Method of manufacturing ace inhibitors for paediatric administration and paediatric dosage forms for ace inhibitors

Abstract

The invention provides a method of manufacture of orodispersible tablets comprising an ACE inhibitor suitable for paediatric administration, and orodispersibie tablets produced by that method.

Description

[0001] METHOD OF MANUFACTURING ACE INHIBITORS FOR PAEDIATRIC ADMINISTRATION AND PAEDIATRIC DOSAGE FORMS FOR ACE INHIBITORS

[0002] FIELD OF INVENTION

[0003] The invention relates to methods of manufacturing dosage forms of ACE inhibitors that are suitable for paediatric ad inistration, in particular orodispersible dosage forms. The invention also relates to paediatric dosage forms of ACE inhibitors.

[0004] BACKGROUND

[0005] Angiotensin-converting enzyme (ACE) inhibitors (hereinafter “ACE inhibitor” or “ACEi”) are used in the treatment of a number of diseases, notably hypertension and heart failure. ACE inhibitors are a well-established class of drugs for the adult population, but their use for paediatric patients is less well defined. As with other drugs, ACE inhibitors formulated for adults may be used off-label or differently than licensed and require manipulation to obtain a dose appropriate for a child. Techniques such as tablet splitting or preparing a suspension from a crushed tablet increase the variability in the product by inaccurate measurement, issues with stability or errors in instruction for manipulation. These are all serious issues, in addition to the practical aspects and inconvenience for patients, parents and caregivers. Other considerations for using a medicine licensed for adults for a paediatric patient are unsuitable dosage form, such as large tablets; safety and efficacy not studied in the paediatric population; excipients that are harmful for children, such as alcohol; dosages that are too high for children; unpalatability of a dosage form decreasing compliance with a dosage regime.

[0006] The WHO Model List of Essential Medicines for Children - 9!hList (2023) includes enalapril as an essential hypertensive medicine, with C09AA ACE inhibitors as therapeutic alternatives. However, the WHO also acknowledges that many medicines are not formulated for children and may be prescribed off-label or in an unlicensed manner. Indeed, the dosage forms of enalapril mentioned in the model list are those authorised for the adult patient population and are likely to require manipulation for treatment of children.There remains a need to provide formulations of ACE inhibitors that are specially designed for the paediatric patient population and methods for the manufacture of these formulations.

[0007] SUMMARY

[0008] In a first aspect, the invention provides a method of producing orodispersible tablets comprising an ACE inhibitor for paediatric use, the method comprising:

[0009] providing (i) the ACE inhibitor in crystalline, micronized form, and (ii) an excipient in particulate form, wherein the excipient has a particle size distribution D90 of 250 μm or less and comprises a sugar alcohol

[0010] dry-mixing the ACE inhibitor and the excipient in a first dry-mixing step to form a mixture: and then

[0011] further dry-mixing the mixture in a second dry-mixing step, wherein the second dry¬ mixing step involves more intensive mixing than the first dry-mixing step, the second dry¬ mixing step involving stirring the mixture using a stirrer having a rotational speed of at least 1000 rpm for at least 1 minute;

[0012] sieving the mixture;

[0013] adding a lubricant to the ACE inhibitor and the excipient at any preceding point during the method,

[0014] compressing the mixture into tablets, each of which has a maximum dimension of 5 or less,

[0015] wherein the ACE inhibitor used in the dry mixing has a particle size distribution D90 of less than 00 pm and / or a D50 of less than 30 pm.

[0016] In embodiments of the first aspect, the API has a particle size distribution D90 of from 60 to 100 μm.In embodiments of the first aspect the ACE Inhibitor has a particle size distribution of d90 up to 20 μm. In these and other embodiments, the method may comprise the step of blending the ACE inhibitor with colloidal anhydrous silica prior to the first dry mixing step.

[0017] in embodiments of the first aspect the excipient comprises mannitol.

[0018] In embodiments of the first aspect the ACE inhibitor is enalapril, preferably in the form of enalapril maleate.

[0019] In embodiments of the first aspect the lubricant is sodium stearyl fumarate.

[0020] In embodiments of the first aspect the excipient comprises mannitol, crospovidone, polyvinyl acetate, povidone, and sodium lauryl sulphate, ‘‘povidone”, where mentioned herein, refers to polyvinylpyrrolidone and is not crosslinked; “crospovidone", wherein mentioned herein, refers to crosslinked polyvinylpyrrolidone.

[0021] In embodiments of the first aspect the lubricant is added to the mixture before sieving, so that the lubricant, ACE inhibitor and the excipient are sieved together.

[0022] In embodiments of the first aspect a further aliquot of the excipient is added to the mixture and the first and second dry-mixing steps are repeated, prior to the sieving step.

[0023] In embodiments of the first aspect each tablet is compressed to a maximum dimension of from 1 mm to 3 mm, e.g. 1.5 mm to 2.5 mm. “Maximum dimension” is the largest dimension measured across the tablet.

[0024] In embodiments of the first aspect the step of compressing the mixture into tablets comprises direct compression.

[0025] In embodiments of the first aspect the first dry-mixing step comprises stirring or rotating the mixture in a blender, e.g. a V-blender,at a rotational speed of from 10 to 50 rpm.

[0026] In embodiments of the first aspect the first dry-mixing step is carried out for a duration of at least 2 minutes, preferably at least 3 minutes.In embodiments of the first aspect the second dry-mixing step comprises stirring the mixture using a stirrer, e.g. an intensifier bar, having a rotational speed of at least 1000 rpm, optionally at least 2000 rpm.

[0027] In embodiments of the first aspect the second dry-mixing step is carried out for a duration of at least 2 minutes.

[0028] In embodiments of the first aspect, the method comprises a third dry mixing step after the sieving step and after the step of adding a lubricant.

[0029] In embodiments of the first aspect the third dry-mixing step comprises stirring or rotating the mixture in a blender for at least 3 minutes at a speed of from 10 to 40 rpm and wherein a more intensive mixing at a speed of at least 2000 rpm is carried out during the final 30 seconds of the third dry-mixing step.

[0030] In embodiments of the first aspect:

[0031] the ACE inhibitor is enalapril maleate;

[0032] in addition to (i) the ACE inhibitor and (ii) the excipient, (lii) colloidal anhydrous silica in particulate form is provided; and

[0033] the method comprises

[0034] dry-mixing the enalapril maleate and the colloidal anhydrous silica thereby providing an API-glidant blend;

[0035] the first dry-mixing step comprises dry-mixing the API-glidant blend and a first aliquot of the excipient in a first dry-mixing step to form a first mixture, which undergoes the second dry-mixing step; and the method further comprises

[0036] adding a second aliquot of the excipient to the first mixture and repeating the first and second dry mixing steps, thereby providing a second mixture;

[0037] adding a third aliquot of the excipient to the second mixture and repeating the first and second dry mixing steps, thereby providing a third mixture;

[0038] adding a fourth aliquot of the excipient to the third mixture and repeating the first and second dry mixing steps, thereby providing a fourth mixture;

[0039] adding a lubricant to the fourth mixture thereby providing a fifth mixture; sieving the fifth mixture;

[0040] dry-mixing the fifth mixture after sieving in a third dry-mixing step.

[0041] In embodiments of the first aspect:the ACE inhibitor is enalapril maleate;

[0042] in addition to (i) the ACE inhibitor and (ii) the excipient, (iii) a colourant in particulate form is provided; and the method comprises

[0043] blending the colourant and a first aliquot of the excipient and sieving the resulting blend to form a first mixture;

[0044] sieving the enalapril maleate;

[0045] the first dry-mixing step comprises dry-mixing the sieved enalapril maleate, the first mixture and a second aliquot of the excipient to form a second mixture, which then undergoes the second dry-mixing step; the method further comprising

[0046] after the second dry-mixing step, adding a lubricant to the second mixture to form a third mixture;

[0047] sieving the third mixture;

[0048] dry-mixing the third mixture after sieving in a third dry-mixing step.

[0049] In a second aspect, the invention provides an oro ispersible tablet for paediatric use, wherein the tablet has a maximum dimension of 5 mm or less and

[0050] comprises:

[0051] (i) an ACE inhibitor and (ii) an excipient comprising a sugar alcohol, a polyvinylpyrrolidone polymer and a polyvinylacetate, (iii) a lubricant comprising a fatty acid fumarate salt.

[0052] In a third aspect, the invention provides an orodispersible tablet comprising an ACE inhibitor for paediatric use, wherein the tablet has a maximum dimension of 5 mm or less and is producible by a method according to claim 1.

[0053] In a fourth aspect, the invention provides a kit of parts comprising

[0054] a. a plurality of orodispersible tablets according to claim 20 or 21 or made according to the method of any or claims 1 to 19;

[0055] b. a bottle in which the plurality of orodispersible tablets is disposed, the bottle comprising a cap comprising a silica desiccant; and

[0056] c. a scoop.

[0057] BRIEF DESCRIPTION OF DRAWINGS

[0058] Figure 1 shows a coefficient plot of the relative effect of two fillers and two lubricants on tensile strength of tablets in Example 3.Figure 2 shows a coefficient plot of the effect of two fillers and two lubricants on disintegration time of tablets in Example 3.

[0059] Figure 3 shows enalapril maleate content at 6 months expressed as a percentage of the initial assay value in Example 3.

[0060] Figure 4 shows coefficient plots of the effect on formulation stability of two fillers and two lubricants in Example 3.

[0061] Figure 5 shows the syringe method in Example 7.

[0062] Figure 6 shows the disintegration time of the ODMTs in various beverages in Example 9.

[0063] Figure 7 shows an SEM of a micronized sample of enalapril maleate.

[0064] Figure 8 shows the particle size distribution of the sample shown in Figure 7.

[0065] Figure 9 shows an exemplary particle size distribution for the excipient.

[0066] Figure 10 shows the dissolution profile for 1 mg enalapril maleate ODMT in pH 6.8 phosphate buffer.

[0067] Figure 11 shows the dissolution profile for the 5 mg adult dose (comparative example). Figure 12 shows mean dissolution results for 1.0 mg enalapril maleate ODMTs, 0.25 mg enalapril maleate ODMTs and Xanef® 5 mg tablets in pH 1.2 dissolution medium. Figure 13 shows mean dissolution results for 1.0 mg enalapril maleate ODMTs, 0.25 mg enalapril maleate ODMTs and Xanef® 5 mg tablets in pH 4.5 dissolution medium. Figure 14 shows mean dissolution results for 1.0 mg enalapril maleate ODMTs, 0.25 mg enalapril maleate ODMTs and Xanef® 5 mg tablets in pH 6.8 dissolution medium. Figure 15 shows a graph of shelf life of ODMTs relative to desiccant in the packaging.

[0068] DETAILED DESCRIPTION

[0069] Definitions

[0070] “Orodispersible” means that the tablet can be dispersed in the mouth, for example when placed sublingually or in the buccal cavity. The alternative term “orally disintegrating" may be used, or “ODT” for “orally disintegrating tablet”.

[0071] “Mini-tablet” herein means a solid dosage form with a largest dimension of no greater than 5 mm, such as a diameter of 2-3 mm.

[0072] “ODMT” means orodispersible mini-tablet.

[0073] “Paediatric patient population" and “paediatric" herein refers to patients from birth to less than 18 years of age.

[0074] “ACEi" and “ACE inhibitor” means angiotensin-converting enzyme inhibitor.

[0075] “API" means active pharmaceutical ingredient, i.e. an “ACEi” and “ACE inhibitor".The terms “sugar alcohol” and “polyol” are used interchangeably.

[0076] “Dry mixing” herein means combining dry ingredients by any means, for example stirring or rotation. Dry mixing is preferably conducted in the absence of intentionally-added liquid components.

[0077] “Blending” herein means combining ingredients by any means, for example stirring or rotation, for example in the dry-mixing steps and / or sieving steps as described herein.

[0078] Unless otherwise specified, particle size distribution is measured by laser diffraction. A Malvern Mastersizer or equivalent instrumentation may be used.

[0079] Paediatric dosage form

[0080] The invention provides ACEi dosage forms that are suitable for paediatric administration. The paediatric patient population is underserved in terms of dosage forms designed specifically for this population. The orally disintegrating mini-tablets (ODMT) of the invention may allow for flexible dosing through the low dose per tablet, and age- appropriate formulation by providing a tablet form that can be easily taken by children and even administered to infants.

[0081] The orodispersible tablets have a largest dimension of up to 5 mm. The orodispersible tables may have a largest dimension of up to 3 mm, preferably about 1.5 mm to about 2.5 mm, such as about 2 mm. The orodispersible tablets may have a substantially cylindrical shape and may be biconvex. The orodispersible tablets may each have a mass of less than 10 mg, for example a tablet mass of about 3 to about 10 mg per tablet. In some embodiments, the orodispersible tablets weigh about 5 to about 8 mg per tablet.

[0082] The orodispersible tablet may have a dispersion time of less than 1 minute in water or saliva, preferably a dispersion time of less than 30 seconds in water or saliva. A method for measuring dispersion time is provided in the examples.

[0083] If required, the method of manufacture may be adapted to formulate larger and / or higher dosage orodispersible tablets, for example for use in the adult patient population. The same manufacturing method may be used, with a larger tablet press at the final stage and / or with a higher proportion of API relative to the total tablet mass.API - ACE inhibitors

[0084] In the methods and products of the invention, the APi comprises or is an ACE inhibitor. ACE inhibitors are referred to herein in by their generic drug name, such as “enalapril”, but may be present in the dosage form as a free acid or base, or a pharmaceutically acceptable salt, for example enalapril maleate.

[0085] The ACE inhibitor may be selected from the group consisting of benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, and combinations thereof. ACE inhibitors may be divided by chemical characteristics, in particular sulfhydryl-containing ACE inhibitors such as captopril; phosphorus-containing ACE inhibitors such as fosinopril; dicarboxylic acid¬ containing ACE inhibitors such as benazepril, enalapril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril.

[0086] In some embodiments, captopril, enalapril, and fosinopril may be preferred.

[0087] In some embodiments, the API comprises or is enalapril. In a preferred embodiment, the API is enalapril. In particular, enalapril maleate is the preferred salt of enalapril for use in the methods and products of the invention. Enalapril maleate is the maleate salt of enalapril, a derivative of two amino-acids, L-alanine and L-proline.

[0088] Enalapril maleate (CAS number 76095-16-4) is

[0089] (2S)-1-[(2S)-2- [(1S)~1~(Ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl]pyrrolidine-2- carboxylic acid hydrogen (Z)-butenedioate

[0090] I I H I

[0091] V, A' " «

[0092] x""" X X ’ I

[0093]

[0094] ''b

[0095] Preferably, the APS is the SSS stereoisomer of enalapril maleate:

[0096]

[0097] API - physical form

[0098] In the method of the invention, the APi is used in powder (particulate) form and has a particle size distribution D90 of less than 100 μm and / or a D50 of less than 30 μm.

[0099] The as-manufactured API may be micronized to achieve a desired particle size distribution. Micronized API, compared to standard grade (not micronized) API may provide a better content uniformity in the finished tablets.

[0100] A standard grade (not micronized) API may have a particle size distribution, determined by laser diffraction, of D10 < 15 pm, such as < 10 pm; D50 from 5 to 25 pm, such as < 15 pm; D90 less than 150 pm, such as up to 100 pm.

[0101] A micronized API may have a particle size distribution, determined by laser diffraction of D10 < 1 pm, such as from 0.5 to 0.8 pm; D50 < 3 pm, such as from 1.5 to 2.5 pm; D90 <10 pm, such as from 4 to 7 pm.

[0102] Micronisation, if required, may be carried out for example by air jet mill, such as by disk air jet mill. Other processes such as sieving may be used to reduce the particle size of the APi.

[0103] A finer particle size distribution may be used for ODMTs prepared to a lower dose.

[0104] For a dosage form of 0.25 mg API, the API used in the method of manufacture may have a d10 of from 1 to 5 pm, such as from 1.5 to 3.5 pm. The d50 may be from 3 to 15 pm, such as from 4 to 12 pm. The d90 may be from 8 to 25 pm, such as from 10 to 23 pm.An SEM of a micronized sample of enalapril maleate suitable for use in the invention is shown in Figure 7 and the particle size distribution is shown in Figure 8.

[0105] Excipients and other non-API components

[0106] In addition to the API, the orodispersible tablets of the invention comprise excipients. The excipients may include one or more selected from the group consisting of a filler, a disintegrant, a binder, a surfactant, a colourant, a flavouring agent, a lubricant, a glidant, and a flow regulator. Some excipients may function to improve the manufacturing process, whereas other excipients may improve the patient experience, for example a colourant may aid in distinguishing between different dosages, or compliance with the treatment regime, for example by decreasing dispersion time in the mouth. Some excipients may have more than one function in the orodispersible tablets and / or in their method of manufacture.

[0107] Two or more excipients may be co-processed, i.e. combined prior to blending, with the other ingredients of the dosage form, e.g. such that the co-processed excipients may be in the form of a particulate material comprising particles of the co-processed excipients, e.g. each particle may comprise each of the co-processed excipients. The components of the co-processed excipients may be combined to form the co-processed excipient by methods such as spray drying or other methods.

[0108] The excipient may comprise a polyol such as mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, erythritol, and combinations thereof. Polyols function as fillers and / or as binders in tablet dosage forms. For example, the orodispersible tablets may comprise one or both of mannitol and isomalt. In a preferred embodiment, the orodispersible tablets comprise mannitol; D-mannitol is especially preferred. The mannitol may function as a filler. Mannitol provides a pleasant mouthfeel and a slight sweet taste and is soluble in aqueous media, therefore is unlikely to leave a residue in the mouth; these characteristics make mannitol particularly suitable for orodispersible tablet dosage forms.

[0109] The excipient may comprise a disintegrant. Suitable disintegrants include crosslinked polyvinyl pyrrolidone (e.g. crospovidone), povidone, sodium starch glycolate, croscarmellose sodium, carmellose sodium, crosalginic acid, cellulose derivatives (e.g. microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose), starches, calcium silicate, and others. Insome embodiments, the disintegrant is selected from the group known as superdisintegrants, including alginic acid derivatives, croscarmellose, hydroxypropyl cellulose, and crospovidone. In a preferred embodiment, the orodispersible tablets comprise crospovidone. Crospovidone may function as a disintegrant in the orodispersible tablets of the invention.

[0110] The excipient may comprise a binder. Suitable binders may be selected from the group consisting of polyvinyl acetate, povidone, polyvinyl acetate phthalate, polyfacrylic acid), polyethylene glycol / polyethylene oxide, poloxamer, and combinations thereof. Preferred binders are polyvinyl acetate and povidone. In some embodiments, the orodispersible tablets comprise polyvinyl acetate and povidone.

[0111] The excipient may comprise a surfactant. The surfactant may be selected from the group consisting of sodium lauryl sulphate, butyric acid, stearic acid, sodium laureth sulphate, dioctyl sulphosuccinate, lecithin, and combinations thereof. In a preferred embodiment, no surfactant is intentionally added in the method of manufacturing the orodispersible tablets.

[0112] The excipient may comprise a co-processed blend of two or more of the components discussed above. In some embodiments, the excipient comprises or consists of a co¬ processed excipient having a particle size distribution of d10 from 15 to 25 pm; d50 from 50 to 80 pm; d90 from 170 to 200 pm, determined by laser diffraction. An exemplary particle size distribution for the excipient is illustrated in Figure 9.

[0113] In some embodiments, the excipient, which may be a co-processed excipient, comprises mannitol, crospovidone, poly(vinyl acetate) and povidone, and co-processed excipient may have the particle size distribution mentioned in the paragraph above. In 100 % w / w of co-processed excipient, there may be from about 80 to about 95 %, such as from 84 to 92 %, of mannitol; from about 2 to about 8 %, such as from 4 to 6 %, of crospovidone; from about 1 to about 8 %, such as 3.5 to 6 %, of polyfvinyl acetate); and from about 0.1 to about 1 %, such as 0.25 to 0.6 %, of povidone. Optionally up to 0.2 %, such as from 0.039 to 0.066 %, of sodium laurylsulphate may be included in a co-processed excipient.

[0114] The orodispersible tablets may comprise a lubricant. The lubricant may be added at a late stage in the manufacturing process, for example after addition of all aliquots of other excipient. Therefore, the excipient as used in the first and second dry-mixing steps maybe substantially free from lubricant. Hydrophilic and water-soluble lubricants such as sodium stearyl fumarate, sodium lauryl sulphate, sodium oleate and others are preferred in the invention to decrease the time for the orodis ersible tablets to disperse in the mouth. In some embodiments, the orodispersible tablets comprise sodium stearyl fumarate. Sodium steary! fumarate may function to reduce friction between the drug product and tablet punch and die surfaces during manufacture, thereby reducing ejection force and preventing sticking and picking of the orodispersible tablets. In some embodiments, the orodispersible tablets do not contain magnesium stearate, which is hydrophobic.

[0115] The orodispersible tablets may comprise a glidant (flow regulator), such as colloidal anhydrous silica. In some embodiments, the orodispersible tablets comprise colloidal anhydrous silica in combination with an API that is micronized to a very fine particle size. Use of silica, such as colloidal anhydrous silica, as a glidant may improve dispersion and homogeneity during the manufacturing process and for the finished tablets, especially when the amount of API per tablet is very low, such as in paediatric dosage forms. In some embodiments, the orodispersible tablets comprise at feast 1 mg API per tablet and colloidal anhydrous silica is not used in the manufacturing process.

[0116] The orodispersible tablets may comprise a colourant. The colourant may be added for dosage identification purposes and may not participate in the tabletting, disintegration, or bioavailability of the API. In some embodiments, the orodispersible tablets comprise iron oxide pigment yellow E 172 as a colourant. In some embodiments, the orodispersible tablets do not contain any colourant and may have a plain white appearance.

[0117] The orodispersible tablets may comprise a flavouring agent to improve payability. In some embodiments, no flavouring agent is included in the tablet composition.

[0118] In a preferred embodiment, the excipient comprises mannitol, crospovidone, polyvinyl acetate and povidone and the API is blended with colloidal anhydrous silica prior to blending with the excipient.

[0119] In a preferred embodiment, the excipient comprises mannitol, crospovidone, polyvinyl acetate and povidone and the orodispersible tablets further comprise a colourant such as an iron oxide based colourant.The excipient particles may be substantially spherical. The API particles may coat the excipient particles following the mixing and sieving steps of the manufacturing method.

[0120] In a preferred embodiment, the excipient comprises mannitol, crospovidone, polyvinyl acetate and povidone. The excipient may comprise, in % w / w, 84.0 to 92.0 % mannitol, 4.0 to 6.0 % crospovidone, 3.5 to 6.0 % poly (vinyl acetate), and 0.25 to 0.6 % povidone, up to 0.066 % (e.g. 0.039 to 0.066 %) sodium lauryl sulphate.

[0121] In a preferred embodiment, the composition is adjusted to provide each tablet with about 0.20 to about 0.30 mg, preferably about 0.25 mg, of API; about 5 to about 6 mg of co¬ processed excipient, preferably the excipient mentioned in the preceding paragraph; about 0.2 to about 0.4 mg of lubricant, preferably sodium stearyi fumarate; about 0.01 to about 0.12 mg of glidant, preferably colloidal anhydrous silica: and a total tablet mass of about 6.0 to about 6.5 mg, e.g. about 6.25 mg.

[0122] In another preferred embodiment, the composition is adjusted to provide each tablet with about 0.75 to about 1.25 g, preferably about 1.0 mg, of API; about 4 to about 6 mg, such as about 4.9 mg, of co-processed excipient, preferably the excipient mentioned in the preceding paragraph; about 0.005 to about 0.011 mg, such as about 0.0078 mg, of a particulate colourant, preferably iron oxide yellow (E172); about 0.2 to about 0.42 mg, such as about 0.31 mg, of lubricant, preferably sodium stearyi fumarate; and a total tablet mass of about 6.0 to about 6.5 mg, e.g. about 6.25 mg. In the method, the components may be added at different time points. The co-processed excipient is preferably split into two or more aliquots and added stepwise in the blending process.

[0123] Method of manufacture of orodisoersible tablets

[0124] The invention provides a method of producing orodispersible tablets comprising an ACE inhibitor for paediatric use, the method comprising:

[0125] providing (i) the ACE inhibitor in crystalline, micronized form, and (ii) an excipient in particulate form, wherein the excipient has a particle size distribution D90 of 250 μm or less and comprises a sugar alcohol;

[0126] dry-mixing the ACE inhibitor and the excipient in a first dry-mixing step to form a mixture; and then

[0127] further dry-mixing the mixture in a second dry-mixing step, wherein the second dry¬ mixing step involves more intensive mixing than the first dry-mixing step, the second dry-mixing step involving stirring the mixture using a stirrer having a rotational speed of at least 1000 rpm for at least 1 minute;

[0128] sieving the mixture;

[0129] adding a lubricant to the ACE inhibitor and the excipient at any preceding point during the method,

[0130] compressing the mixture into tablets, each of which has a maximum dimension of 5 mm or less,

[0131] wherein the ACE inhibitor used in the dry mixing has a particle size distribution D90 of less than 100 μm and / or a D50 of less than 30 μm.

[0132] The dry mixing steps may be conducted using any suitable type of blender. For example, a V-blender may be used. A V-blender comprises a V-shaped mixing cavity, which is essentially two tubes that meet at one end. The entire V-shape is rotated about a horizontal axis so that the powder mixes at the point where the blender is V-shaped and is split between the two cylinders when the blender is upended as an n-shape. The first dry-mixing step may involve this kind of rotation as its form of dry-mixing.

[0133] The blender is preferably equipped with an intensifier bar. An intensifier bar is a separate element within the cavity of the blender, that is capable of more intensive mixing than the main mixing speed (for example, the speed of rotation of the V-blender as a whole). “More intensive” in the present context indicates a greater degree of agitation within a given period of time, for example, by stirring or rotating the mixture during the second dry mixing step at a higher speed than the first dry mixing step. An intensifier bar can take any suitable shape, not limited to an oblong bar shape. For example, an intensifier bar may take the shape of an Archimedes screw, of rotating blades, of a brush-like rod, or other formats. The purpose of the intensifier bar is to improve powder mixing and to reduce the overall time taken to achieve a given level of homogeneity. The second dry mixing step may involve this kind of rotation as its form of dry mixing. The second dry mixing step may overlap with the first dry-mixing step, for example as the final portion of the first dry mixing step. In other words, the blender in which the mixture is being mixed is capable of simultaneously carrying out the first dry mixing step and the second dry mixing step, e.g. with two rotational mixing devices, a first mixing device (e.g. a V-blender) capable of rotating at a first speed (for the first dry mixing step) and a second mixing device (e.g. an intensifier bar, which may be located within the V-blender) capable of rotating at a second speed (for the second dry mixing step), with the second speed being greater than the first speed; and the first dry mixing step is carried out first in theblender, e.g. with the first mixing device, and then the second dry mixing step is carried out while the first dry mixing step is continued, e.g. with the second mixing device operating at the same time as the first mixing device. The first mixing device may be a V-blender as described herein and the mixing may be the rotation of the blender, with the speed of rotation being the speed of rotation of the V-blender. The second mixing device may, for example, be an intensifier bar, which may be located in the V-blender, as described herein.

[0134] Other types of blender suitable for the dry-mixing and blending steps include double cone mixers, ribbon blenders, planetary mixers, vertical cone mixers and others. The blending mechanism may include one or more selected from the group consisting of rotation of the entire vessel; physical agitation inside the vessel, for example with blades, paddles, ribbons, etc.; use of gas jets; fluidised bed principles. Preferably, the blender for use in the method is equipped for rotation of the entire vessel and physical agitation inside the vessel. In some embodiments, the blender for use in the method may be equipped with two or more types and / or speeds of physical agitation inside the vessel.

[0135] The final dry mixing step may be carried out in a blender with a larger internal volume than the blender used for the first mixing step. To minimise loss of API, a portion of the excipient to be added next may be used to rinse the previous blender, for example by running the blender with only the excipient.

[0136] in the method, the lubricant may be added to the mixture before the step of sieving the mixture, so that the lubricant, ACE inhibitor and the excipient are sieved together, along with the optional glidant.

[0137] In the method, prior to the sieving step, a further amount of the excipient may be added to the mixture and the first and second dry-mixing steps repeated. Adding the excipient to the API in smaller aliquots may improve blending and product homogeneity. In some embodiments, the excipient is added to the API in two or more stages, with the first and second dry mixing steps repeated after each addition of excipient. In some embodiments, the excipient is added to the API in at least three stages, preferably at least four stages, with the first and second dry mixing steps repeated after each addition of excipient. In some embodiments, the excipient is added to the API in five stages, with the first and second dry mixing steps repeated after each addition of excipient.In the method, after the sieving step, there may be a third dry mixing step. The third dry mixing step may be the same as the first dry mixing step, the same as the second dry mixing step, may comprise a repetition of the first dry mixing step followed by a repetition of the second dry mixing step, or may be different to both the first and second dry-mixing steps. Further mixing after sieving may improve product homogeneity.

[0138] The method may comprise additional sieving steps. In some embodiments, the complete blend may be sieved again after the third dry mixing step. In some embodiments, each aliquot of excipient may be sieved prior to adding to the blender. I n some embodiments, the API is sieved before adding to the blender. In some embodiments, the API is sieved together with the optional glidant before adding to the blender. Additional sieving may help to break up clumps of the powdered ingredient from bulk storage before the mixing steps, which may decrease the amount of mixing energy (time and / or speed) required.

[0139] In the method, the sieving step or steps function to break up agglomerates and to improve homogeneity, e.g. by controlling particle size passing through the sieve. Sieving in the invention is not intended to remove material from the process. Therefore, although appropriate mesh sizes are provided in this description, any appropriate sieve size to achieve deagglomeration may be used in the method.

[0140] In some embodiments, a colourant may be combined with the first aliquot of excipient prior to blending with the API or at the same time as blending with the API. The colourant may also be powdered, for example iron oxide powder such as iron oxide yellow (E171). Blending the colourant with the excipient may be carried out by manually mixing, stirring or otherwise combining these two components, or by using a blender or other machine. Blending may be carried out until a visually homogeneous mixture is achieved. The colourant may be added at a later stage; however, it is preferred to add the colourant to the first aliquot of excipient, because the relative volume of colourant is much smaller than the volume of other components, and so blending it at an early stage may facilitate more even distribution of the colourant throughout the batch.

[0141] If used in the method, the blend of colourant and excipient may be sieved prior to adding to the API. A sieve having mesh size of about 50 pm to about 150 pm, such as about 100 pm, for example, may be used.In some embodiments, the API is sieved prior to mixing with the excipient. For example, a mesh size of from about 300 pm to about 400 pm, such as about 355 pm, may be used to sieve the API.

[0142] in some embodiments, the API is mixed with colloidal anhydrous silica prior to mixing with the excipient. Colloidal anhydrous silica functions as a glidant when used in this manner and may be preferred when the API has a fine particle size distribution (e.g. micronized API) and / or when the dosage per ODMT is especially low. For example, it may be preferred to combine the API with colloidal anhydrous silica when the dosage is <: 0.5 mg per ODMT, especially when the API is micronized enalapril maleate.

[0143] In some embodiments, the ACE inhibitor has a particle size distribution of d90 up to 20 μm and wherein the method comprises the step of blending the ACE inhibitor with colloidal anhydrous silica (glidant) prior to the first dry mixing step. Preferably the ACE inhibitor that is preblended with the glidant has a d90 of up to 15 pm, such as from 3 to 10 pm; the ACEi may have a d50 of from 1 to 5 pm and a d10 of from 0.25 to 3 pm. Preferably the ACEi that is preblended with the glidant is enalapril maleate.

[0144] In some embodiments, the API has a particle size distribution D90 of from 60 to 100 μm, for example when the API is not micronized.

[0145] In some embodiments, the mixture is discharged to a storage container after the mixing and sieving steps and before the compression step. The mixture may be kept in a storage container for up to 84 days prior to compression.

[0146] In some embodiments, the step of compressing the mixture into tablets, each of which has a maximum dimension of 5 mm or less, is a direct compression process. The compressing step may suitably be carried out using by filling the final blend into a rotary tablet press hopper and compressing it into ODMTs using multi-tip round punches of up to 5 mm maximum internal dimension, such as 1.5 mm to 3 mm maximum internal dimension. The rate of tabletting may be about 150 to about 250 rpm, such as about 200 rpm.

[0147] In a first preferred embodiment, the method of the invention comprises:

[0148] providing (i) enalapril maleate in crystalline, micronized form, and (ii) an excipient in particulate form, wherein the excipient has a particle size distribution D90 of 250 μmor less and comprises a sugar alcohol, and (Hi) colloidal anhydrous silica in particulate form;

[0149] dry-mixing the enalapril maleate and the colloidal anhydrous silica thereby providing an API-glidant blend;

[0150] dry-mixing the API-glidant blend and a first aliquot of the excipient in a first dry¬ mixing step to form a first mixture; and then

[0151] further dry-mixing the first mixture in a second dry-mixing step, wherein the second dry-mixing step involves more intensive mixing than the first dry-mixing step, the second dry-mixing step involving stirring the mixture using a stirrer having a rotational speed of at least 1000 rpm for at ieast 1 minute;

[0152] adding a second aliquot of the excipient to the first mixture and repeating the first and second dry mixing steps, thereby providing a second mixture;

[0153] adding a third aliquot of the excipient to the mixture and repeating the first and second dry mixing steps, thereby providing a third mixture:

[0154] adding a fourth aliquot of the excipient to the mixture and repeating the first and second dry mixing steps, thereby providing a fourth mixture:

[0155] adding a lubricant to the fourth mixture thereby providing a fifth mixture; sieving the fifth mixture;

[0156] dry-mixing the fifth mixture after sieving in a third dry-mixing step; compressing the fifth mixture into tablets, each of which has a maximum dimension of 5 mm or less,

[0157] wherein the enalapril maleate used in the dry mixing has a particle size distribution D90 of less than 100 μm and / or a D50 of less than 30 μm.

[0158] In the first preferred embodiment, the relative amounts of API, excipient, glidant and lubricant may be fixed such that each tablet has an API amount of about 0.25 mg and a tablet mass of about 5 to about 8 mg. An overage of API of about 3 % may be included to account for product loss on mixing vessel transfer.

[0159] In the first preferred embodiment, the step of dry-mixing the enalapril maleate and the colloidal anhydrous silica thereby providing an API-glidant blend may be carried out manually or in a blender. Manual blending may be carried out by any suitable means.

[0160] In the first preferred embodiment, optionally a fifth aliquot of the excipient is added and blended prior to adding the lubricant.In the first preferred embodiment, each aliquot of excipient may be larger (greater mass) than the preceding aliquot.

[0161] In the first preferred embodiment, the first and second dry mixing steps may be altered when blending to produce the fourth mixture, by increasing the mixing time and the more intensive mixing time compared to the previous dry-mixing repetitions.

[0162] In the first preferred embodiment, the third mixture may be transferred to a larger blender, and a portion of the fourth aliquot of the excipient may be used to rinse the original blender, for example by adding the portion to the original blender and operating the blender, e.g. at low intensity.

[0163] In the first preferred embodiment, the third dry-mixing step may comprise the first drymixing step followed by a shorter duration of more intensive mixing than the second dry¬ mixing step.

[0164] In a second preferred embodiment, the method of the invention comprises:

[0165] providing (i) enalapril maleate in crystalline, micronized form, and (ii) an excipient in particulate form, wherein the excipient has a particle size distribution D90 of 250 μm or less and comprises a sugar alcohol, and (iii) a colourant in particulate form;

[0166] blending the colourant and a first aliquot of the excipient and sieving the resulting blend to form a first mixture;

[0167] sieving the enalapril maleate;

[0168] dry-mixing the sieved enalapril maleate, the first mixture and a second aliquot of the excipient in a first dry-mixing step to form a second mixture; and then

[0169] further dry-mixing the second mixture in a second dry-mixing step, wherein the second dry-mixing step involves more intensive mixing than the first dry-mixing step, the second dry-mixing step involving stirring the mixture using a stirrer having a rotational speed of at least 1000 rpm for at least 1 minute;

[0170] after the second dry-mixing step, adding a lubricant to the second mixture to form a third mixture;

[0171] sieving the third mixture;

[0172] dry-mixing the third mixture after sieving in a third dry-mixing step; compressing the third mixture into tablets, each of which has a maximum dimension of 5 mm or less,wherein the enalapril maleate used in the dry mixing has a particle size distribution D90 of less than 100 μm and / or a D50 of less than 30 μm prior to sieving.

[0173] In the second preferred embodiment, in the step of blending the colourant and a first aliquot of the excipient and sieving the resulting blend to form a first mixture. Optionally, a sieve having a mesh size of about 75 to about 125 pm may be used, such as a mesh size of about 100 pm. The aim of the sieving is to break up agglo erations and enhance homogeneity, rather than to remove any material. The blending time may be up to 10 minutes, such as from 3 to 7 minutes or about 5 minutes. Blending may be manual, for example using a plastic mortar, or automated, for example using a blender.

[0174] In the second preferred embodiment, the relative amounts of API, excipient, colourant and lubricant may be fixed such that each tablet has an API amount of about 1 mg and a tablet mass of about 5 to about 8 mg. An overage of API of about 2-3 % may be included to account for product loss on mixing vessel transfer.

[0175] In the second preferred embodiment, in the step of sieving the enaiapril maleate, a sieve having a mesh size of about 300 to about 400 pm may be used, such as a mesh size of about 355 pm.

[0176] In the second preferred embodiment, the second aliquot of excipient may be used to rinse the container of the enalapril maleate, to reduce loss of API on transfer between containers. The second aliquot of excipient may be sieved prior to the first dry-mixing step, for example by using a sieve having a mesh size of about 300 to about 400 pm may be used, such as a mesh size of about 355 pm.

[0177] In the second preferred embodiment, in the step of dry-mixing the sieved enalapril maleate, the first mixture and a second aiiquot of the excipient in a first dry-mixing step to form a second mixture, a blending time of from about 3 to about 10 minutes may be used, such as a blending time of about 5 minutes. The blending speed may be about 10 to about 50 rpm, such as from about 20 to about 30 rpm. The blending rotation may comprise rotation of the entire blending vessel, such as a V-blender.

[0178] In the second preferred embodiment, in the step of further dry-mixing the second mixture in a second dry-mixing step, wherein the second dry-mixing step involves more intensive mixing than the first dry-mixing step, the second dry-mixing step involving stirring themixture using a stirrer having a rotational speed of at least 1000 rpm for at least 1 minute, the during of more intensive mixing may be from about 1 to about 10 minutes, such as from about 1 to about 5 minutes, such as about 3 minutes. The speed of the more intensive mixing may be at least 2000 rpm, such as from about 2000 to about 5000 rpm, for example from about 3000 to about 4000 rpm. The more intensive mixing may be conducted by an intensifier bar or other internal rotational device installed inside the blender. The more intensive mixing step is preferably superimposed with the first dry¬ mixing step, preferably at the end of the first dry-mixing period. For example, the blender may be operated for a total of 5 minutes, with an intensifier bar switched on for the final 3 minutes.

[0179] In the second preferred embodiment, in the step of sieving the third mixture, a sieve having a mesh size of about 600 to about 1000 pm may be used, such as a mesh size of about 800 pm.

[0180] In the second preferred embodiment, in the step of dry-mixing the third mixture after sieving in a third dry-mixing step, a similar blender to that used for the first and second dry-mixing step may be used, of the same or larger blender volume. The third dry-mixing step may comprise rotation of the blender at a low speed, for example from 15 to 35 rpm, with a period of more intensive mixing, for example by using an intensifier bar or other internal rotation device, at a speed of about 3000 to about 4000 rpm. The total duration of the third dry-mixing step may be from about 2 to about 10 minutes, such as from about 2 to about 5 minutes, for example about 3 minutes. The more intensive mixing, if present in the third dry-mixing step, may be carried out for the final 10 seconds to 2 minutes of the duration, such as the final 20 seconds to1 minute of the duration of the third dry¬ mixing step.

[0181] In the first and second preferred embodiments, the sugar alcohol is preferably mannitol.

[0182] in the first and second preferred embodiments, the lubricant is preferably sodium stearyl fumarate.

[0183] In the first and second preferred embodiments, the excipient preferably comprises mannitol, crospovidone, polyvinyl acetate, povidone, and sodium lauryl sulphate.Orodispersible tablet

[0184] The step of making tablets preferably is a direct compression step. The orodispersible tablets are preferably “minitablets” (orodispersible minitablets or ODMTs) and have a largest dimension no greater than 5 mm. In some embodiments, each tablet is compressed to a maximum dimension of from 1 mm to 3 mm.

[0185] The ODMTs made by the method may be white if no colourant is added. The ODMTs may have another colour, such as a pale yellow, if a colourant is added, such as iron oxide yellow.

[0186] The ODMTs made by the method may be substantially cylindrical, spherical, or another appropriate shape. In some embodiments, the ODMTs have a biconvex cylindrical shape.

[0187] In an embodiment, there is provided an orodispersible tablet for paediatric use, wherein the tablet has a maximum dimension of 5 mm or less and

[0188] comprises:

[0189] (I) an ACE inhibitor and (ii) an excipient, which may be as described herein, (iii) a lubricant comprising, which may be as described herein.

[0190] In an embodiment, there is provided an orodispersible tablet for paediatric use, wherein the tablet has a maximum dimension of 5 mm or less and

[0191] comprises:

[0192] (I) an ACE inhibitor and (ii) an excipient comprising a sugar alcohol, a polyvinylpyrrolidone polymer and a polyvinylacetate, (iii) a lubricant comprising a fatty acid fumarate salt.

[0193] In an embodiment, there is provided an orodispersible tablet comprising an ACE inhibitor for paediatric use, wherein the tablet has a maximum dimension of 5 mm or less and is producible by a method described herein.

[0194] In a preferred embodiment, the tablet comprises, consists essentially of or consists of about 0.20 to about 0.30 parts by weight (pbw), preferably about 0.25 pbw, of API, preferably enalapril maleate; about 5 to about 6 pbw of so-processed excipient, preferably the excipient mentioned herein, for example as described in the paragraph below; about 0.2 to about 0.4 pbw of lubricant, preferably sodium stearyl fumarate; about0.01 to about 0.12 pbw of glidant, preferably colloidal anhydrous silica; and the total parts by weight of the tablet may be about 6.0 to about 6.5 pbw, e.g. about 6.25 pbw.

[0195] In a preferred embodiment, the tablet comprises, consists essentially of or consists of about 0.20 to about 0.30 mg, preferably about 0.25 mg, of APS, preferably enalapril maleate; about 5 to about 6 mg of co-processed excipient, preferably the excipient mentioned herein, for example as described in the paragraph below; about 0.2 to about 0.4 mg of lubricant, preferably sodium stearyl fumarate; about 0.01 to about 0.12 mg of glidant, preferably colloidal anhydrous silica; and a total tablet mass of about 6.0 to about 6.5 mg, e.g. about 6.25 mg.

[0196] In a preferred embodiment, the excipient comprises mannitol, crospovidone, polyvinyl acetate and povidone. The excipient may comprise, in % w / w, 84.0 to 92.0 % mannitol, 4.0 to 6.0 % crospovidone, 3.5 to 6.0 % poly (vinyl acetate), and 0.25 to 0.6 % povidone, up to 0.066 % (e.g. 0.039 to 0.066 %) sodium lauryl sulphate.

[0197] In a preferred embodiment, the tablet comprises, consists essentially of or consists of about 0.20 to about 0.30 mg, preferably about 0.25 mg, of enalapril maleate; about 5 to about 6 mg of co-processed excipient, comprising mannitol, crospovidone, polyvinyl acetate and povidone; about 0.2 to about 0.4 mg of sodium stearyl fumarate; about 0.01 to about 0.12 mg of colloidal anhydrous silica; and has a total tablet mass of about 6.0 to about 6.5 mg, e.g. about 6.25 mg.

[0198] In an embodiment, the tablet comprises, consists essentially of or consists of

[0199] about 0.25 mg enalapril maleate,

[0200] about 4.7250 - 5.1750 mg of mannitol (E421 ),

[0201] about 0.2250 - 0.3375 mg of crospovidone,

[0202] about 0.1969 - 0.3375 mg of poly(vinyl acetate),

[0203] about 0.0141 ~ 0.0338 mg of povidone,

[0204] about 0.00217 - 0.00371 mg of sodium lauryl sulphate,

[0205] about 0.01 to about 0.1 mg, e.g, 0.0625 mg, of colloidal anhydrous silica, and about 0.2 to about 0.4 mg, e.g. 0.3125 mg, of sodium stearyl fumarate

[0206] and the tablet's total mass may be about 6 - 6.5 mg.In a preferred embodiment, the tablet comprises, consists essentially of or consists of In another preferred embodiment, the tablet comprises, consists essentially of, or consists of about 0.75 to about 1.25 pbw, preferably about 1.0 pbw, of API, preferably enalapril maleate; about 4 to about 6 pbw, such as about 4.9 pbw, of co-processed excipient, preferably the excipient mentioned in the preceding paragraph; about 0.005 to about 0.011 pbw, such as about 0.0078 pbw, of a particulate colourant, preferably iron oxide yellow (E172); about 0.2 to about 0.42 pbw, such as about 0.31 pbw, of lubricant, preferably sodium stearyl fumarate; and the total parts by weight of the tablet may be about 6.0 to about 6.5 pbw, e.g. about 6.25 pbw. The tablet may lack a glidant, such as colloidal silica. In the method, the components may be added at different time points, as described herein. The co-processed excipient is preferably split into two or more aliquots and added stepwise in the blending process (i.e. in the dry mixing steps as described herein).

[0207] In another preferred embodiment, the tablet comprises, consists essentially of, or consists of about 0.75 to about 1.25 mg, preferably about 1.0 mg, of API, preferably enalapril maleate; about 4 to about 6 mg, such as about 4.9 mg, of co-processed excipient, preferably the excipient mentioned in the preceding paragraph; about 0.005 to about 0.011 mg, such as about 0.0078 mg, of a particulate colourant, preferably iron oxide yellow (E172); about 0.2 to about 0.42 mg, such as about 0.31 mg, of lubricant, preferably sodium stearyl fumarate; and a total tablet mass of about 6.0 to about 6.5 mg, e.g. about 6.25 mg. The tablet may lack a glidant, such as colloidal silica, in the method, the components may be added at different time points, as described herein. The co¬ processed excipient is preferably split into two or more aliquots and added stepwise in the blending process (i.e. in the dry mixing steps as described herein).

[0208] In another preferred embodiment, the tablet comprises, consists essentially of, or consists of about 0.75 to about 1.25 mg, preferably about 1.0 mg, of enalapril maleate; about 4 to about 6 mg, such as about 4.9 mg, of co-processed excipient comprising comprising mannitol, crospovidone, polyvinyl acetate and povidone; about 0.005 to about 0.011 mg, such as about 0.0078 mg, of a particulate colourant, preferably iron oxide yellow (E172); about 0.2 to about 0.42 mg, such as about 0.31 mg, of sodium stearyl fumarate; and have a total tablet mass of about 6.0 to about 6.5 mg, e.g. about 6.25 mg. In the method, the components may be added at different time points. The co-processed excipient is preferably split into two or more aliquots and added stepwise in the blending process (Le. in the dry mixing steps described herein).

[0209] In an embodiment, the tablet comprises, consists essentially of or consists of

[0210] about 1 mg of enalapril maleate,

[0211] about 4.1409 - 4.5353 mg of mannitol (E421),

[0212] about 0.1972 - 0.2958 mg of crospovidone,

[0213] about 0.1725 - 0.2958 of poly(vinyl acetate),

[0214] about 0.0123 - 0.0296 of povidone,

[0215] about 0.00190 - 0.00325 of Sodium lauryl sulphate,

[0216] about 0.005 to about 0.011 mg, such as about 0.0078 mg, of a particulate colourant, e.g. iron oxide yellow (E172), and

[0217] about 0.2 to about 0.42 mg, e.g. 0.3125 mg, of sodium stearyl fumarate,

[0218] and the tablet's total mass may be about 6 - 6.5 mg.

[0219] The tablets described herein may have been produced according to the method described herein.

[0220] Methods of administration

[0221] The ODMT disperse quickly in the mouth and may be placed on or under the tongue or in the buccal cavity, for example, where the tablet will disperse.

[0222] Where the starting dose is less than the amount in a single ODMT, a lower dose can be achieved by placing one tablet in an oral syringe, adding tap water, rolling the syringe for 3 minutes to fully disperse the tablet, and administering the required volume to the patient. Sterile water should be used in children under 6 months. After full dispersion of the orodispersible tablet in the oral syringe, the required volume should be used immediately.

[0223] Some patients may require administration via an enteral feeding tube. The ODMT of the invention rapidly disperse in tap water or sterile water (e.g. for babies under 6 months of age) and can be administered once dispersed. The dispersion can be administered through a feeding tube and then the tube flushed with at least 3 ml of water after administration of the medicine.Kit of parts

[0224] The invention also provides a kit of parts. The ODMTs according to the product of the invention and / or manufactured according to the method of the invention may be provided in a package, which may be selected from a bottle with a cap and a blister pack; and, where the package is a bottle with a cap, the kit may further comprise a scoop. The scoop allows the user to retrieve tablets from the bottle easily and with minimal handling, since the API may be sensitive to humidity and the orodispersible dosage form may be less resistant to handling than adult oral solid dosage formats. The scoop may be plastic, for example high impact polystyrene, a polyethylene, polypropylene or any suitable polymer. The scoop may be provided with a colour that contrasts with the ODMT colour, to aid in dispensing the ODMTs, which may be significantly smaller than more familiar adult oral solid dosage forms. The bottle may be plastic, for example high density polyethylene. The cap may also be plastic, for example polypropylene. The cap is preferably equipped with a child-resistant, tamper evident closure system and an integrated silica desiccant. The number of ODMTs per bottle before unsealing may be from 25 to 500, for example from 50 to 250, such as 50, 100, 200 or 250 ODMTs per bottle before unsealing.

[0225] The amount of silica desiccant per bottle cap may be at least 0.25 g, such as from 0.25 to 1.5 g, such as about 0.5 g or about 1.0 g.

[0226] The method and the tablets will now be further described in the following non-limiting Examples.EXAMPLES

[0227]

[0228] 1: il 0.25

[0229] Step 1: Micronized enalapril maleate (0.050 kg) was mixed manually with colloidal anhydrous silica (0.206 kg) for 5 minutes and then transferred to a 3.75 L blender. Evaluation of mixing was conducted by visual inspection: the target is a visually homogenous blend free of lumps.

[0230] Step 2: Pre-mixed, i.e. co-processed, excipients (Ludiflash®, BASF) (0.250 kg) were added to blender with the API and silica mixture from step 1. To avoid loss of API, a proportion of the excipient mixture was used to rinse the mixing vessel from the previous step.

[0231] Step 3: Mixing was carried out for 5 minutes at 25 rpm. After 1 minute, an intensifier bar operating at 3600 rpm was switch on for 3 minutes. Evaluation of mixing was conducted by visual inspection.

[0232] Step 4: A further 0.500 kg of the excipient mixture was added to the biender with the mixture from step 3.

[0233] Step 5: The mixing process was repeated (5 minutes at 25 rpm; after 1 minute an intensifier bar at 3600 rpm switched on for 3 minutes). Evaluation of mixing was conducted by visual inspection.

[0234] Step 6: A further 1.000 kg of the excipient mixture was added to the blender with the mixture from step 5.

[0235] Step 7: The mixing process was repeated. Evaluation of mixing was conducted by visual inspection.

[0236] Step 8: The mixture resulting from step 7 was transferred to a 15 L biender.Step 9: A further 0.500 kg of the excipient mixture was added to the previous 3.75 L blender, which was operated for 2 minutes at 25 rpm, to rinse the blender and to avoid loss of API.

[0237] Step 10: This blend from step 9 was added to the API mixture from step 8 with a further 2.244 kg of the excipient mixture in the 15 L blender.

[0238] Step 11: Mixing was carried out for 15 minutes at 25 rpm. After 1 minute, an intensifier bar operating at 3600 rpm was switched on for 5 minutes. Evaluation of mixing was conducted by visual inspection.

[0239] Step 12: The mixture resulting from step 11 was sieved with sodium stearyl fumarate (0.250 kg) using an 800 pm mesh size sieve. The sieved mixture was transferred back to the 15 L blender, ensuring no material was left on the sieve.

[0240] Step 13: The sieved mixture in the 5 L blender was mixed for 5 minutes at 25 rpm; after 2 minutes the intensifier bar operating at 3600 rpm was switched on for 30 seconds. Evaluation of mixing was conducted by visual inspection.

[0241] Step 14: The final blend resulting from step 13 was formed into tablets by rotary tablet compression using multi-tip 2 mm round punches at a machine rate of between 160 and 240 rpm. Tabletting of the final blend was performed by stepwise addition of about 1 kg until the whole amount of 5 kg was consumed. The 5 kg batch corresponds to 800,000 tablets. Tabletting efficacy was evaluated via appearance, average mass, hardness, thickness, individual mass, friability and disintegration. The tablets were white, round biconvex tablets. Acceptance criteria include an average tablet weight 5.95 to 6.56 mg, hardness < 15N (Ph. Eur. 2.9.8), thickness 1.8 to 2.2 mm, friability not more than 1.0 % (Ph. Er. 2.9.7), and a disintegration time of no more than 3 minutes in water at 37 °C (Ph. Er. 2.9.1). If required, the final blend may be stored for up to 84 days (12 weeks) prior to compression, if stored in a controlled warehouse at 15-25 °C and no more than 40% relative hu idity.

[0242] Step 15: The tablets were filled into bottles using a table counting machine and a cap applied to the bottle. Secondary packaging was then applied.An exemplary composition for use in this method is provided in the table below, if required, the ratio of enalapril maleate to total excipients may be adjusted to provide an overage of API, to account for losses when transferring between vessels in the manufacturing procedure. An overage of about 3 % enalapril maleate may be used in the method.

[0243] In the method of this example, the ingredients marked “excipient” were provided in a co¬ processed form as part of the commercial product Ludiflash® (BASF).

[0244] Ingredients Component Quantity (mg) per Function

[0245] 0.25 mg ODMT

[0246] Active Enalapril maleate 0.2500 Active Excipient Mannitol (E421) 4.7250 - 5.1750 Filler

[0247] Excipient Crospovidone 0.2250 - 0.3375 Disintegrant Excipient Poly(vinyl acetate) 0.1969 - 0.3375 Dry binder Excipient Povidone 0.0141 - 0.0338 Dry binder / disintegrant Excipient Sodium lauryl 0.00217 - 0.00371 Surfactant sulphate

[0248] Glidant Silica, colloidal 0.0625 Glidant anhydrous

[0249] Lubricant Sodium stearyl 0.3125 Lubricant fumarate

[0250] Total mass of 6.25

[0251] ODMT

[0252]

[0253] Table 1

[0254] Example 2: enaiapril 1 mo orodispersible tablet

[0255] An exemplary manufacturing method in accordance with the invention is provided below. The method produces 1 mg enalapril maleate orodispersible minitablets (ODMTs).

[0256] Step 1: 0.050 kg of an excipient blend (Ludiflash®, BASF) and 0.00125 kg of yellow iron oxide (E171) were combined and premixed manually and then transferred into a plastic mortar, where the mixture was blended for 5 minutes until a visually homogeneous mixture is achieved; the target is a homogenous mixture that is free of lumps.Step 2: The bend from Step 1 was sieved (mesh size: 100 pm). Integrity of the sieve and appearance of blend were evaluated for process control.

[0257] Step 3: The blend from step 2 and 0.6856 kg of the excipient blend were added to the 3.75L blender.

[0258] Step 4: 0.1632 kg enalapril maleate was sieved (mesh size: 355 pm) and transferred to the 3.75 L V blender. An additional 0.050 kg of the excipient blend was used to rinse the storage container previously containing the enalapril maleate. Subsequently, this amount of the excipient blend was also sieved (mesh size: 355 pm) and added to the 3.75 L V blender. Integrity of the sieve was evaluated for process control.

[0259] Step 5: Blending as performed for a total of 5 minutes (blend speed: 25 rpm). After 1 minute the intensifier bar was switched on for 3 minutes (intensifier speed: 3600 rpm). The appearance of the blend was evaluated for process control.

[0260] Step 6: 0.050 kg sodium stearyl fumarate and the blend from Step 4 were sieved (mesh size: 800 pm) and transferred back into the 3.75 L V blender. The integrity of the sieve was evaluated for process control.

[0261] Step 7: Blending was performed for a total of 3 minutes (blend speed: 25 rpm). After 2 minutes the intensifier bar as switched on for 30 seconds (intensifier speed: 3600 rpm). The appearance of the blend was evaluated for process control.

[0262] Step 8: The final blend was discharged into a suitable container and transferred to compression.

[0263] If required, the final blend may be held prior to compression for a maximum of 84 days ( 2 weeks). Storage conditions: controlled warehouse at 15-25 °C and NMT 40% RH.

[0264] Step 9: The final blend was filled into a rotary tablet press hopper and compressed into ODMTs using multi-tip 2 mm round punches (machine rate between: 160 - 240 rpm with target 200 rpm). The tablets were yellowish to yellow, round, biconvex, 2 mm diameter tablets. Tabletting efficacy was established by evaluating the appearance, average mass, hardness, thickness, individual mass, friability and disintegration of the tablets. The same acceptance criteria as described in example 1 were used.Step 10: The tablets were filled into bottles using a tablet counting machine and a cap was applied to the botles. Secondary packaging was then applied.

[0265] Step Parameters Target Target speed setting time (range)

[0266] Excipient and iron oxide Pre-blending 5 min. N / A (manual mixing mixing time within a plastic mortar) Blending Total blending 5 min. 25 rpm (fixed)

[0267] time

[0268] Intensifier bar 3 min. 3600 rpm (fixed) time

[0269] Blending after addition of Total blending 3 min. 25 rpm (fixed) lubricant and sieving time

[0270] Intensifier bar 30 sec. 3600 rpm (fixed) time

[0271] Compression Machine rate N / A 200 rpm (160 - 240 rpm)

[0272]

[0273] An exemplary composition for use in this method is provided in the table below. If required, the ratio of enalapril maleate to total excipients may be adjusted to provide an overage of API, to account for losses when transferring between vessels in the manufacturing procedure. An overage of about 3 % enalapril maleate may be used in the method.

[0274] In the method of this example, the ingredients marked “excipient” were provided in a co¬ processed form (Ludiflash®, BASF).

[0275] Ingredients Component Quantity (mg) per 1 Function

[0276] mg ODMT

[0277] Active Enalapril maleate 1.0000 Active Excipient Mannitol (E421) 4.1409 -4.5353 Filler

[0278] Excipient Crospovidone 0.1972 - 0.2958 Disintegrant Excipient Poly(vinyl acetate) 0.1725 - 0.2958 Dry binder

[0279]

[0280] Excipient Povidone 0.0123 - 0.0296 Dry binder / disintegrant Excipient Sodium lauryl 0.00190-0.00325 Surfactant sulphate

[0281] Colourant Iron oxide yellow 0.0078 Colourant (E172)

[0282] Lubricant Sodium stearyl 0.3125 Lubricant fumarate

[0283] Total mass of 6.25

[0284] ODMT

[0285]

[0286] Table 3

[0287] Example 3: excipient tests

[0288] Prototype ODMT were prepared with different excipients as follows:

[0289] Percentage Concentration, % w / w

[0290] Prototype Enalapril Lactose Mannitol- Crospovid Mg Na stearyl formulate maleate monohydr based one stearate fumarate n no. ate excipient

[0291] pre-mix

[0292] (Ludiflash

[0293] ®, BASF)

[0294] 1 4 89 2 5 *

[0295] 2 8 85 2 5

[0296] 3 20 73 2 5

[0297] 4 4 89 2 * 5

[0298] 5 8 85 2 * 5

[0299] 6 20 73 2 - 5

[0300] 7 4 * 91 * 5 *

[0301] 8 8 - 87 - 5 - 9 20 - 75 - 5 - 10 4 - 91 - - 5

[0302] 11 8 - 87 - * 5

[0303] 12 20 - 75 - * 5

[0304]

[0305] Table 4Enalapril maleate % w / w corresponds to mg dose as follows: 0.25 mg for tablets with 4 %w / w; 0.5 mg for tablets with 8 % w / w and 1.25 mg for tablets with 20 % w / w.

[0306] The procedure of Example 2 may be followed to prepare these tablets. Different excipients were used to investigate storage stability. The combinations of primary excipient (lactose (FlowLac®, MEGGLE GmbH & Co. KG) or mannitol (Ludiflash®, BASF)) with lubricant (magnesium stearate or sodium stearyl fumarate) were investigated.

[0307] The hardness of 20 ODMTs per prototype formulation was measured and tensile strength calculated from the mean using the following formula:

[0308] 2^F

[0309]

[0310] rr d * t

[0311] F is the breaking force (hardness) in N; d is tablet diameter in mm; t is tablet thickness. Prototype Mean hardness, N Standard deviation Calculated tensile formulation no. (n=20) strength, N / mm21 2.84 0.64 0.48

[0312] 2 3.33 0.72 0.57

[0313] 3 3.54 0.59 0.61

[0314] 4 3.22 0.80 0.55

[0315] 5 3.28 0.68 0.56

[0316] 6 4.13 1.03 0.71

[0317] 7 5.19 0.97 0.89

[0318] 8 6.00 0.74 1.02

[0319] 9 5.56 1.41 0.97

[0320] 10 7.49 1.27 1.23

[0321] 11 6.85 1.20 1.15

[0322] 12 6.80 1.47 1.15

[0323]

[0324] Table 5

[0325] A coefficient plot of the relative effect of each filler and each lubricant on tensile strength of tablets is shown in Figure 1. The mannitol-based filler and the sodium stearyl fumarate lubricant increased the tensile strength, whereas the lactose filler and the magnesium stearate lubricant decreased the tensile strength. The biggest effect was from the filler.From these data, a combination of a mannitol-based filler and sodium stearyl fumarate as lubricant is preferred, for increasing the mechanical strength of ODMTs.

[0326] The disintegration time of 5 of each prototype formulation was measured using the Hermes disintegration tester.

[0327] Prototype formulation no. Mean disintegration time, Standard deviation seconds

[0328] 1 3.21 0.41

[0329] 2 2.74 0.19

[0330] 3 3.30 0.80

[0331] 4 1.94 0.26

[0332] 5 1.67 0.22

[0333] 6 1.83 0.58

[0334] 1 8.99 1.33

[0335] 8 10.45 2.78

[0336] 9 8.64 2.48

[0337] 10 6.49 1.22

[0338] 11 4.89 0.71

[0339] 12 4.60 0.41

[0340]

[0341] Table 6

[0342] A coefficient plot of the effect of filler and lubricant on disintegration time is shown in Figure 2. The largest effect is from the filler, in which the mannitol performed better (faster disintegration). A combination of lactose monohydrate filler and sodium stearyl fumarate provided the shortest disintegration time.

[0343] The stability of these twelve formulations was evaluated after a period of 6 months storage. Samples of the ODMTs were stored in open dishes and in sealed aluminium sachets and stored at 25 °C / 60% RH and 40 °C / 75% RH, respectively. Enalapril maleate content was determined by HPLC at the start and at the end of the study period. Enalapril maleate content at 6 months is expressed as a percentage of the initial assay value for comparison and the results are shown in Figure 3. For the samples stored in open dishes at 25 °C / 60% RH, the API content appeared unchanged for the combination of mannitol and sodium stearyl fumarate, whereas tablets containing magnesium stearate lubricant showed a reduction in content. For the samples stored in sealed aluminium sachets at40 °C / 75% RH, the trends were clearer and showed that significant AP! reduction occurred for tablets containing lactose. Coefficient plots of the effect of filler and lubricant type are shown in Figure 4.

[0344] Example 4: batch size and tabettinq speed

[0345] Batches were prepared as follows. Enalapril maleate was mixed with a mannitol-based excipient pre-mix (Ludiflash®, BASF) and iron oxide yellow (previously sieved) in a V- blender equipped with an intensifier bar (3.75L), and the lubricant sodium stearyl fumarate (previously sieved) was added in a final blending step. The intensifier bar was used for 30 seconds. The blend was compressed using a conventional rotary press equipped with 2 mm tablet punches to ODMTs with the target properties indicated in the table below. Batch size varied and the tabletting speed were varied as follows:

[0346] Batch 1: 500 g batch size (equivalent to 80,000 ODMTs)

[0347] Batch 2: 1 kg batch size (equivalent to 160,000 ODMTs)

[0348] Batch 3: 1.8 kg batch size (equivalent to 288,000 ODMTs)

[0349] Property Target Batch number and results

[0350] Batch 1: Batch 2: Batch 2: Batch 3: 250,000 162,000 251,000 250,000 tablets per tablets per tablets per tablets per hour hour hour hour Mean mass, 5.94 - 6.56 6.44 6.29 6.22 6.35 mg

[0351] Hardness, N 9.4 9.4 10.4 9.8 Thickness, Approx. 2 2.0 1.9 1.9 1,9 mm mm

[0352] Friability Not more B: 0.117 B: 0.101 M: 0.131 B: 0.223 than 1 % E:0.098 E: 0.075 E: 0.051 Disintegration Not more B: 5s B: 7s M: 5s B: 0s time, Ph. Eur. than 3 E: 5s E: 7s E: 3s 2.9.1 minutes

[0353]

[0354] 3 = beginning; M = middle; E = end (of the batch)

[0355] Table 7The results show that varying the batch size between 0.5 kg and 1.8 kg does not appear to influence the physical properties of the ODMTs. In addition, the effect of compression speed on ODMT physical properties appears to be negligible.

[0356] Example 5: manufacturing steps and ODMT homogeneity

[0357] To improve the homogeneity of ODMTs, the process of Exampie 4 was modified by adding a further sieving step after blending the ingredients and by increasing the time of the intensifier bar from 30 seconds to 3 minutes. The use of micronized, rather than as- manufactured, API was also investigated. Samples were taken from the beginning, middle and end of each batch for testing.

[0358] Sample time Enalapril Mean content % RSD Acceptance maleate grade uniformity, % Value Beginning Micronized 90.2 5.52 21.5 Middle Micronized 93.1 2.89 12.4

[0359] End Micronized 96.1 4.09 12.2 Beginning Standard 100.7 4.34 10.5 Middle Standard 98.4 2.79 6.8

[0360] End Standard 99.4 3.14 7.6

[0361]

[0362] Table 8

[0363] The additional process steps improved homogeneity for ODMTs comprising standard grade API, but not those containing micronized API. This is shown by the acceptance values (AV) which, according to Ph. Eur. 2.9.40 criteria should be < 15 (Level 1 results 6.8-10.5). In addition, mean assay values (98.4 to 100.7 %) were all within acceptable limits. The micronized API had a d90 of 34.5 pm (measured by laser diffraction).

[0364] Example 6: manufacturing steps and ODMT homogeneity

[0365] The manufacturing process using standard grade API was further investigated. The rotation of the V-blender was fixed at 25 rpm and the speed of the intensifier bar was fixed at 3600 rpm. To assess the impact of the blending process parameters on the quality of the finished product, a study was performed to investigate the effect of different intensifier bar mixing times on the physical properties and homogeneity of ODMTs manufactured with the standard grade enalapril maleate as API.Blending step Process 1 Process 2 Blending time Intensifier bar Blending time Intensifier bar time time

[0366] 1 5 minutes 30 seconds 5 minutes 3 minutes 2 3 minutes 30 seconds 3 minutes 30 seconds Batch size 1 kg 1 kg

[0367]

[0368] Table 9

[0369] The resulting ODMTs from both batches had a hardness of < 15 N, a disintegration time of < 3 minutes and a mass uniformity within + 10% of the mean. However, the AV values (a low value being indicative of uniformity of content) were significantly less for the second batch, demonstrating that homogeneity was improved by an increase in intensifier bar mixing time.

[0370] Batch 1 2

[0371] Mixing process Process 1 Process 2

[0372] Mean assay, % 104.86 98.4

[0373] Standard deviation 4.00 2.79

[0374] AV 12.96 6.78

[0375]

[0376] Table 10

[0377] Example 7: dispersion in water

[0378] Dispersibility of the ODMTs in water was investigated for enalapril maleate as API. It is foreseen that a dose lower than that provided by a single ODMT may be required, for example dose titration for neonates. The dosage uniformity obtained from two methods of water dispersion was evaluated.

[0379] First method: Five 0.25 mg ODMTs were dispersed in 25 mL fresh tap water in a measuring cylinder and stirred for 3 minutes until the ODMTs were fuliy dispersed. To simulate dose administration, the volume for the required dose of enalapril maleate (0.125 mg and 0.025 mg) was withdrawn using a 10 mL syringe. These samples were evaluated for uniformity of content according to Ph. Eur. 2.9.6.

[0380] Second method: To achieve a target concentration of 0.025 mg / mL enalapril maleate, one 0.25 mg ODMT was dispersed in 10 mL of tap water within a capped syringe and the syringe was rolled for 3 minutes until the ODMT was fully dispersed as shown inFigure 5. To simulate dose administration, a proportion of the dispersion was discharged from the syringe to waste until the required volume remained within the syringe. The volume remaining in the syringe was then evaluated for uniformity of content according to Ph. Eur. 2.9.6. The above process was repeated 10 times for both the 1 mL extraction process (equating to a 0.025 mg dose) and the 5 mL extraction process (equating to a 0.125 mg dose). Individual assay results are provided below. This preparation method complies with requirements as not more than one of the individual contents of the 31 units tested was outside 85% to 115% of the average content and none were outside the limits of 75% to 125% of the average content.

[0381] Dilution Mean assay, RSD, % Failures (enalapril %

[0382] maleate dose)

[0383] First method: 10 % 113.65 3.02 3 dispersion in a (0.025 mg)

[0384] measuring 50 % 109.31 1.60

[0385] cylinder (0.125 mg)

[0386] Second 10 % 98.99 6.67 1

[0387] method: (0.025 mg)

[0388] dispersion in a 10 % 101.38 6.51

[0389] syringe (0.025 mg)

[0390] 50 % 96.64 2.06 *

[0391] (0.125 mg)

[0392]

[0393] Table 1

[0394] The data show that uniform doses of 0.125 mg enalapril maleate can be administered using the measuring cylinder dispersion method. By using the syringe dispersion method, doses of 0.025 mg and 0.125 mg enalapril maleate in conformity with Ph. Eur.

[0395] 2.9.6 can be administered and the method is less complex to execute compared to the measuring cylinder approach.

[0396] Example 8: dispersion in an enteral tube

[0397] Patients may require medicine administration via nasogastric tube (NGT) and the feasibility of administering the ODMTs via this route was investigated. Dose recovery and NGT blocking were considered and evaluated with polyurethane (PUR), silicone and polyvinyl chloride (PVC) NGTs.Test 1: tube blockage test

[0398] Four 0.25 mg enalapril maleate tablets were dispersed in a 10 ml enteral syringe with 1.0 mL water. The silicone CH4 tube was clamped in a vertical position and primed with 3 mL of potable water prior to use, to simulate clinical practice. The dispersion was then passed through the tube. No evidence of blockage was observed, showing that the ODMT dispersion could be successfully administered through NGTs of this internal dimension.

[0399] Test 2: dose recovery and rinse volume test

[0400] One 0.25mg tablet was dispersed with 10.0mL of water, within an enteral syringe for each test. Each tube was clamped in a vertical position and primed with 3 mL of potable water prior to use, to simulate clinical practice. The dispersion was then passed through the tube and collected into a volumetric flask: the contents of the flask were then prepared for assay analysis. After collecting this initial dose, each tube was rinsed with 5 aliquots of 1 mL of water and each individual aliquot was collected into separate 10.0 mL volumetric flasks, which were then individually prepared for assay analysis. Cumulative recoveries have been reported in the table below.

[0401] Tube Type / Dose Recovered without Cumulative dose recovered Replicate number Rinse (%LC) (%LC)

[0402] 1 2 3 4 5 Silicon CH10 R1 96.58 99.33 ND ND ND ND Silicon CH10 R2 91.40 94.28 94.90 ND ND ND PVC CH10 R1 9Z12 10T85 10229 ND ND ND PVC CH 10 R2 85.50 98.69 ND ND ND ND PUR CH10 R1 74.17 84.81 91.21 ND ND ND PUR CH10 R2 63.62 82.55 90.75 ND ND ND

[0403]

[0404] Table 12

[0405] Dose recoveries of 90% were achieved for all tube types, following 2mL rinse volume (minimum recovery obtained = 90.75%).

[0406] Test 3: repeat use test

[0407] Four 0.25mg tablets were dispersed with 1. OmL of water, within an enteral syringe for each test. The tube was clamped in a vertical position and primed with 3 mL of potablewater prior to use, to simulate clinical practice. The dispersion was then passed through the tube and collected into a volumetric flask. The tube was then rinsed with 3mL of water (as defined following the rinse volume determination test) and the rinse was collected Into the same volumetric flask as the initial dose was collected within. The contents of the flask were then prepared for assay analysis. The above was repeated a further two times, to total 3 dose deliveries with subsequent 3mL rinses through the same tube. Cumulative recoveries are reported in the table below.

[0408] Dose Number Dose Recovered (%LC)

[0409] 1 92.67

[0410] 2 92.12

[0411] 3 96.66

[0412]

[0413] Table 13

[0414] Dose recoveries are consistent across the 3 repeats, with the third recovery slightly higher than the first two; it can be concluded that a rinse volume of 3mL is sufficient for dose delivery (as all recoveries are above 90%), and that issues such as residue build¬ up are not a significant concern when the same tube is used up to and including 3 times to deliver the 0.25mg strength product.

[0415] Test 4: tube blockage test (higher strength)

[0416] Four 1 mg enalapril maleate tablets were dispersed in a 10 ml enteral syringe with 1.0 ml_ water. The silicone CH5 tube was clamped in a vertical position. The dispersion was then passed through the tube, and observations were made. No evidence of blockage was observed, showing that the ODMT dispersion could be successfully administered through NGTs of this internal dimension.

[0417] Test 5: dose recovery and rinse volume test (higher strength)

[0418] One 1mg tablet was dispersed with lO. OmL of water, within an enteral syringe for each test. Each tube was clamped in a vertical position and primed with 3 mL of potable water prior to use, to simulate clinical practice. The dispersion was then passed through the tube and collected into a volumetric flask: the contents of the flask were then prepared for assay analysis. After collecting this initial dose, each tube was rinsed with 5 aliquots of 1 mL of water and each individual aliquot was collected into separate 10.0 mL volumetric flasks, which were then individually prepared for assay analysis. Cumulative recoveries are reported in the table below.Tube type / Dose recovered without Cumulative dose recovered (%LC) Replicate rinse (%LC) 1 2 3 4 5 number

[0419] Silicon CH10 64.60 94.03 94.89 94.97 ND ND R1

[0420] Silicon CH10 ND189.18 90.14 90.22 ND ND R2

[0421] PVC CH10 ND136.001 91.86 92.43 ND ND R1

[0422] PVC CH10 71.88 102.28 103.43 103.50 ND ND R2

[0423] PUR CH10 74.55 95.51 96.29 96.39 ND ND R1

[0424] PUR CH 10 44.5T 97.19 98.04 98.10 ND ND R2

[0425]

[0426] Table 14

[0427] 1Due to the tong length of the tubes chosen for analysis to represent worst-case experimental conditions (125cm), issues with air entrapment within the tube were encountered when dosing 1. OmL of the 1 mg strength tablets via gravity under laboratory conditions. This issue was less apparent in the 0.25mg strength data set. Following three flushes with 1.0mL of water, >90% of the 1 g dose was recovered in all cases (minimum recovery obtained = 90.22%), providing assurance that a 1mg / mL dose of the 1 mg strength product can be successfully delivered with a minimal flush volume of 3mL.

[0428] This study also shows that a 3mL rinse volume is sufficient for all tube types at a low 1 mg strength dose of 1 mg / mL.

[0429] Test 6: repeat use study (higher strength)

[0430] Four 1 mg tablets were dispersed with 1. OmL of water, within an enteral syringe, for each test. The tube was clamped in a vertical position and primed with 3 mL of potable water prior to use, to simulate clinical practice. The dispersion was then passed through the tube and collected into a volumetric flask. The tube was then rinsed with 3mL of water (as defined following the rinse volume determination test) and the rinse was collected into the same volumetric flask as the initial dose was collected within. The contents of the flask were then prepared for assay analysis.The above was repeated a further two times, to total 3 dose deliveries with subsequent 3mL rinses through the same tube. Cumulative recoveries are reported in the table below.

[0431] Dose Number Dose Recovered (%LC)

[0432] 1 98.88

[0433] 2 101.01

[0434] 3 99.76

[0435]

[0436] Table 15

[0437] Dose recoveries are consistent across the 3 repeats, with no apparent increasing trend; it can therefore be concluded that a rinse volume of 3mL is sufficient for dose delivery (as all recoveries are above 90%), and that issues such as residue build-up are not apparent when the same tube is used up to and including 3 times to deliver the 1 mg strength product.

[0438] Example 9: compatibility with beverages

[0439] Parents and caregivers may administer paediatric medicines mixed with beverages to facilitate dosing and therefore the compatibility and stability of the ODMTs dispersed in commonly used beverages was investigated; tap water, apple juice, orange juice, cow's milk (3.5 %) and formula milk.

[0440] The physicochemical compatibility of 8 x 1 mg ODMTs (enalapril maleate) dispersed in 100 mL of each beverage was evaluated by visual inspection after 2 hours storage at room temperature. In addition, the disintegration time of the ODMTs in the beverages was determined using the Hermes tester.

[0441] Chemical compatibility was also investigated; the stability of the ODMTs in each beverage was investigated by dispersing the ODMTs in 1.0mL of tap water and then adding to 9.0mL of each beverage and mixing. An enalapril maleate stock solution mixed with the beverages was included as a control. The samples were stored for 240 minutes at both room and refrigerated conditions. Assay analysis was conducted at each of the following time points: initial, 30 minutes, 60 minutes, 120 minutes and 240 minutes. Enalapril assay was determined according to the test protocol shown in the table below.Storage Time, minutes

[0442] condition 0 30 120 240

[0443] 20-25°C X X X X

[0444] 2-8“C X X X X

[0445]

[0446] Table 16

[0447] X = assay

[0448] No visual changes, for example discolouration or precipitation, were observed for the beverage samples containing dispersed ODMTs compared to beverage only controls, after storage for 2 hours at room temperature. However, it was found that disintegration time was highly dependent on the medium, as shown in Figure 6 (N=10, mean ± SD). Indeed, the ODMTs disintegrated in less than 8 seconds in aqueous solutions, whilst milk, especially that containing 3.5 % fat, significantly prolonged disintegration time, it was estimated that the ODMTs required up to five times longer to disintegrate in the different media compared to distilled water.

[0449] Enalapril maleate content was found to be consistent over the 240-minute time-period, irrespective of storage conditions, with no apparent enalapril maleate degradation, as shown in the table below (assay n = 3, mean ± SD). However, some variability in assay results was seen in the formula milk and cow’s milk samples, which may have potentially been due to sample preparation.

[0450] Overall, it was concluded that enalapril ODMTs were found to be chemically stable in all the beverages investigated, for at least 4 hours when stored at room temperature or in a refrigerator.

[0451] However, since beverage type appeared to Impact ODMT disintegration time, the preferred vehicle for dispersion, if required, is tap water. This would avoid the potential risk of partial disintegration and associated incomplete dosing.

[0452] Beverage Test Storage Time (minutes)

[0453] Material Condition 0 30 60 120 240 Tap water EM 101.25 ± 99.49 ± 99.71 ± 99.54 ± 99.26 ± control 1.6 0.6 0.8 0.5 0.8

[0454]

[0455] 1 mg 25 °C 98.65 ± 99.64 ± 100.86 100.3 ± 101.19 ODMT 0.9 2.8 ± 0.5 2.0 ± 1.1 1 mg 8 “C 101.52 ± 100.77 97.2 ± 98.67 + 98.61 ± ODMT 5.1 ± 1.1 2.3 4.1 1.2 Apple EM 100.4 ± 99.31 ± 99.4 ± 99.77 ± 99.33 ± juice control 1.1 0.1 0.2 1.7 0.6

[0456] 1 mg 25 °C 102.84 ± 96.47 ± 99.2 ± 100.25 101.65 ODMT 8.3 7.5 3.0 ± 1.0 + 0.8 1 mg 8 °C 99.71 ± 97.5 ± 97.2 ± 100.35 97.47 ± ODMT 4.0 1.8 1.3 ± 2.7 2.2 Orange EM 97.78 + 96.56 ± 98.64 ± 97.7 ± 97.47 + juice control 2.8 3.0 0.9 2.2 2.7

[0457] 1 mg 25 °C 104.54 ± 100.93 99.44 ± 101.52 100.97 ODMT 6.8 ± 2.0 1.4 ± 5.7 ± 4.1 1 mg 8 °C 100.66 ± 99.68 ± 100.62 98.69 ± 99.93 ± ODMT 3.2 4.4 ± 5.2 3.4 5.1 Milk (3.5 EM 99.1 ± 107.49 102.71 101.37 103.6 ± %) control 2.2 ± 1.0 ± 2.2 ± 0.9 3.4

[0458] 1 mg 25 °C 90.34 ± 92.81 ± 91.52 ± 88.86 ± 89.78 ± ODMT 2.7 1.6 5.3 5.5 2.5 1 mg 8 °C 96.66 ± 97.38 ± 99.24 ± 100.04 99.14 ± ODMT 1.7 2.1 1.5 ± 1.6 2.9 Formula EM 97.33 + 97.0 + 96.97 + 97.07 + 97.77 ± milk control 0.4 1.0 0.8 2.8 2.5

[0459] 1 mg 25 °C 100.48 ± 100.52 100.23 100.17 99.57 ± ODMT 2.5 ± 4.4 ± 4.7 ± 3.9 2.4 1 mg 8BC 97.86 ± 96.38 ± 98.51 ± 97.08 ± 96.78 ± ODMT 2.2 2.3 2.9 1.9 3.6

[0460]

[0461] Table 17

[0462] Example 10: dissolution and bioavailabilitv

[0463] Two types of ODMT in accordance with the invention were compared to commercially available tablets of the same API (enalapril maleate) formulated for adults. The ODMTs had an API strength of either 0.25 mg of 1.0 mg, with the formulations given inTables 18 and 19 below, respectively. The adult formulation had an API strength of 5 mg (Renitec®).

[0464] Ingredients Component Quantity (mg) per Function 0.25mg ODMT

[0465] Active Enalapril Maleate § 0.2500 Active Excipients Co- processed § 5.6250 Filler / Disintegrant / excipient Binder (Ludiflash®),

[0466] consisting of:

[0467] Mannitol (E421) § 4.7250-5.1750 Filler Crospovidone § 0.2250-0.3375

[0468] Poly(vinyl acetate) § 0.1969-0.3375

[0469] Povidone § 0.0141-0.0338

[0470] Sodium laurilsulfate § 0.00217-0.00371 Surfactant Glidant Silica, colloidal § 0.0625 Glidant anhydrous

[0471] Lubricant Sodium s teary I § 0.3125 Lubricant fumarate

[0472] Total mass of 6.25

[0473] ODMT

[0474]

[0475] Table 18

[0476] Ingredients Component Quantity (mg) per Function

[0477] 1 mg ODMT

[0478] Active Enalapril Maleate 1.0000 Active Excipients Co-processed 4.9297 §§ Filler / Disintegrant / excipient Binder (Ludiflash®),

[0479] consisting of:

[0480] Mannitol (E421) 4.1409- 4.5353 § Filler

[0481] Crospovidone 0.1972- 0.2958

[0482] Poly(vinyl acetate) 0.1725- 0.2958

[0483] Povidone 0.0123- 0.0296

[0484]

[0485] Sodium laurilsulfate 0.00190-0.00325 Surfactant Colourant Iron oxide yellow 0.0078 Colourant

[0486] (El 72)

[0487] Lubricant Sodium stearyl 0.3125 Lubricant fumarate

[0488] Total mass of 6.25

[0489] ODMT

[0490]

[0491] Table 19

[0492] Study 1

[0493] A relative bioavailability study was conducted to assess the relative bioavailability of 1 mg enalapril administered as ODMT versus a standard enalapril tablet formulation (reference product: Renitec® 2 x 5 mg tablets, MSD Belgium BVBA / SPRL).

[0494] The dissolution of both products was evaluated in 900 ml of pH 6.8 buffer as the dissolution vehicle, using paddles. The results are provided in the tables below.

[0495] Enalapril Released (%)

[0496] Time (Minutes) 5 10 15 20 30 Vessel 1 66.2 91.2 99.9 103.9 104.8 Vessel 2 74.6 96.5 103.7 103.1 103.7 Vessel 3 71.6 91.8 102.7 107.5 107.8 Vessel 4 72.1 92.5 101.9 104.4 103.6 Vessel 5 73.0 92.5 100.7 102.8 104.1 Vessel 6 67.2 87.5 98.8 102.9 102.9 Mean 70.8 92.0 101.3 104.1 104.5 % RSD 4.73 3.15 1.83 1.70 1.65

[0497]

[0498] Table 20: dissolution for 1 mg ODMT

[0499] The dissolution profile for 1 mg enalapril maleate ODMT in pH 6.8 phosphate buffer is graphed in Figure 10.

[0500] Enalapril Released (%)

[0501] Time 5 10 15 20 30

[0502] (Minutes)

[0503]

[0504] Vessel 1 77.8 99.4 99.5 99.6 99.8 Vessel 2 71.9 98.5 99.5 99.3 99.1 Vessel 3 65.1 98.0 100.5 100.9 100.3 Vessel 4 78.1 98.0 100.3 99.6 99.2 Vessel 5 62.5 99.7 101.4 101.5 101.1 Vessel 6 64.0 99.7 100.6 100.6 100.3 Mean 69.9 98.9 100.3 100.3 100.0 % RSD 10.03 0.81 0.72 0.86 0.76

[0505]

[0506] Table 21: dissolution for Renitec®

[0507] The dissolution profile for the 5 mg adult dose is graphed in Figure 11.

[0508] Study 2

[0509] A second dissolution study was conducted to compare the dissolution profiles of two batches of enalapril maleate 1 mg and 0.25 mg ODMTs, manufactured at commercial scale, with a batch of the commercially available reference enalapril maleate product, Xanef® 5 mg tablets (in the EU, Xanef®, Renitec®, Enapren® and Innovace® are all invented names used for the same reference product). Dissolution experiments were conducted in dissolution media at three different pH values: pH 1.2, pH 4.5 and pH 6.8, in accordance with the “Guideline on the Investigation of Bioequivalence” (CPMP / EWP / QWP / 1401 / 98 Rev. 1 / Corr). The updated dissolution methodology, as described below and summarised in Table 22, was applied (500 mL, Apparatus 1 (baskets)), and samples were taken at five different time points (excluding zero) from twelve vessels for each batch of drug product, in each dissolution medium. Mean results are provided in Tables 23 to 25 below.

[0510] Dissolution Test

[0511] A dissolution method was developed for the enalapril ODMTs based upon the USP monograph for enalapril maleate tablets and in accordance with Ph Eur 2.9.3. The method utilised 900 mL pH 6.8 phosphate buffer as the dissolution medium, with Apparatus 2 (paddles) at a speed of 50 rpm. HPLC was used to evaluate enalapril maleate. The release specification was not less than 80 % (Q) of the labelled amount dissolved in 30 minutes. To support the relative bioavailability study and enable the comparison of the in vitro dissolution rate of enalapril maleate from the ODMTs with that from the marketed product, the method utilised 10 x 1 mg enalapril maleate ODMTs per vessel. Since paediatric patients may take a single enalapril ODMT per dose, thedissolution method was updated and re-validated whereby the dissolution of one ODMT per vessel was evaluated, in line with the Ph. Eur 2.9.3. definition of a dosage unit. In addition, the volume of dissolution medium per vessel was reduced to 500 mL and Apparatus 1 (baskets) was used instead of Apparatus 2. Modifications were also made to the HPLC chromatographic conditions and volumes of solutions. A comparison of the dissolution method parameters is provided below in Table 22.

[0512] Parameter Original method Updated method Dissolution tester Apparatus 2 (paddle), 37 Apparatus 1 (basket), 37

[0513] °C °C

[0514] Dissolution preparation 10 tablets per vessel 1 tablet per vessel Dissolution medium 900 mL phosphate buffer 500 mL phosphate buffer pH 6.8 pH 6.8

[0515] Stirring speed 50 rpm 50 rpm Chromatographic conditions

[0516] Column NUCLEOSIL 100-5 Cl 8 Zorbax Eclipse XDB-C18,

[0517] HD, 250 x 4.0 mm, 5 pm or 100 x 2.1mm, 3.5pm or equivalent equivalent

[0518] Mobile Phase Acetonitrile / phosphate Acetonitrile / 1 mM buffer pH 2.0 (25:75 v / v) phosphate buffer pH 2.0

[0519] (23:77 v / v)

[0520] Injection volume: 30 pL 50 pL

[0521] Flow 1.2 mL / min 0.6 mL / min Temperature 65PC 60 °C

[0522] Stop time 12.0 min 3.0 min

[0523]

[0524] Table 22: comparison of original (Study 1) and updated (Study 2) dissolution method parameters

[0525] Resu / ts (Study 2)

[0526] Product Mean Enalapril Released (%) and RSD (%) (n~12)

[0527] pH 1.2

[0528] Time 5 10 15 20 30 (Minutes)

[0529] 0.25 mg Mean 86.8 98.6 99.5 99.4 100.3 ODMTs RSD 14.1 2.6 3.0 2.9 5.1

[0530]

[0531] (Batch A)

[0532] 0.25 mg Mean 89.8 96.0 96.5 96.7 96.8 ODMTs RSD 4.8 2.5 2.5 2.6 2.3 (Batch B)

[0533] 1.0 mg Mean 67.7 95.3 102.6 103.7 104.2 ODMTs RSD 1.4 8.9 5.7 4.7 4.5 (Batch C)

[0534] 1.0 mg Mean 57.4 85.7 96.1 98.3 98.9 ODMTs RSD 8.7 8.8 6.5 5.3 4.9 (Batch D)

[0535] Xanef® 5 mg Mean 48.0 93.4 100.0 101.8 102.5 RSD 15.1 7.5 3.9 2.1 1.4

[0536]

[0537] Table 23: mean dissolution results for 1.0 mg enalapril maleate ODMTs, 0.25 mg enalapril maleate ODMTs and Xanet® 5 mg tablets in pH 1.2 dissolution medium. The mean values are graphed in Figure 12.

[0538] Product Mean Enalapril Released (%) and RSD (%) (n=12)

[0539] pH 4.5

[0540] Time 5 10 15 20 30 (Minutes)

[0541] 0.25 mg ODMTs i Mean 87 98.4 99.9 99 99.3 (Batch A)

[0542] RSD 12 4.9 3.4 2.6 2.5 0.25 mg ODMTs § Mean 91.7 101.9 100.4 102.1 102.6 (Batch B)

[0543] RSD 8.1 6.6 2.4 3.5 3.1 1.0 mg ODMTs i Mean 65.9 89.7 100.6 102.1 102.5 (Batch C)

[0544] RSD 15.5 15 7.9 6.7 6.2 1.0 mg ODMTs i Mean 60.5 90.6 99.5 101.2 101.6 (Batch D)

[0545] RSD 10 9.6 8.1 7.7 7.6 Xanet® 5 mg i Mean 42.2 93.3 100.1 101.7 102.1

[0546] RSD 15.4 5.9 2.6 1.5 1.3

[0547]

[0548] Table 24: mean dissolution results for 1.0 mg enalapril maleate ODMTs, 0.25 mg enalapril maleate ODMTs and Xanef® 5 mg tablets in pH 4.5 dissolution medium. The mean values are graphed in Figure 13.

[0549] Product Mean Enalapril Released {%) and RSD (%) (n=12)

[0550] pH 6.8

[0551] Time 5 10 15 20 30 (Minutes)

[0552] 0.25 mg Mean 91.3 100.5 101.2 101.5 101.5 ODMTs RSD 6.1 4.5 3.0 2.9 2.9 (#251860)

[0553] 0.25 mg Mean 94.3 99.8 101.6 101.6 101.6 ODMTs RSD 3.6 1.5 3.6 2.3 2.6 (#251863)

[0554] 1.0 mg Mean 75.4 98.7 103.5 104.4 104.3 ODMTs RSD 19.0 9.6 7.4 7.4 7.3 (#252767)

[0555] 1.0 mg Mean 73.2 96.8 100.4 100.8 100.5 ODMTs RSD 12.9 5.8 6.1 5.1 5.8 (#252768)

[0556] Xanef® 5 mg Mean 46.9 98.2 102.1 102.6 102.9 (#T039961) RSD 18.8 4.9 1.8 1.2 1.3

[0557]

[0558] Table 25: mean dissolution results for 1.0 mg enalapril maleate ODMTs, 0.25 mg enalapril maleate ODMTs and Xanef® 5 mg tablets in pH 6.8 dissolution medium. The mean values are graphed in Figure 14.

[0559] Example 11: uniformity of content

[0560] In spite of careful rinsing of equipment, some API may be lost during the manufacturing process, especially during transfer of the blends between mixing vessels. The API content uniformity was investigated with and without an API overage. An overage is an excess of the amount of API compared to what is needed to make the specified number of doses at the specified strength. A process and recipe similar to example 1 was used, with a first batch having no overage and a second batch having 3% overage of enalapril maleate. Tablet samples were taken from the beginning, middle and end of the tabletting run for each batch and assessed for the amount of API per tablet.Overage Content Uniformity

[0561] Mean (%) % RSD Acceptance Value Beginning no enalapril 96.6 1.46 5.3 Middle maleate overage 95.8 2.03 7.4

[0562] End 95.4 2.35 8.5 Beginning 3 % enalapril 101.4 1.46 3.6 Middle maleate overage 100.2 2.65 6.4

[0563] End 101.1 2.71 6.6

[0564]

[0565] Table 26: summary of uniformity of content results for 0.25 mg enalapril maleate ODMTs in a 5 kg batch using micronized API.

[0566] Including an overage of 3% resulted in ODMTs that consistently met finished product specification, as shown by the AV results.

[0567] Example 12: process parameters

[0568] The effect of various blending steps on content uniformity was investigated. ODMTs were prepared with a target of 0.25 mg per tablet. The API was initially combined with a glidant (silicon dioxide).

[0569] API Enalapril Excipients Manufacturing Content Uniformity Batch maleate Process

[0570] % RSD Acceptance Value

[0571] F i Standard Ludiflash® Dry blend in 7.4 23.8

[0572] i grade (BASF), sodium three steps

[0573] stearyi fumarate

[0574] G i Standard Ludiflash® Dry blend in 5.2 14.7

[0575] § grade (BASF), sodium four steps

[0576] stearyi fumarate

[0577] H i Standard Ludiflash® Dry blend in 9.8 25.6

[0578] § grade (BASF), sodium four steps

[0579] stearyi fumarate

[0580]

[0581] J Standard Ludiflash® Dry blend in 7.7 21.3 grade (BASF), sodium four steps,

[0582] stearyl fumarate prolonged

[0583] blending times

[0584] K Micronized Ludiflash® Dry blend in 4.1 11.2

[0585] (BASF), sodium four steps

[0586] stearyl

[0587] fumarate, silicon

[0588] dioxide

[0589]

[0590] Table 27

[0591] The results show that, for a 0.25 mg strength ODMT of enalapril maleate, a combination of micronized API and silicon dioxide glidant, with four blending steps, is a preferred manufacturing method due to the good homogeneity achieved with this method.

[0592] Example 13: packaging

[0593] An Accelerated Stability Assessment Programme (ASAP) using ASAPprime® software was conducted. ASAP studies were designed to test product to a defined failure point, called Isoconversion, across a series of temperature and humidity conditions; the data is then entered into ASAPprime® software, which is a statistical package that analyses data and can make predictions on the shelf life of the tested material or product. The results from this study suggested that the product was sensitive to moisture, with humidity affecting samples more than temperature. The results are shown in Figure 15.

[0594] Figure 15 shows how the shelf life, and thus stability, of the product in all blends tested was significantly improved in the presence of silica desiccant in the packaging configuration. Blends 3 and 4 used micronized enalapril maleate as API and blends 5 and 6 used non-micronized enalapril maleate as API. Ail blends were prepared using 16 % API for consistency and comparability. Blends 3 and 5 were prepared with colloidal silicon dioxide (glidant) and blends 4 and 6 were prepared without colloidal silicon dioxide. Blend 6 therefore is comparable to the blend prepared in Example 2 (1 mg ODMTs).

[0595] Figure 15 shows the predicted significant improvement of drug product stability with the addition of a desiccant as part of the packaging configuration.

Claims

CLAIMS1. A method of producing orodispersible tablets comprising an ACE inhibitor for paediatric use, the method comprising:providing (i) the ACE inhibitor in crystalline, micronized form, and (ii) an excipient in particulate form, wherein the excipient has a particle size distribution D90 of 250 μm or less and comprises a sugar alcohol;- dry-mixing the ACE inhibitor and the excipient in a first dry-mixing step to form a mixture; and then- further dry-mixing the mixture in a second dry-mixing step, wherein the second dry-mixing step involves more intensive mixing than the first dry¬ mixing step, the second dry-mixing step involving stirring the mixture using a stirrer having a rotational speed of at least 1000 rpm for at least 1 minute;- sieving the mixture;- adding a lubricant to the ACE inhibitor and the excipient at any preceding point during the method,- compressing the mixture into tablets, each of which has a maximum dimension of 5 mm or less,wherein the ACE inhibitor used in the dry mixing has a particle size distribution D90 of less than 100 μm and / or a D50 of less than 30 μm.

2. The method of claim 1, wherein the ACE inhibitor has a particle size distribution D90 of from 60 to 100 μm.

3. The method of claim 1 or claim 2, wherein the ACE inhibitor has a particle size distribution of d90 up to 20 μm and wherein the method comprises the step of blending the ACE inhibitor with colloidal anhydrous silica prior to the first dry mixing step.

4. The method of any preceding claim, wherein the excipient comprises mannitol.

5. The method of any preceding claim, wherein the ACE inhibitor is enalapril, preferably in the form of enalapril maleate.

6. The method of any preceding claim, wherein the lubricant is sodium stearyl fumarate.

7. The method of any preceding claim, wherein the excipient is a co-processed excipient and / or comprises mannitol, crospovidone, polyvinyl acetate, povidone, and sodium lauryl sulphate.

8. The method of any preceding claim, wherein the lubricant is added to the mixture before sieving, so that the lubricant, ACE inhibitor and the excipient are sieved together.

9. The method of any preceding claim, wherein a further aliquot of the excipient is added to the mixture and the first and second dry-mixing steps are repeated, prior to the sieving step.

10. The method of any preceding claim, wherein each tablet is compressed to a maximum dimension of from 1 mm to 3 mm.

11. The method of any preceding claim, wherein the step of compressing the mixture into tablets comprises direct compression.

12. The method of any preceding claim, wherein the first dry-mixing step comprises Stirring or rotating the mixture in a blender at a rotational speed of from 10 to 50 rpm.

13. The method of any preceding claim, wherein the first dry-mixing step is carried out for a duration of at least 2 minutes, preferably at least 3 minutes.

14. The method of any preceding claim, wherein the second dry-mixing step comprises stirring the mixture using a stirrer having a rotational speed of at least 2000 rpm.

15. The method of any preceding claim, wherein the second dry-mixing step is carried out for a duration of at least 2 minutes.

16. The method of any preceding claim, comprising a third dry mixing step after the sieving step and after the step of adding a lubricant.

17. The method of claim 16, wherein the third dry-mixing step comprises stirring or rotating the mixture in a blender for at least 3 minutes at a speed of from 10 to 40 rpm and wherein a more intensive mixing at a speed of at least 2000 rpm is carried out during the final 30 seconds of the third dry-mixing step.

18. The method of any preceding claim, wherein:the ACE inhibitor is enalapril maleate;in addition to (i) the ACE inhibitor and (ii) the excipient, (iii) colloidal anhydrous silica in particulate form is provided; andthe method comprisesdry-mixing the enalapril maleate and the colloidal anhydrous silica thereby providing an API-glidant blend;the first dry-mixing step comprises dry-mixing the API-glidant blend and a first aliquot of the excipient in a first dry-mixing step to form a first mixture, which undergoes the second dry-mixing step; and the method further comprises adding a second aliquot of the excipient to the first mixture and repeating the first and second dry mixing steps, thereby providing a second mixture; adding a third aliquot of the excipient to the second mixture and repeating the first and second dry mixing steps, thereby providing a third mixture;adding a fourth aliquot of the excipient to the third mixture and repeating the first and second dry mixing steps, thereby providing a fourth mixture;adding a lubricant to the fourth mixture thereby providing a fifth mixture; sieving the fifth mixture;dry-mixing the fifth mixture after sieving in a third dry-mixing step.

19. The method of any of claims 1 to 17, wherein:the ACE inhibitor is enalapril maleate;in addition to (i) the ACE inhibitor and (ii) the excipient, (iii) a colourant in particulate form is provided; and the method comprisesblending the colourant and a first aliquot of the excipient and sieving the resulting blend to form a first mixture;sieving the enalapril maleate;the first dry-mixing step comprises dry-mixing the sieved enalapril maleate, the first mixture and a second aliquot of the excipient to form a second mixture, which then undergoes the second dry-mixing step; the method further comprisingafter the second dry-mixing step, adding a lubricant to the second mixture to form a third mixture;sieving the third mixture;dry-mixing the third mixture after sieving in a third dry-mixing step.

20. An orodispersible tablet for paediatric use, wherein the tablet has a maximum dimension of 5 mm or less andcomprises:(i) an ACE inhibitor and (ii) an excipient comprising a sugar alcohol, a polyvinylpyrrolidone polymer and a polyvinylacetate, (iii) a lubricant comprising a fatty acid fumarate salt.

21. An orodispersible tablet according to claim 20, wherein the excipient comprising a sugar alcohol, a polyvinylpyrrolidone polymer and a polyvinylacetate, is a co¬ processed excipient.

22. The tablet according to claim 20 or 21, wherein tablet comprises, consists essentially of or consists of about 0.20 to about 0.30 mg, preferably about 0.25 mg, of an ACE inhibitor, preferably enalapril maleate; about 5 to about 6 mg of the excipient which is a co-processed excipient comprising a sugar alcohol, a polyvinylpyrrolidone polymer and a polyvinylacetate; about 0.2 to about 0.4 mg of sodium stearyl fumarate; and about 0.01 to about 0.12 mg of a glidant, preferably colloidal anhydrous silica;and has a total tablet mass of about 6.0 to about 6.5 mg, e.g. about 6.25 mg.

23. The tablet according to claim 20 or 21, wherein the tablet comprises, consists essentially of, or consists of about 0.75 to about 1.25 mg, preferably about 1.0 mg, of an ACE inhibitor, preferably enalapril maleate; about 4 to about 6 mg, such as about 4.9 mg, of the excipient, which is a co-processed excipientcomprising a sugar alcohol, a polyvinylpyrrolidone polymer and a polyvinylacetate; about 0.005 to about 0.011 mg, such as about 0.0078 mg, of a particulate colourant, preferably iron oxide yellow (E172); about 0.2 to about 0.42 mg, such as about 0.31 mg, of sodium stearyl fumarate, and optionally lacks a glidant, such as colloidal anhydrous silica;and has a total tablet mass of about 6.0 to about 6.5 mg, e.g. about 6.25 mg.

24. An orodispersible tablet comprising an ACE inhibitor for paediatric use, wherein the tablet has a maximum dimension of 5 mm or less and is producible by a method according to any one of claims 1 to 19, and optionally is as defined in any one of claims 20 to 23.

25. A kit of parts comprisinga. a plurality of orodispersible tablets according to any one of claims 20 to 24 or made according to the method of any or claims 1 to 19;b. a package containing the orodispersible tablets, which may be selected from a bottle having a cap and a blister pack.

26. A kit of parts according to claim 25, wherein the package is a bottle having a cap, and comprising a silica dessicant, and the kit further comprises a scoop.

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