阅读说明：本技术 用于配制油溶性物质的方法以及由其可获得的粉末 (Method for formulating oil-soluble substances and powders obtainable therefrom ) 是由 C·波佩斯库 于 2018-10-30 设计创作，主要内容包括：本发明涉及一种用于配制油性物质的新方法,以及由其可获得的粉末和固体剂型。该方法包括喷雾干燥水包油乳液的步骤,所述水包油乳液包含辛烯基琥珀酸淀粉酯和麦芽糊精。(The present invention relates to a novel process for formulating oily substances, as well as to the powders and solid dosage forms obtainable therefrom. The method comprises the step of spray drying an oil-in-water emulsion comprising starch octenyl succinate and maltodextrin.)

1. A method for preparing a powder by electrostatic spray drying of an oil-in-water emulsion, wherein the oil-in-water emulsion comprises starch octenyl succinate and maltodextrin.

2. The process according to claim 1, wherein the maltodextrin is derived from starch having at least 20% amylose, preferably from 25% to 50% amylose, further preferably from 25% to 45% amylose, further preferably from 30% to 45% amylose, further preferably from 35% to 45% amylose; expressed as dry weight relative to the total dry weight of the starch.

3. The method of any one of claims 1 and 2, wherein the maltodextrin is derived from legume starch.

4. A process according to any one of claims 1 to 3, wherein the starch octenylsuccinate is derived from a starch having more than 50% amylopectin, preferably at least 60% amylopectin, further preferably at least 80% amylopectin, further preferably at least 90% amylopectin, further preferably at least 95% amylopectin; expressed as dry weight relative to the total dry weight of the starch.

5. The process of any one of claims 1 to 4, wherein the starch octenyl succinate ester is sodium starch octenyl succinate.

6. The process according to any one of claims 1 to 5, wherein the starch octenylsuccinate has a Hydrophilic Lipophilic Balance (HLB) selected in the range from 8 to 16, preferably at least 10, further preferably selected in the range from 12 to 16, further preferably selected in the range from 14 to 16, for example equal to 15.

7. The process of any one of claims 1 to 6, wherein the oil-in-water emulsion exhibits a weight ratio of octenyl succinate starch ester to maltodextrin selected in the range of from 1:1 to 1:100, further preferably from 1:2 to 1:50, further preferably from 1:5 to 1:40, further preferably from 1:10 to 1:30, further preferably from 1:15 to 1: 25.

8. The process of any one of claims 1 to 7, wherein the oil-in-water emulsion has a solids content selected in the range of from 20% to 80%, further preferably from 30% to 70%, further preferably from 40% to 60%, further preferably from 50% to 55%; this percentage corresponds to the weight of solids relative to the total weight of the oil-in-water emulsion.

9. The process of any of claims 1 to 8, wherein the oil phase of the oil-in-water emulsion represents from 1% to 50%, further preferably from 5% to 40%, further preferably from 10% to 30% by weight of the total solids content of the oil-in-water emulsion.

10. The method of any of claims 1 to 9, wherein the starch-containing material of the oil-in-water emulsion comprises at least 40%, further preferably at least 50%, further preferably at least 60%, such as from 70% to 90%, preferably from 70% to 85% by weight of the total solids content of the oil-in-water emulsion.

11. A powder obtainable by the method of any one of claims 1 to 10.

12. Powder according to claim 11, wherein the powder has a bulk density selected at least 0.30g/ml, further preferably in the range from 0.30 to 0.70g/ml, further preferably from 0.40 to 0.60 g/ml.

13. Powder according to any one of claims 11 and 12, wherein the powder has a tapped density selected in the range of at least 0.30g/ml, further preferably from 0.30 to 0.70g/ml, further preferably from 0.40 to 0.60 g/ml.

14. Powder according to any one of claims 11 to 13, wherein the powder has a carr index of less than 15%, preferably selected in the range from 5 to 15%, further preferably less than 12%, further preferably less than 10%.

15. A solid dosage form comprising the powder of any one of claims 11 to 14.

16. The solid dosage form of claim 15, wherein the solid dosage form is selected from a powdered composition, a tablet, or a hard capsule.

17. The solid dosage form according to any of claims 15 and 16, wherein the solid dosage form exhibits a disintegration time of less than 90 seconds, further preferably less than 80 seconds, further preferably less than 70 seconds, further preferably less than 60 seconds, such as from 10 to 60 seconds.

Background

Oil soluble materials are typically delivered in the form of an oily composition embedded in a soft gelatin capsule. However, this technique has the disadvantage of being expensive, labor intensive and requires specialized equipment in order to obtain both a satisfactory formulation and a satisfactory process. Moreover, these formulations have a short shelf life.

Conversely, it has a longer shelf life compared to oil due to the higher chemical and physical stability of the dry powder mixture. A good alternative would therefore be to be able to formulate the oily substance in the form of a powder (solid dispersion) composition. Furthermore, powders are an effective means for increasing the dissolution rate of hydrophobic drugs and thus their bioavailability.

For this reason, it has recently been proposed to use electrostatic spray drying techniques in order to formulate oily substances into powders. This technique has the advantage of being carried out at low temperatures, compared to classical spray drying, thereby avoiding degradation of heat-sensitive substances. Furthermore, electrostatic spray drying is run under inert gas, thus protecting the formulation from oxidation.

This is the subject of patent application WO 2016/123224, which describes a process for formulating oily substances by electrostatic spray drying. WO 2016/123224 provides a process comprising the steps of emulsifying a core material with a solution or suspension of a wall material, and then atomizing this emulsion by electrostatic spray drying, wherein the emulsion has a solids content of 15-50% by weight. The core material may be selected from, for example, carbohydrates, proteins, gums, lipids, waxes, food grade polymers, and cellulosic materials.

However, the emulsions of WO 2016/123224 still need to be improved in order to obtain powders with satisfactory properties.

Object of the Invention

It is therefore an object of the present invention to provide improved formulations of oily substances. More specifically, it is an object of the present invention to provide powders of oily substances suitable for solid dosage forms like tablets, in particular orodispersible tablets.

Disclosure of Invention

The inventors have successfully improved previous formulations by developing a new emulsion formulation particularly suitable for processing oil soluble actives by electrostatic spray drying. The formulation comprises two different starch-containing materials, the two materials being starch octenyl succinate and maltodextrin, in particular maltodextrin derived from amylose-rich starch.

The powders obtained are directly compressible and can therefore be advantageously used for the manufacture of tablets. Moreover, the powders obtained thereof exhibit excellent chemical and physical stability (oxidation, light stability, temperature, etc.).

Although patent application WO2016/123224 gives a list of potential materials in which various starch-containing materials are cited that can be used as wall materials, WO2016/123224 neither discloses nor suggests combining them. More specifically, WO2016/123224 neither discloses nor suggests the combination of an octenyl succinate starch ester with a maltodextrin, in particular an amylose-rich maltodextrin.

Without being bound by any theory, the inventors believe that the two starch-containing materials used according to the invention play a different role in oil-in-water emulsions. In contrast to octenyl succinate starch ester (acting as a surfactant), which may be at the interface between the aqueous phase and the oil phase, maltodextrin is part of the aqueous phase.

This provides advantageous properties to the obtained powder, in particular for tabletting, and more particularly for orodispersible tablets.

Brief description of the invention

The invention therefore relates firstly to a process for preparing powders by electrostatic spray drying of an oil-in-water emulsion, wherein the oil-in-water emulsion comprises starch octenyl succinate and maltodextrin. The invention further relates to a powder obtainable by the process of the invention. The invention further relates to a solid dosage form comprising the powder of the invention.

Detailed Description

A first object of the present invention is a process for the preparation of a powder by electrostatic spray drying of an oil-in-water emulsion, wherein the oil-in-water emulsion comprises starch octenyl succinate and maltodextrin.

Both starch octenyl succinate and maltodextrin useful in the present invention are starch-containing materials. The expression "starch-containing material" classically refers to a substance obtained from starch. It is to be reminded that the expression "starch" classically refers to starch isolated from any suitable plant source by any technique well known to the person skilled in the art. The isolated starch typically contains no more than 3% impurities; the percentages are expressed as dry weight of impurities relative to the total dry weight of the isolated starch. These impurities typically comprise proteins, colloidal substances and fibre residues. Suitable plant sources include, for example, legumes, cereals, and tubers.

The first starch-containing material useful in the present invention is starch octenyl succinate.

Such starch octenylsuccinates are well known to those skilled in the art. They are in particular and advantageously starch octenyl succinates of food grade. Such starch octenyl succinates are typically obtainable by esterification, e.g. from the reaction of starch-containing materials with octenyl succinic anhydride.

Preferably, the starch octenyl succinates useful in the present invention are cold water soluble. In particular, this means that the typical insoluble particle structure observed in raw starch disappears in octenyl succinate starch esters. This can be done, for example, by subjecting the starch-containing material to a so-called cooking step. This can be carried out, for example, on raw starch before the esterification step.

Preferably, the starch octenyl succinate esters useful in the present invention are further partially hydrolyzed.

Preferably, the octenyl succinate starch ester useful in the present invention is derived from a starch comprising more than 50% amylopectin, expressed as dry weight relative to the total dry weight of said starch. This amylopectin content can be classically determined by the person skilled in the art by potentiometric analysis of the iodine taken up by amylose for the formation of a complex. Preferably, the starch octenyl succinate esters useful in the present invention are derived from starches exhibiting an amylopectin content of at least 60%, further preferably at least 80%, further preferably at least 90%, further preferably at least 95%.

Preferably, the starch octenyl succinates useful in the present invention are derived from waxy starch, even more preferably from waxy corn starch.

Preferably, the starch octenyl succinate ester useful in the present invention is sodium starch octenyl succinate.

Preferably, the starch octenyl succinate esters useful in the present invention have a Hydrophilic Lipophilic Balance (HLB) as determined by the griffin method selected in the range from 8 to 16. It is preferably at least 10, further preferably chosen in the range from 12 to 16, further preferably chosen in the range from 14 to 16, for example equal to 15.

Preferably, the starch octenyl succinate esters useful in the present invention have a Brookfield viscosity selected in the range of from 50 to 300 cps; the viscosity was determined on a solution containing 24% by dry weight of the starch octenylsuccinate relative to the total weight of the solution, at 20 ℃, after 20min using a SC4-18 rotor at 60 rpm. Also preferably, this viscosity is selected in the range from 90 to 150 cps.

The starch octenyl succinate ester which can be used in the present invention may be subjected to other chemical and/or physical modifications than the preferred modification previously subjected, as long as it does not interfere with the desired characteristics, notably in terms of safety and efficacy of the final powder. However, and because it does not appear to be essential in the present invention, the starch octenyl succinate esters of the present invention are preferably not further modified.

As examples of suitable commercially available starch octenylsuccinates, mention may be made of the namesCO01 or

CO03Starch octenyl succinate sold by Roguette corporation.

A second starch-containing material useful in the present invention is maltodextrin. Maltodextrin has a Dextrose Equivalent (DE) of 1 to 20, referring to the conditioning state. Preferably, the maltodextrins useful in the present invention have a DE selected in the range from 5 to 20, preferably from 10 to 20, preferably from 15 to 20, for example equal to 17.

Maltodextrins are classically cold water soluble. They are classically obtained by enzymatic hydrolysis of starch-containing pastes. The following facts should be noted: maltodextrin is distinct from pyrodextrins (also often referred to simply as "dextrins") which are obtained by the action of heat and chemical agents on starch powders. As a result, the molecular structure of the starch-containing material is notably different with respect to the glycosidic bond character.

Preferably, the maltodextrins useful in the present invention are derived from a starch comprising at least 20% amylose, expressed as dry weight relative to the total dry weight of said starch. This amylose content can be classically determined by the person skilled in the art by potentiometric analysis of the iodine taken up by amylose for the formation of complexes. Preferably, the maltodextrins useful in the present invention are derived from starches exhibiting an amylose content selected in the range from 25% to 50%, preferably from 25% to 45%, further preferably from 30% to 45%, further preferably from 35% to 45%.

Preferably, the maltodextrins useful in the present invention are derived from legume starch, also preferably pea starch, also preferably rounded pea starch.

Preferably, the maltodextrins useful in the present invention have a weight average molecular weight selected in the range from 5000 to 15000 daltons (Da), preferably from 10000 to 15000 Da, further preferably from 10000 to 14000 Da, for example equal to 12000 Da. This weight average molecular weight can be determined in particular by the person skilled in the art by liquid chromatography (detection by means of a differential refractometer), preferably by using pullulan standards.

The maltodextrins useful in the present invention may be subjected to other chemical and/or physical modifications than the preferred modification previously subjected, provided that it does not interfere with the desired characteristics, notably in terms of safety and efficacy of the final powder. However, and because it does not appear to be essential in the present invention, the maltodextrins useful in the present invention are preferably not further modified.

As examples of suitable commercially available maltodextrins, mention may be made ofMaltodextrin sold by Linecaps (luggate corporation).

Preferably, the weight ratio of octenyl succinate starch ester to maltodextrin of the oil-in-water emulsion of the present invention is selected in the range of from 1:1 to 1:100, further preferably from 1:2 to 1:50, further preferably from 1:5 to 1:40, further preferably from 1:10 to 1:30, further preferably from 1:15 to 1: 25.

The oil phase of the oil-in-water emulsion of the present invention is comprised of oil, wherein oil soluble substances can be further solubilized.

Examples of oils useful in the present invention are animal or vegetable oils such as castor oil, soybean oil, palm oil, coconut oil, corn oil, cottonseed oil, olive oil, rapeseed oil, safflower oil, sesame oil, palm kernel oil, sunflower oil, peanut oil, and combinations thereof. Preferably, the oil useful in the present invention comprises (or is) corn oil.

The expression "oil-soluble substances" classically covers substances which are very readily soluble to slightly soluble in oil at room temperature (20 ℃). This typically means that 1 to 100ml of oil is needed in order to dissolve 1g of the substance (International pharmacopoeia 2017, "General rules", "Solubility" (International pharmacopoeia 2017, "General notes", "Solubility")). Preferably, the oil-soluble materials of the present invention are highly soluble, readily soluble or soluble in oil. That is to say 1 to 30ml of oil are required in order to dissolve 1g of the substance.

Preferably, the oil phase comprises an active substance. The active substance may be the oil itself and/or an oil soluble substance contained therein. The expression "active substance" classically means a substance having a food, pharmaceutical, veterinary, nutritional, or cosmetic value (interest). Other examples of active substances are substances of chemical or agricultural value. Preferably, the active substances useful in the present invention are pharmaceutical, veterinary, nutraceutical, food or cosmetic active substances, in particular intended for oral administration. Suitable active substances may be selected, for example, from among: phenolic compounds, extracts from plants, animals or microorganisms like essential oils, antineoplastic agents, benzylphenylurea compounds, steroids, antiviral agents, antifungal agents, antitubercular agents, and anti-inflammatory agents (e.g. ibuprofen), colorants (e.g. carotenoids), vitamins (e.g. vitamin a, vitamin E, vitamin D and vitamin K) or selected from mixtures thereof. Preferably, the active substance of the present invention comprises (or is) an oil soluble vitamin, further preferably vitamin D3.

Preferably, the viscosity of the oil-in-water emulsion to be spray dried is selected in the range of from 10 to 500cps, further preferably from 50 to 200cps, further preferably from 90 to 150 cps; the viscosity is measured at room temperature (20 ℃ to 25 ℃).

Preferably, the solids content of the oil-in-water emulsions useful in the present invention is selected in the range of from 20% to 80%, further preferably from 30% to 70%, further preferably from 40% to 60%, further preferably from 50% to 55%; this percentage corresponds to the weight of solids relative to the total weight of the oil-in-water emulsion. The expression "solid" is understood to mean a substance of the oil-in-water emulsion other than an aqueous solvent, in particular other than water. These solids notably include starch-containing materials and an oil phase.

Preferably, the oil phase of the oil-in-water emulsion useful in the present invention represents from 1% to 50%, further preferably from 5% to 40%, further preferably from 10% to 30% by weight of the total solids content of the oil-in-water emulsion.

Preferably, the starch-containing material useful in the oil-in-water emulsion of the present invention comprises at least 40%, further preferably at least 50%, further preferably at least 60%, such as from 70% to 90%, preferably from 70% to 85% by weight of the total solids content of the oil-in-water emulsion.

For carrying out electrostatic spray drying, the person skilled in the art can refer to the previously mentioned patent application WO2016/123224, which describes suitable conditions for carrying out this process.

The invention further relates to a powder obtainable by the method according to the invention.

Preferably, the powder according to the invention exhibits a moisture content of less than 10.0%, still preferably less than 7.0%, still preferably less than 5.0% by weight.

Preferably, the powder according to the invention has a bulk density selected in the range of at least 0.30g/ml, further preferably from 0.30 to 0.70g/ml, further preferably from 0.40 to 0.60 g/ml. Preferably, the powder according to the invention has a tapped density selected in the range of at least 0.30g/ml, still preferably from 0.30 to 0.70g/ml, still preferably from 0.40 to 0.60 g/ml. These bulk and tapped densities may typically be determined by one skilled in the art according to the USP II method as validated at 2017 on day 10, month 1, for example according to the method described in the working examples.

Preferably, the powder according to the invention has a carr index of less than 15%, in particular selected in the range from 5% to 15%, preferably less than 12%, still preferably less than 10%. In other words, the powder according to the invention has excellent flowability. It is to be reminded that the carr index (C) is a well-known parameter in the field of powder characterization and it is calculated as follows:

Wherein

■V_BIs the volume that a given mass of powder would occupy if allowed to settle freely, an

■V_TIs the volume that the same mass of powder would occupy after "tapping".

It can also be expressed as:

wherein

■ρ_BIs the bulk density of the powder, and

■ρ_Tis the tapped density of the powder.

Preferably, the powder according to the invention has a particle size ranging from 1.0 to 2.0g/cm³Also preferably from 1.3 to 1.8g/cm³Also preferably from 1.4 to 1.7g/cm³Also preferably from 1.5 to 1.6g/cm³Selected true density within the range of (a). This true density can typically be determined by a person skilled in the art by means of a helium gravimeter at 25 ± 2 ℃, for example according to the method described in the working examples.

The emulsions and powders of the invention may comprise other ingredients than those discussed above, provided that it does not interfere with the desired characteristics of the obtained powder, in particular in terms of safety and performance. Examples of such ingredients are fillers like mannitol, dextrose, maltitol, xylitol, lubricants, surfactants, flavors, sweeteners and pigments.

The invention further relates to a solid dosage form comprising the powder of the invention, preferably intended for oral administration. Preferably, the solid dosage form is selected from a powdered composition, a tablet or a hard capsule.

In the case of a powdered composition, the latter may be packaged in any suitable packaging, such as a sachet or straw (e.g. LifeTop)^TMA straw). In the case of hard capsules, the powder is typically included in the fill material of the hard capsules. For use in tablets, the powder is typically compressed.

Preferably, the solid dosage form is a fast dissolving solid dosage form, in particular an orodispersible solid dosage form. More specifically, the solid dosage form of the invention, in particular the tablet of the invention, preferably exhibits a disintegration time of less than 90 seconds, further preferably less than 80 seconds, further preferably less than 70 seconds, further preferably less than 60 seconds, for example from 10 to 60 seconds. This Disintegration can be determined by the person skilled in the art according to the united states pharmacopoeia, see "General Methods, Disintegration <701> (General Methods, Disintegration <701 >)" as validated at 1/10 in 2017.

Preferably, the tablets of the invention have a friability of less than 0.80, still preferably less than 0.70, still preferably less than 0.60, still preferably less than 0.50. This Friability can be determined by one skilled in the art according to the U.S. pharmacopoeia, as validated at 1/10 in 2017, see "General Chapters, Tablet Friability <1216> (General Chapters; Tablet Friability <1216 >)".

The solid dosage form of the invention may comprise compounds other than the powder of the invention, as long as it does not interfere with the desired properties, notably the safety and advantageous properties aspects of the solid dosage form. Such other possible compounds are well known to those skilled in the art and are typically selected according to the solid dosage form under consideration. Examples of such other compounds are lubricants, glidants, (super) disintegrants, binders, flavours, sweeteners, and pigments.

For example, in the case of tablets, in particular fast dissolving tablets, the latter typically further comprise a lubricant, preferably magnesium stearate.

In a preferred embodiment, the solid dosage form of the invention, in particular the tablet of the invention, in particular the fast-dissolving tablet of the invention, comprises a filler, preferably selected from a binder and/or a (super) disintegrant. These binders are typically intended to provide hardness to the tablet, while (super) disintegrants typically provide fast dissolving properties. Also preferably, the filler of the present invention comprises (or is) a dual function filler, i.e. a filler with disintegrating and binding properties. Examples of bifunctional fillers particularly useful in the present invention are co-processed compounds of mannitol and starch, such as for example by name Compounds of lactose and starch sold by Flash (Rogat Corp.), or co-processed, e.g. as under the name(Rogat Corp.).

Examples of the invention

1.Preparation of the powder according to the invention

In this test, the inventors formulated the oily composition of vitamin D3 into a powder using electrostatic spray drying.

Will be at 1 million IU/g and 50cp at 22 DEG CViscosity of s (Rapid viscosity Analyzer from Perten Instruments) vitamin D3 dissolved in corn oil was used in combinationLinecaps and

CO01 in an oil-in-water emulsion. Vitamins were prepared by high speed homogenization at approximately 4500rpm (using an IKA mixer) followed by high pressure homogenization (Danfoss Corp. (Danfuss))

Stable oil-in-water emulsions of CO 01.

The formulation and characteristics of the emulsion were as follows:

the resulting emulsion was atomized into a drying chamber through an electrostatic spray nozzle at an atomizing air pressure of 25 psi. The electrostatic nozzle was charged at 20 kilovolts (kV) for starch hydration. Within the drying chamber, a drying gas (90 ℃) was delivered at 25scfm to aid in water evaporation. The drying gas applied to this technique is a mixture of air and nitrogen to control the oxygen level below 5% in order to minimize oxidation. A powder of vitamin D3 was obtained at 212,000 IU/g.

2.Characterization of the powder of the invention

The moisture content, bulk density, tapped density, compressibility and flowability of two different batches of powder obtained according to part 1 were evaluated. The primary particle size distribution (prior to agglomeration) was also evaluated.

More specifically, the primary particles were measured by a particle size analyzer (Malvern) having a zeta potentialPrimary particle size distributionAnd, andaverage particle diameter D3,2AndD4,3. By specific gravity of heliumThe instrument (AccuPyc 1330, MicroMeritics, US) measures triplicates at 25. + -. 2 ℃ CTrue density. Of the final powderBulk densityThe assay was performed in triplicate by adding an accurately weighed amount (about 4g) of powder to a 25mL graduated cylinder. The corresponding volume was measured to obtain the bulk density. Of the final powderTapped densityMeasured according to the USP II method using an automatic patting machine (tapper) (Stav 2003, Stampfvolumeter, Switzerland). Of the final powderFlowable propertyIs by calculationKarl indexAnd (4) determining.

The results obtained are presented in table 1.

Table 1:

3.compression of the powder according to the invention

The powder of the invention was then evaluated for tableting properties. For this purpose, these powders were formed into 400mg tablets with 1,000IU vitamin D3 (tablet "IN-1,000 IU" according to the invention) or with 10,000IU vitamin D3 (tablet "IN-10,000 IU" according to the invention) by means of a single punch (Korsh XP1), and the hardness, friability and disintegration were evaluated.

The formulations of these tablets were as follows:

tablet friability according to the united states pharmacopoeia, e.g. effective at 10/1/2017, see general section<1216>"measurement ofBrittleness. Disintegration according to the united states pharmacopoeia, as validated at 10 months and 1 day in 2017, see "general methods, disintegration<701>"measurement ofDisintegration property。

As a comparison, a commercial tablet of vitamin D3 at 1,000IU of vitamin D3 was also evaluated (compare "CP-commercial 1,000 IU").

The compression settings and the results obtained are presented in table 2.

Table 2:

tablet index number	IN-10,000IU	IN-1,000IU	CP-commercial 1,000IU
				Fc(KN)	11.3	9.8	N/A
Fe(N)	86	111	N/A
				Relative humidity	28％	27％	N/A
Average value of hardness	50.4	47.5	N/A
				Disintegration	56 seconds	57 seconds	1 minute and 16 seconds
Brittleness	0.49	0.69	0.82

The powder according to the invention exhibits good tabletting ability as evidenced by its ability to form tablets with good hardness. Moreover, the tablets obtained thereof disintegrate in a short period of time of less than 60 seconds, which makes them suitable for use in fast dissolving solid dosage forms, in particular for orodispersible tablets.