids, surfactants, lubricants, sweeteners, flavourings and other pharmaceutically acceptable excipients .

In a preferred embodiment, the formulation comes in a solid form as a granulate; in a particularly preferred embodiment, said granulate is characterised by a moisture content of less than 5, 0% . In a possible embodiment, said granulate is dosed in a stick-pack packaging, or in capsules . In a further embodiment of the invention, said granulate is used for the preparation of tablets, either simple or coated. Coating is optional, e . g. , it can be aimed to improve taste or facilitate the swallowing of the tablet, and it can be accomplished with a thin film layer . Eventually, said coating can impart particular delivery properties of the active principle to the tablet, e . g . , a gradual, delayed or colon-specific delivery .

In further embodiments, said granulate can contain other active principles : e . g. , omega-3/6/9 fatty acids, fat-soluble vitamins such as vitamine A, vitamine E, ascorbyl-palmitate, carotenes, or other plant extracts, and in particular : chamomile, hawthorn, valerian, St John' s wort, tea .

In a possible embodiment, the invention consists of a method for obtaining a stable ademetionine formulation and a low melting point fatty matter . In a further aspect, the invention consists of a method for drying ademetionine . In a further aspect, the invention consists of a method for obtaining a non hygroscopic ademetionine preparation .

The method of the invention for obtaining a stable ademetionine formulation and a low melting point fatty matter comprises : a) dosing a low melting point fatty matter and heating it until melting; b) dosing other possible components and/or excipients; c) dissolving the dosed components and/or excipients of article b) in the melted fatty matter of article a) , by further heating, if necessary, until the mixture is fully melted; d) dosing ademetionine or a salt thereof; e) mixing ademetionine in the melted mixture obtained in article c) ; f ) keep stirring for a sufficient time to homogenise the mixture; g) optionally, cooling the formulation below melting temperature; h) optionally, granulating and sieving the obtained formulation in order to ensure homogeneity of particle size .

The steps described above can also be performed in a different order, as long as the formulation components homogenisation is carried out completely, before moving on to the granulation step; mixing, heating and cooling times can vary according to the equipment used and the working scale .

Preferably, for better drying of the granules, steps f) and g) listed above are carried out under vacuum.

In further embodiments, the above-described method can be advantageously applied to other active principles, in particular to strongly hygroscopic active principles such as choline and salts thereof, chondroitin sulfate, carnitine and salts thereof, arginine and esters and salts thereof .

The following examples illustrate the invention in more detail . DEFINITIONS

By low melting point fatty matter, it is meant a fat or fat mixture approved for food or pharmaceutical use such as, for example : vegetable oil, animal or vegetable butter, margarines or other hydrogenated fats, purified triglycerides, mono- or di-glycerides or tri-glycerides of fatty acids, polyethers such as polyethylene or polypropylene glycols and esters thereof, sugar fatty acid esters or other polyalkaloids . Preferably, said fatty matter has a melting point comprised between +30 °C and +80 °C, more preferably between +30°C and +65 °C, even more preferably between +30°C and +60°C . By pharmaceutically acceptable excipient it is meant an excipient is either edible or acceptable for preparing a pharmaceutical formulation and it is generally considered safe, non-toxic and can be administered to humans and animals . Exemplary excipients include arginine base, sodium, potassium or calcium carbonates or bicarbonates, or mixtures thereof .

By ademetionine, also abbreviated as Adm, it is meant S-adenosyl methionine and salts thereof, preferably ademetionine 1, 4-butanedisulfonate or ademetionine sulf ate/p-toluenesulf onate or ademetionine phytate . PREFERRED FORMS OF EXECUTION

Example 1 Ademetionine formulations and general method of preparation

Pure ademetionine powder ( sulfate/p-toluenesulfonate salt) was mixed with various fatty matters, obtaining the corresponding granules; the stability of the active principle was then measured from those granulates . In some cases, emulsifiers were added to improve the homogeneity of the formulations .

For each experiment, 485 g of mixed sulfate/p-toluenesulfonate salt were used with 51, 5% (w/w) of ademetionine-ion, corresponding to 250 grams of active principle, mixing this amount of ademetionine salt with the amounts indicated in Table 1 of the different fatty matter components used.

Table 1 Ademetionine formulations and low melting point fatty matters

In which: Ryoto sugar ester® P-1670 and P-1570 are mixtures of mono-, di- and tri-glycerides of fatty acids, Geleol® NMB is a glyceryl palmitostearate, Ligamed SA-l-V® is a mixture of stearic and palmitic acid. All excipients appear as low melting point waxes or solids (<75°C) . Capmul GMS 50K® is a glyceryl monostearate . The general processing method comprises : a) dosing a low melting point fatty matter and heating it until melting; b) dosing eventual excipients or additional components; c) dissolving the excipients or additional components in the melted fatty matter of article a) ; d) dosing the ademetionine salt; e) mixing the ademetionine in the melted mixture obtained in article c) ; f ) keep stirring for approximately 30 minutes; g) cooling the formulation below +30°C .

All formulations were then preferably granulated and sieved on a 500 micron steel mesh sieve .

All granulates proved to be low in hygroscopicity, flowable and easy to process; ademetionine stability, as follows, is more than satisfactory .

Example 2 Ademetionine and polyethylene glycol formulations

Further formulations of ademetionine and polyethylene glycols (PEGs ) were prepared, operating as described in example 1 but using the components shown in table 2 below .

To further improve the formulations, mixing step (f ) and cooling step (g) were carried out under vacuum for 30-60 minutes; compared to the mixture of components powder, the obtained granulates are drier .

Table 2 Ademetionine and polyethylene glycol formulations

All granulates obtained proved to be low in hygroscopicity, flowable and easy to process .

Ademetionine stability was verified in a consistent manner with experiment 4 : in all preparations, the residual ademetionine titre after 3 months is higher than 97% of the initial titre .

Example 3 Additional formulations of ademetionine

Additional formulations of ademetionine and fatty matter were prepared, operating under vacuum as described in example 2 but using the components shown in TABLE 3 below.

Table 3 Ademetionine and fatty matter formulations

In which: MCT oil (medium chain triglyceride) is a mixture of di- and tri-glycerides of medium or long chain carboxylic acids, such as preferably C6-C12, mainly coconut and palm oil .

Granulates are used for tablet formulation, possibly with citric acid added ( 10% compared to the granulate) : 3P and 3Q granulates are used to prepare 1 gram of orosoluble tablets, 30 granulate is used to prepare 1 gram of effervescent tablets . Example 4 Ademetionine stability in the formulations .

The formulations prepared according to the previous examples were placed in dark glass jars in temperature and relative humidity- controlled cabinets ( + 40 °C and 75% RH) , periodically verifying the active principle content .

Raw material stability (ademetionine sulfate/p-toluenesulfonate) is used as reference . As an ulterior reference, a commercial ademetionine preformulation stabilised with inorganic dehydrants (according to EP2170920) containing 46% (w/w) as ademetionine ion, is used.

In Table 4 , the active principle content is indicated as ademetionine ion as a percentage w/w of the total formulation (prepared by using a salt with 51, 5% titre as ademetionine ion) .

Table 4 : Ademetionine stability in the formulations

Stabilised Adm: ademetionine stabilised with inorganic desiccants .

% residue : active principle content at three months in % compared to time zero .

Results show that the formulations of experiments A, B, C, D are more stable than ademetionine sulf ate/p-toluenesulf onate .

Compared to the ademetionine preformulation with inorganic desiccants used as reference, the stability of formulations A, B and D is similar or better . In addition, for B, C, and D the active principle content (at time zero) is higher compared to that of the reference .

Mixing with a low melting point fatty matter yielded stable and easily usable ademetionine formulations, without the need for additional excipients .

Example 5 Hygroscopicity and ademetionine stability

Hygroscopicity of some of the obtained preparations in the previous experiments is evaluated, by observing the ability of preparations to absorb moisture from the surrounding environment; as it is known, absorption of water leads to a rapid degradation of ademetionine and thus adversely affects the shelf life of preparations . As a reference, pure ademetionine powder (sulf ate/p-toluenesulf onate salt) not subjected to granulation is used. As a reference for the capsules, capsules described in US20170239187 are prepared, Table 1, Formula C (average dose of 350 mg of active principle) .

Preparations were examined in the forms of : a) granulate as obtained in the above experiments, weight is reported in mg; b) set of 5 gelatine capsules filled with the same granulate, average weight per capsule is reported; c) set of 5 non film-coated tablets, obtained from the same granules, average weight per tablet is reported.

Samples were placed on watch glasses and stored in a thermostatic oven at +25 °C with controlled humidity at 60% RH : unlike in experiment 2, samples are not in a closed container and can absorb moisture from the environment .

All samples were examined at regular intervals by assessing visual appearance and weight; residual moisture was assessed on the granulate at the beginning of the test and on all samples at the end of the test .

Results shown in table 5 below were obtained.

Table 5 Hygroscopicity of preparations

5 KF : determination by titration according to Karl-Fisher

* : capsules prepared as described in US20170239187

Ademetionine sulf ate/p-toluenesulf onate powder ( sample 10 ) became deliquescent at 24 hours, after 4 days it acquired a dark colour .

As can be inferred from the above reported results, samples 1, 4

10 and 7 proved to be low in hygroscopicity : although they are able to absorb moisture from the environment, their weight increases only slightly compared to the non-granulated active principle (sample 10) .

Capsules and tablets prepared with granulates B, N and G are in all cases less hygroscopic than capsules and tablets prepared with the 15 active principle powder (samples 11 and 12 ) .

Determination of residual water by titration according to Karl- Fisher essentially confirms the ponderal data, samples weight increase in correspondence to a moisture increase .

Therefore, the intended purposes were achieved, namely, to make a food or pharmaceutical formulation, solid, for oral use, comprising ademetionine, capable of ensuring ademetionine stability in solid form, namely granulated, capsuled or tableted. Furthermore, a method for obtaining said ademetionine formulation in a solid form and a method for obtaining said formulation in a dried form have been provided.

Even though in the course of describing the preferred forms of execution a specific reference was also made to a single fatty matter, it should be noted that the invention also comprises the use of a matrix of different fatty matters .

The invention is not, however, limited to the preferred forms of execution described above, and other possible solutions may nevertheless fall within the scope of protection of the present invention, as defined by the appended claims .

Claims

1) Food or pharmaceutical formulation, solid, for oral use, comprising ademetionine or a salt thereof in an amount equal to or greater than 80% in weight, and at least one edible or pharmaceutically acceptable fatty matter, in an amount comprised between 0, 1% and 20% in weight, characterised in that said at least one fatty matter has a melting point comprised between +30 °C and +65 °C, and preferably between +30 °C and +60°C .

2 ) Food or pharmaceutical formulation, solid, as in claim 1, wherein ademetionine or a salt thereof is present in an amount greater than 85% in weight, and preferably greater than 90% in weight .

3) Food or pharmaceutical formulation, solid, as in claim 1 or in claim 2, wherein said at least one fatty matter is present at a maximum amount of less than 15% in weight, preferably less than 10% in weight .

4 ) Food or pharmaceutical formulation, solid, as in any of the preceding claims 1 to 3, wherein said at least one fatty matter is a mono- or di-glyceride of fatty acid or a mixture of mono-/di-glycerides of fatty acids .

5 ) Food or pharmaceutical formulation, solid, as in any of the preceding claims 1 to 3, wherein said at least one fatty matter is a polyethylene glycol or an ester thereof, preferably polyethylene glycol stearate .

6) Food or pharmaceutical formulation, solid, as in any of the preceding claims 1 to 3, wherein said at least one fatty matter is a medium or long chain fatty acid or an ester thereof, preferably MCT oil, stearic or palmitic acid, or mixtures thereof .

7 ) Food or pharmaceutical formulation, solid, as in any of the preceding claims 1 to 3, comprising additionally at least one edible or pharmaceutically acceptable excipient .

8 ) Food or pharmaceutical formulation, solid as in claim 7, wherein said excipient is selected from arginine base, sodium, potassium or calcium carbonates or bicarbonates, or mixtures thereof .

9) Food or pharmaceutical product in the form of tablet, coated tablet, capsule, gastro-resistant capsule, stick pack, containing the formulation of any of the claims 1 - 8 .

10) Food or pharmaceutical product as in claim 9 consisting of tablets not packaged in a blister pack .

11) Solid food or pharmaceutical formulation, for oral use as in claim 1, characterised in that said at least one edible or pharmaceutically acceptable fatty matter consists of a matrix of multiple edible or pharmaceutically acceptable fatty matters .

12 ) Method for preparing a food or pharmaceutical formulation based on strongly hygroscopic active principles, comprising the steps of : a) dosing at least one edible or pharmaceutically acceptable fatty matter having a melting point comprised between +30°C and +65°C, and preferably between +30°C and +60°C, and heating until melting; b) optionally, dosing other components or excipients, c) optionally, dissolving the dosed components and/or excipients of article b) in the melted fatty matter of article a) , by further heating, if necessary, until the mixture is fully melted; d) dosing ademetionine or a salt thereof; e) mixing ademetionine in the melted mixture of article a) , or in the melted mixture of article c) ; f ) keep stirring until the mixture is completely homogenised, optionally while working under vacuum, g) cooling the obtained formulation, optionally while working under vacuum; h) optionally, granulating and sieving the obtained formulation .

13) Method for preparing a food or pharmaceutical formulation as in 12, wherein said strongly hygroscopic active principles are ademetionine and salts thereof, choline and salts thereof, chondroitin sulfate, carnitine and salts thereof, arginine and esters and salts thereof . 14 ) Method for drying ademetionine or salts thereof by vacuum granulation in a mixture with at least one edible or pharmaceutically acceptable fatty matter having a melting point comprised between +30 °C and +65 °C and preferably between +30°C and +60°C .

15) Method for drying ademetionine or salts thereof as in 14 , wherein the obtained granulate has a final moisture content of less than 5, 0% .