GB2634218A - Powder for oral solution formulations - Google Patents

Abstract

A powder for oral solution formulation comprising an active pharmaceutical agent in an amount of 1-25 % w/w, a taste masking bulking agent in an amount of 60-99 % w/w, a binder in an amount of 0-10 % w/w, a taste modifying component in an amount of 0-10 % w/w and a flow agent in an amount of 0-10 % w/w. The taste-masking bulking agent may comprise a sugar alcohol (e.g., mannitol, sorbitol, xylitol); the binder may be a polysaccharide (e.g., starch, cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose); the taste-modifying agent may comprise a flavouring (e.g., fruit or herb oil, synthetic flavouring) and/or sweetener (e.g., acesulfame salt); the flow agent may comprise a silicate, talc, stearic acid or salt thereof, and/or a phosphate. The active pharmaceutical agent may be an analgesic or an anti-epileptic agent; and may not be a beta lactam. The formulation may include less than 0.1 % w/w each of a preservative and/or sugar. Also disclosed is a method of preparing the described powder, wherein the method comprises blending the active pharmaceutical agent with the taste masking bulking agent, and optionally with the binder, taste-modifying agent and/or flow agent.

Description

Intellectual Property Office Application No G132315017.0 RTM Date:27 March 2024 The following terms are registered trade marks and should be read as such wherever they occur in this document: M ethocel Perlitol Intellectual Property Office is an operating name of the Patent Office www.gov.uk /ipo Powder for Oral Solution Formulations The present invention relates to powder for oral solution formulations.

The majority of pharmaceutical formulations are solid or liquid oral dosage forms, such as tablets/capsules or solutions/suspensions because the oral route of administration should always be used when available and clinically appropriate. Formulations typically only deviate from such forms in situations where there is an over-riding factor, such as the stability or bioavailability of the active ingredient. Formulations which are not tablets or solutions/suspensions tend to be more expensive and/or difficult to prepare.

A powder for oral solution is a formulation that is prepared and stored as a powdered solid product, but is dissolved or dispersed in a liquid carrier (e.g., water) prior to use.

Typically, powder for oral solution formulations include a preservative and/or an alcohol component. However, if the formulation may be used for children (e.g., a paediatric formulation or a formulation suitable for use with paediatric patients), then it is clinically desirable to omit from the formulation any preservatives and/or alcohol components if possible.

Such formulations may also be useful for adults, including the elderly, who are unable to tolerate certain preservative agents and/or alcohol components, or who have a limited tolerance for such components.

It may also be desirable to provide powder for oral solution formulations which also do not include glycol, sucrose, aspartame, colourants, sodium benzoate or glycerine.

Certain preservatives, such as benzalkonium chloride and thimerosal may have toxicity concerns associated with them, especially when the formulation may be used as a paediatric formulation.

Alcohols, such as ethanol and benzyl alcohol, for example, can be problematic for paediatric formulations due to their potential for toxicity and bitter taste.

The excessive use of propylene glycol may lead to toxicity issues in the patient and may also cause irritation.

A high content of sugars, such as sucrose, in a formulation may not be suitable for patients with certain medical conditions, such as diabetes.

Aspartame is an artificial sweetener that should be avoided, particularly in patients with certain medical conditions, such as phenylketonuria (PKU), as they cannot metabolise phenylalanine, a component of aspartame.

Brightly coloured additives may cause allergic reactions in certain patients, especially children.

Sodium benzoate may be converted to benzene in the presence of vitamin C, which may be problematic for patients who are taking vitamin C supplements or have naturally high vitamin C levels.

Glycerine in excessive amounts can cause diarrhoea and other gastrointestinal issues in patients.

However, the excipients discussed above also tend to have beneficial properties in pharmaceutical formulations, especially in terms of stability of the formulation, required storage conditions and its shelf life.

It is therefore desirable to provide alternative pharmaceutical formulations that exclude one or more of the above excipients, yet still provides a stable pharmaceutical formulation that has an acceptable bioavailability and shelf life.

It has been found that dispersing a solid active pharmaceutical agent in a taste masking bulking agent, such as mannitol, for example, may provide a powdered formulation which has the desired stability characteristics without the need to add a preservative, buffer or other excipients.

According to a first aspect of the invention, there is provided a powder for oral solution formulation comprising an active pharmaceutical agent in an amount of 1% to 25% w/w, a taste masking bulking agent in an amount of 60% to 99% w/w, a binder in an amount of 0 to 10% w/w, a taste modifying component in an amount of 0 to 10% w/w and a flow agent in an amount of 0 to 10% w/w.

The taste masking bulking agent is suitably non-hygroscopic.

The taste masking bulking agent may comprise a sugar alcohol, for example a sugar alcohol having a five-carbon chain or a six-carbon chain, or a sugar alcohol derivative.

Examples of five-carbon chain sugar alcohols include arabitol, xylitol and ribitol.

Examples of six-carbon chain sugar alcohols include mannitol, sorbitol, galactitol, fucitol, iditol and inositol.

For example, the taste masking bulking agent may comprise a five-carbon chain sugar alcohol, a six-carbon chain sugar alcohol and mixtures thereof. For example, the taste masking bulking agent may comprise mannitol, sorbitol, xylitol and mixtures thereof. Suitably, the taste masking bulking agent is mannitol.

Sugar alcohols are white, water-soluble solids that contain multiple hydroxyl groups. Accordingly, they are classified as polyols. Sugar alcohols are used in the food industry as sweeteners.

Mannitol is a sugar alcohol that may be used as a sweetener. When taken orally, mannitol is poorly absorbed by the intestines, so it is considered to be a low-calorie excipient.

It has been found that sugar alcohols may be used as taste masking agents for active pharmaceutical agents. As they tend to be poorly absorbed by the body, they may also be used as bulking agents.

It has been found that powder for oral solution formulations that use a sugar alcohol-based taste masking bulking agent do not support bacterial growth. Accordingly, such formulations do not require an additional preservative.

Accordingly, in an embodiment of the invention, the formulation is substantially free from preservatives. The skilled person will understand that the term "preservative" refers to components of the formulation that reduces or prevents microbial growth or undesirable chemical changes in the active pharmaceutical agent. By the term "substantially free" it is meant that the formulation contains less than 0.1%w/w of a preservative agent. Suitably, the formulation contains less than 0.01% w/w of a preservative agent, for example, 0% w/w of a preservative agent.

In order to ensure a pharmaceutically acceptable dispersion of the active agent throughout the formulation (solid phase of the dry powder), the formulation may further include a binder. The binder may be present in an amount of up to 10% w/w. The binder may be a polysaccharide, such as a starch, a cellulose, a modified cellulose and/or a cellulose ether. Examples of modified cellulose materials include microcrystalline cellulose. Examples of cellulose ethers include hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC). The binder suitably comprises one or more cellulose ethers, such as HPC and/or HPMC.

The sugar alcohol provides a relatively sweet taste to the formulation. However, for oral administration, it may be desired to add a further taste modifying component, such as a flavouring. The flavouring may be an artificial flavour (i.e., a synthetic flavour component), a natural flavour (e.g., a natural oil) or a combination thereof. For example, the flavouring component may comprise a fruit oil.

Additionally or alternatively, the formulation may include an acceptable sweetener, such as for example, an acesulfame salt or derivative, stevia and/or cinnamon. The sweetener may comprise acesulfame potassium.

In an embodiment of the invention, the formulation is sugar free. In other words, the formulation does not include a sugar.

In an embodiment of the invention, the formulation further comprises a flow agent. The flow agent may comprise a silicate (e.g., sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, sodium aluminosilicate, calcium aluminosilicate, potassium aluminium silicate and/or aluminium silicate), talc, stearic acid or a stearate salt, or a phosphate (e.g., calcium phosphate and/or tricalcium phosphate). The flow agent may function as an anticaking agent which prevents aggregation or agglomeration of the formulation.

Suitably, the flow agent is a silicate, such as for example, silicon dioxide.

As noted above, the taste modifying component suitably does not include sucrose and/or aspartame. Accordingly, the formulation may be free from sucrose and/or aspartame.

The formulation according to the subject invention may comprise a blend of the active agent and excipients as individual free flowing particles. For powder blends used in dry powder for oral liquid formulations, the weight average particle size range may vary, but is typically in the range 10 to 200 micrometres. This range permits acceptable flow properties and uniform mixing during formulation.

Alternatively, the formulation may comprise a blend of the active agent and excipient particles which have been granulated to form a slightly coarser powder within which the homogeneity of the powder blend is static: Powder blends can be susceptible to segregation during compounding, storage, transport and filling due to differences in particle size, density, concentration and build-up of electrical charge (static electricity). Granulating the homogenous powder blend can overcome this problem. Granules are larger particles formed by agglomerating smaller particles. Their weight averageparticle size can range from 200 pm to several millimetres.

The formulation is soluble in water. For example the formulation suitably has a solubility in water of at least 0.1g/mL, for example, at least 0.5g/mL or at least 1g/mL. The formulation may dissolve in the appropriate volume of water within 3 minute of gentle shaking at room temperature (20°C), for example within 2 minutes of gentle shaking.

The active pharmaceutical agent may be selected from known solid pharmaceutical agents that are used in the following indications/therapeutic targets or fall within the following class of active 25 agents: Agents for the treatment or management of anaemia Agents used in anaesthesia Analgesics and agents used in the treatment or management of pain Antibacterial agents Antidepressant agents Antifungal agents Antihistamines and agents used allergen immunotherapy and allergic emergencies Antihypertensive agents Antiplatelet agents Antiprotozoal agents Antispasmodic agents Cough preparations and systemic nasal decongestants Agents used in the treatment or management of arrhythmia Agents used in the treatment or management of asthma Agents used in the treatment or management of ADHD Calcium channel blockers Cardiac glycosides Agents used in the treatment or management of cerebral palsy and spasticity Agents used in the treatment or management of cholestasis Agents used in the treatment or management chronic heart failure Agents used in the treatment or management of cluster headaches and other trigeminal autonomic cephalalgias Agents used in the treatment or management of coeliac disease Agents used in the treatment or management of constipation Corti co steroids Agents used in the treatment or management of Crohn's disease Agents used in the treatment or management of Cushing's disease Agents used in the treatment or management of cystic fibrosis Agents used in the treatment or management of dementia Agents used in the treatment or management of depression Agents used in the treatment or management of diabetes Agents used in the treatment or management of diarrhoea Diuretics Agents used in the treatment or management of diverticular disease Dopamine receptor agonists Agents effective in the renin-angiotensin system Agents used in the treatment or management of dyslipidaemia Agents used in the treatment or management of dyspepsia Agents used in the treatment or management of epilepsy Agents used in the treatment or management of tremors, chorea, tics and related disorders Agents used in the treatment or management of gastro-oesophageal reflux disease Agents used in the treatment or management of gout Agents used in the treatment or management of hyperthyroidism or hypothyroidism Hypnotics and anxiolytics Agents used in the treatment or management of IBS Agents used in the treatment or management of mania and hypomania Agents used in the treatment or management of migraine Agents used in the treatment or management of motor neurone disease Agents used in the treatment or management of nausea and labyrinth disorders Agents used in the treatment or management of neural tube defects Nitrates Agents used in the treatment or management of nocturnal enuresis Agents used in the treatment or management of nocturnal leg cramps Non-steroidal anti inflammatory agents Agents used in the treatment or management of obesity Oral anticoagulants Agents used in the treatment or management of oral ulceration and inflammation Agents used in the treatment or management of osteoarthritis Agents used in the treatment or management of osteoporosis Agents used in the treatment or management of Parkinson's disease Agents used in the treatment or management of peripheral vascular disease Proton pump inhibitors Agents used in the treatment or management of psychoses and related disorders Quinolones Agents used in the treatment or management of respiratory system diseases Agents used in the treatment or management of rheumatic diseases or rheumatoid arthritis Agents used in the treatment or management of rosacea Agents used in the treatment or management of angina Agents used in the treatment or management of stroke Tetracyclines Agents used in the treatment or management of ulcerative colitis In an embodiment of the invention, the active pharmaceutical agent does not include beta-lactams.

According to a second aspect of the invention, there is provided a method of preparing a powder for oral solution formulation as defined anywhere herein in connection with the first aspect of the invention, wherein the method includes blending the active pharmaceutical agent with the taste masking bulking agent and optionally, the binder, taste modifying agent and/or the flow agent.

In an embodiment of the invention, the method further includes granulation of the blended mixture with water, followed by drying of the granules. Suitably, the drying step comprises a flow of heated air. The air may have an inlet temperature of 40 to 60°C, for example, 45 to 55°C. The air may have a flow rate of 50 to 250 m3/hr, for example, 75 to 200m3/hr or 100 to 150m3/hr.

In a further embodiment of the invention, the method includes the step of milling the granules. The milling step suitably includes a mill which includes a screen having apertures of 0.75 to 2mm, for example, 1 to 1.5mm.

The method may include a second blending step in which the milled granules are blended.

The method may further include a packaging step in which the powdered formulation is filled into suitable containers, such as bottles.

Examples

The following example formulations were prepared using the following method: 1. Add active pharmaceutical agent and excipients to a mixing drum after screening excipients through a 850micrometer sieve.

2. Dry mix the components at impeller speed I for 5 minutes 3. Add sterile water to the mixed components to form a liquid/solid ratio of 0.08-0.09 at an addition rate of 100-105 g/min while granulating the mixture (impeller speed I; chopper speed I) 4. Process the wet mixture for 1 minute.

5. Dry the mixture in a fluid bed dryer having an air inlet temperature of 50°C and an inlet flow rate of 100-150m3/hr.

6. Mill the dried granules using a Co-mill 197 milling machine equipped with a 1.3mm grater and a milling speed of 1678rpm.

7. Blend the milled powder at 12rpm for 20 minutes.

8. Fill into PET bottles and seal Example 1: Formulation 1 n 10mg/rni Pher b vcie.)-for re.con.stitution (final Materials % (w/w) on dry mg/mL (for g/150mL bottle Batch basis 150mL)* fill weights formulation size/kg Phenobarbital Sodium 14.47 11.73 1.76 0.232 Mannitol (taste masking 82.24 66.67 10.00 1.319 bulking agent) Strawberry Flavour ** 1.64 1.33 0.20 0.013 Sweetener Acesulfame K ** 1.64 1.33 0.20 0.026 Total 100.00 81.07 12.16 1.591

I I I

Example 2: Formulation 2 of 10mg/mL Phenobarbital* powder for reconstitution (final volume 150mL) Materials % (w/w) on dry mg/mL (for g/150mL bottle Batch basis 150mL)* fill weights formulation size/kg Phenobarbital Sodium 14.45 11.73 1.76 0.207 Mannitol 82.10 66.67 10.00 1.328 Strawberry Flavour ** 1.64 1.33 0.20 0.032 Sweetener Acesulfame K ** 1.64 1.33 0.20 0.010 Si02 (flow agent) 0.16 0.13 0.02 0.015 Total 100.00 81.20 I 12.18 1.592

I I

Example 3. )ormulation 3 of 10mq/int Phenobarbital* powder for reconstitution (final volume 150mL) Materials % (w/w) on dry mg/mL (for g/150mL bottle Batch basis 150mL)* fill weights formulation size/kg Phenobarbital Sodium 24.41 11.73 1.76 0.387 Mannitol 69.35 33.33 5.00 1.100 Strawberry Flavour ** 2.77 1.33 0.20 0.022 Sweetener Acesulfame K ** 2.77 1.33 0.20 0.044 Si02 0.69 0.33 0.05 0.044 Total 100.00 48.07 7.21 1.597 *Note that the values given in Formulations 1-3, for mg/mL refers to Phenobarbital Sodium. This value accounts for the salt form and loss on drying % from the C of A. The amount of phenobarbital sodium (RMM=254.221 g/mol) equivalent to base (RMM=232.239 g/mol). Values for Phenobarbital Sodium are equivalent to 10mg/ml Phenobarbital protonated.

**For masking the bitter API taste, Acesulfame K and Givaudan strawberry flavour will be added. The level of strawberry flavour in the formulation will be assessed in a subsequent taste trial. A similar formulation uses 5%w/w strawberry oil.

The above Formulations were blended in a 5L drum. Samples were taken from the top, middle and bottom portions of the drum and analysed for uniformity of the blend throughout the drum and for physical characteristics.

One of the physical characteristics tested as Cares Index in relation to the flowability of the formulation.

The following table shows the correlation between the Carr's Index value and the flowability of the formulation: Carr's Index State of Flowability 5-15 Excellent 12-16 Good 18-21 Fair 23-35 Poor 33-38 Very poor >40 Very very poor Results Flowability Formulation ref.* Sample point Carr's index Formulation 1 Top 9.6 Middle 9.9 Bottom 9.9 Formulation 2 Top 15.2 Middle 16.0 Bottom 16.0 Formulation 3 Top 22.5 Middle 19.7 Bottom 21.0 Percentage of API present in samples taken from different positions within the drum Sample ID Result (% of APO Sample 1 Sample 2 Mean Form. 1 Top 95.0 95.0 95.0 Form. 1 Middle 96.3 95.4 95.8 Form. 1 Bottom 99.0 93.7 96.3 Form. 2 Top 94.7 99.3 97.0 Form. 2 Middle 96.6 96.6 96.6 Form. 2 Bottom 92.2 92.6 92.4 Form. 3 Top 96.5 94.8 95.6 Form. 3 Middle 93.2 92.6 92.9 Form. 3 Bottom 94.6 94.7 94.6 Formulation 1 was tested for the presence of the active agent and impurities after dissolution in sterile water to a total volume of 150mL At a storage temperature of 2-8°C, 99.6% of the API was detected after 28 days (desired

specification 95%-105%).

Additionally, at a storage temperature of 2-8°C, 0.055% impurities were detected (desired specification: no individual impurity >0.1%; total impurities <0.2%).

The analysis of the solution of the powdered formulation showed that when refrigerated, the solution is stable over a 28 day period and passes criteria for both assay and impurities.

Example 4:

Using the same method discussed above, a formulation containing morphine sulfate as the active ingredient was prepared as set out the following table: Morphine Sulfate 228.5 * 0.571 4.57 Mannitol (Peal-Mot 50C) 11.429 4571.5 "* 91.43 Acesulfame K 50.0 0.125 1.00 Purified water 394.0 "*" n/a n/a 5000.0 12.5 100.00 Total 3.00 Methocel E6 (FIPMC) Composition % / ) Presentation (g / bottle) Batch Composition (g I batch) 0.375 150.0 *Equivalent to 200mg of morphine sulfate anhydrous.

** Mannitol (e.g., Pearlitol 50C) is q.s. to the final weight, 5kg *** amount of water corresponding to a liquid/solid ratio of 0.08, water is removed during processing and is not present in the final product.

The 5kg batch was used to fill 400 bottles, such that each bottle contained 12.5g of formulation.

The flowability of the batch was determined to be good (Carr's Index: 16.3) Samples of the formulation according to Example 4 were made up to 250m1 with sterile water. The morphine sulfate solutions were then tested for Assay and impurities.

Test Specification TO Result T7 Result T14 result

Assay (*) 92.5-107.5% 98.4% 98.2% 98.2% Related Substances Impurity A: NMT 0.5% Impurity B: NMT 0.4% Impurity F: NMT 0.3% Other impurity: NMT 0.3% Total impurities: NMT 2.0% Impurity A: 0.1% Impurity B:<DL Impurity F:0.1% Other:0.1% Total: 0.4% Impurity A:0.1% Impurity B:<DL Impurity F:<DL Other:0.1% Total: 0.3% Impurity A:0.1% Impurity B:<DL Impurity F:<DL Other:0.1% Total: 0.3% Microbiology TAMC: NMT 102 cfu/g TYMC: NMT 10 cfu/g E.Coli: Absent in lg <100 <100 <100 <10 <10 <10 Not detected Not detected Not detected (*) expressed as % of nominal content of Morphine Sulfate anhydrous NMT = Not More Than DL = detection level Impurity A = codeine Impurity B = 2,2'-bimorphine Impurity F = morphine N-oxide Other impurities: oripavine, morphinone, 10s-hydroxymorphine

Claims (18)

1. Claims 1. A powder for oral solution formulation comprising an active pharmaceutical agent in an amount of 1% to 25% w/w, a taste masking bulking agent in an amount of 60% to 99% w/w, a binder in an amount of 0 to 10% w/w, a taste modifying component in an amount of 0 to 10% w/w and a flow agent in an amount of 0 to 10% w/w.
2. 2. A powder for oral solution formulation according to Claim 1, wherein the taste masking bulking agent comprises a sugar alcohol.
3. 3. A powder for oral solution formulation according to Claim 2, wherein the sugar alcohol comprises a five-carbon chain, a six-carbon chain or mixtures thereof.
4. 4. A powder for oral solution formulation according to Claim 3, wherein the sugar alcohol comprises mannitol, sorbitol, xylitol and mixtures thereof.
5. 5. A powder for oral solution formulation according to Claim 4, wherein the sugar alcohol comprises mannitol.
6. 6. A powder for oral solution formulation according to any of Claims 1 to 5, wherein the binder is a polysaccharide.
7. 7. A powder for oral solution formulation according to Claim 6, wherein the polysaccharide is selected from a starch, a cellulose, a modified cellulose and/or a cellulose ether.
8. 8. A powder for oral solution formulation according to Claim 7, wherein the polysaccharide is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and mixtures thereof.
9. 9. A powder for oral solution formulation according to any of Claims 1 to 8, wherein the taste modifying component comprises a flavouring and/or a sweetener.
10. 10. A powder for oral solution formulation according to Claim 9, wherein the flavouring is a fruit oil, a herb oil, a synthetic flavouring or a mixture thereof.
11. 11. A powder for oral solution formulation according to Claim 9, wherein the sweetener is an acesulfame salt or derivative.
12. 12. A powder for oral solution formulation according to any of Claims 1 to 11, wherein the flow agent comprises a silicate, talc, stearic acid or a salt thereof, and/or a phosphate.
13. 13. A powder for oral solution formulation according to Claim 12, wherein the flow agent is selected from sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, sodium aluminosilicate, calcium aluminosilicate, potassium aluminium silicate, aluminium silicate, calcium phosphate and/or tricalcium phosphate.
14. 14. A powder for oral solution formulation according to any of Claims 1 to 13, wherein the active pharmaceutical agent is an analgesic or an anti-epileptic agent.
15. 15. A powder for oral solution formulation according to any of Claims 1 to 14, wherein the formulation includes less than 0.1% w/w of a preservative.
16. 16. A powder for oral solution formulation according to any of Claims 1 to 15, wherein the formulation includes less than 0.1% w/w of a sugar.
17. 17. A powder for oral solution formulation according to any of Claims 1 to 16, wherein the active pharmaceutical agent is not a beta lactam.
18. 18. A method of preparing a powder for oral solution formulation as defined in any of Claims 1 to 17, wherein the method includes blending the active pharmaceutical agent with the taste masking bulking agent and optionally, with the binder, taste modifying agent and/or the flow agent.