IES20110480A2

IES20110480A2 - A solid formulation for oral administration comprising polyethylene glycol and mannitol

Info

Publication number: IES20110480A2
Application number: IE20110480A
Authority: IE
Inventors: Peter Stein; Ian Cox; Samuel Smith; Leighton Jones; Plessl
Original assignee: Norgine Bv
Priority date: 2010-11-04
Filing date: 2011-11-04
Publication date: 2012-07-18
Also published as: DK201100161U3; FI9608U1; FR2967069B3; FR2967069A3; AT12928U1

Abstract

The invention relates to solid forulations for oral administration comprising polyethylene glycol, mannitol, magnesium stearate and flavouring, and to use of the formulations for treating or preventing gastrointestinal disorders or maintaining gastrointestinal health in a subject.

Description

The present invention relates to solid formulations, particularly to chewable or suckable solid formulations (for example tablets), comprising polyethylene glycol and mannitol.

Polyethylene glycol (PEG) has been shown to have beneficial effects in healthy subjects in low doses. For example, Hudziak et al. (Hudziak, H. et al., Gastroenterol. Clin. Biol., 1996,20,418-423) showed that healthy subjects taking 20g of PEG 4000 per day (without accompanying electrolytes) had a significantly increased stool frequency. Mean stool weight was also shown to be increased. In a similar study, Fiourie ei al. (Flourie, B et al., Gastroenterol. Clin. Biol., 1994,18, A108) showed that stool weight and stool frequency was significantly increased in healthy subjects taking low doses of PEG with electrolytes (sodium chloride, sodium bicarbonate and potassium chloride). Bernier and Donazzolo (Bernier, J-J., and Donazzolo, Y., Gastroenterol. Clin. Biol., 1997, 21, 7-11) reported that low doses of PEG 3350 in the presence of electrolytes (5.9g PEG per day with 146mg sodium chloride, 568mg sodium sulphate, 75mg potassium chloride and 168mg sodium bicarbonate) led to stool softening in healthy subjects.

In the vast majority of published work regarding PEG-based products for oral ingestion, the PEG is taken as a solution/suspension in water. Taking compositions as solutions or suspensions is in many cases less convenient than taking a solid composition, as solutions and suspensions require the subject to carry a larger quantity of composition with them, or else require the subject to make use of a vessel and a source of liquid. Particularly for compositions that may be taken several times per day and/or at a time of the subject’s choosing, solid compositions offer many advantages to a subject.

Solid PEG products for ingestion in solid form have been described in some patent specifications. For example, in W02005/102364, there is described a solid pharmaceutical composition comprising PEG and electrolytes for treating constipation, faecal impaction, faecal retention, intestinal gas and cramping, flatulence, or for cleansing the colon, wherein the PEG makes up from 80 to 99.5% by weight of the composition. In UNDER SECTION 28 AND ROLE 23 IEU 4 80 W02006/122104, there are described possible ingredient ranges for a solid colonic purgative composition comprising PEG and various other ingredients.

To date, no PEG-based products for ingestion in solid form have reached the market. There may be several reasons for this. Preparation of solid dosage forms that simultaneously have good structural integrity (ie sufficient hardness to hold together), but yet are comfortably chewable by a subject (ie a hardness that is not so high as to affect the subject’s ease of taking the dosage) is not straightforward. It is known to add excipients to solid dosage forms to assist in achieving satisfactory overall properties. In order for good compliance to be maintained, the subject must not experience discomfort or inconvenience when taking the dosage form. Accordingly, each tablet should be of a size that can be chewed, sucked or swallowed without any discomfort, and it should not be necessary to take more than three tablets per day. Therefore, if an active component is to be taken in quantities of over 500mg per day, for example over lg or over 2g per day (as is the case with PEG), then the total amount of excipients that can be included is limited by the overall size of a tablet, and the number of tablets that might be needed to accommodate the total amount of actives and excipients. In addition, a solid dosage form must have good manufacturing properties (minimal capping or laminating of tablets, or sticking to tableting machinery) and excipients must not impart an unpleasant taste or mouthfeel to the formulation. Formulation of a PEG solid dosage form that has good manufacturing properties and good subject compliance is thus difficult.

The present invention provides a solid formulation for oral administration as a solid, comprising; (a) (b) about 82 to 84% w/w (for example 2273.7mg) polyethylene glycol (PEG) having an average molecular weight within the range 3,000 to 4,000 Da; about 14 to 17% w/w (for example 420.75 mg) mannitol; (c) about 0.5% w/w (for example 13.75mg) magnesium stearate; and (d) flavouring. “% w/w” of a component is understood herein to mean the proportion, as a percentage, that the weight ofthe component makes up of the total weight of the solid formulation.

IE110 4 80 Preferably, the solid formulation is chewable and/or suckable. It may be a solid tablet, for example a chewable and/or suckable tablet.

It has surprisingly been found that a solid formulation of the invention is pleasantly chewable or suckable, has good taste, structural integrity and beneficial manufacturing properties. By chewable or suckable is meant herein that the formulation is for oral administration and not to be swallowed whole but chewed or sucked in the mouth so that the first step in the digestive process starts in the buccal cavity. Herein, a powder formulation is not considered suitabie for administration as a solid. A formulation of the invention is preferably not effervescent in contact with water.

Formulations of the invention are preferably substantially free from electrolytes. For example, they are preferably substantially free from sodium chloride, potassium chloride and sodium bicarbonate. They are preferably substantially free from sulphates or phosphates, for example, they are preferably from free sodium sulphate. Formulations of the invention are preferably substantially free from carbonates or bicarbonates. In many instances, flavourings, lubricants and sweeteners may contain small amounts of electrolytes. Such amounts are not considered herein to be “substantial”. Formulations of the invention are preferably substantially free from alginates.

It has been found by the present inventors that a solid formulation of the invention is more palatable than a solid formulation comprising PEG and no mannitol, even if flavouring is added. In particular, it has been found that a tablet of the invention has a low requirement for lubricant or lubrication during tablet manufacture. A high level of a lubricant in a tablet generally makes the tablet have an unacceptable taste.

The polyethylene glycol (PEG) for use in solid formulations of the invention has an average molecular weight (for example a weight average molecular weight), in Daltons, within the range 3,000 to 4,000. For example, the PEG may be, or comprise PEG 3,350, PEG 4,000 as defined in national pharmacopoeias. Further examples of suitable PEGs recognized in some national pharmacopoeias include Macrogols, for example Macrogol 4,000. Optionally, the PEG used in compositions of the invention may comprise two or IE 1 1 Ο 4 eo more different PEG components. PEG of the relevant molecular weights in a form suitable for use in humans is available commercially.

— -Typically, solid formulations of dry ingredients are manufactured using dry granulation followed by punching with punch and die equipment. In a punch and die machine, dry ingredients are compressed together. It has surprisingly been found that a solid formulation of the invention has good structural integrity and is convenient to manufacture. Solid formulations of the invention are not susceptible to capping and laminating during punch and die manufacture. Solid formulations that become capped or laminated during die pressing are not suitable for use and they become waste. It has been found by the current inventors that a solid fonnulation of the invention has good tablet pressing characteristics. Mannitol is commercially available from several suppliers, including Merck, SPI Polyols Inc and Roquette.

It has also surprisingly been found that a solid fonnulation of the invention is not prone to sticking to punch and die equipment A solid formulation of the invention can be of any convenient size. A tablet should be sufficiently large to provide thedesired quantity of PEG to the subject, but not be so large as to be uncomfortable in the mouth, difficult to chew or suck, or difficult to package.

In one embodiment, a tablet of the invention has a mass of 2.75g.

For example, a soiid formulation of the invention comprises: (a) 82.7% w/w (for example 2273.7mg) polyethylene glycol (PEG) having an average molecular weight within the range 3,000 to 4,000 Da; (b) 15.3% w/w (for example 420.75 mg) mannitol; (c) 0.5% w/w (for example 13.75mg) magnesium stearate; and (d) 1.5% w/w (for example 41.8mg) flavouring.

For example, a solid formulation of the invention comprises; (a) 82.9%w/w (for example 2284mg) polyethylene glycol (PEG) having an average molecular weight within the range 3,000 to 4,000 Da; (b) 16.2% w/w (for example 446 mg) mannitol; IE1 1 0 4 80 .- (c) 0.5% w/w (for example 13.75mg) magnesium stearate; and (d) 0.4% w/w (for example 1 lmg) flavouring.

The solid formulations of the invention can be taken on their own as presented and chewed or sucked by a subject. It is not necessary for a subject to take water or another drink with the solid formulation. Some subjects may wish to drink water or another fluid with or soon after taking a solid formulation of the invention so as to facilitate the intake. The convenient packaging and the lack of a need to take water or another drink greatly increases the convenience of the solid formulations to subjects in comparison with other forms of PEG-based products currently on the market.

The number of solid formulations (and thus the total mass of PEG) that a subject takes depends on the subject’s perceived needs.

In one embodiment, a solid formulation of the invention may be used as a PEG-based composition to prevent gastrointestinal disorders. The composition may be particularly beneficial for maintenance of good health, in particular maintenance of good gastrointestinal health. It may, for example, prevent dehydration of the stool, soften the stool for ease of defaecation, prevent constipation and allow regular gastrointestinal transit. The solid formulation of the invention may be used to promote stool softening, increase stool weight and/or increase stool frequency in healthy subjects. Improvement of those features may lead to an increased sensation of well-being.

The invention thus provides a method of preventing gastrointestinal disorders in a healthy subject, for example softening the stool, increasing stool weight and/or increasing stooi frequency, preventing dehydration of the stool, softening the stool for ease of defaecation or preventing constipation in a healthy subject, comprising administering a solid formulation according to the invention. In particular, it provides a method of non25 therapeutically preventing gastrointestinal disorders in a healthy subject, for example softening the stool, increasing stool weight and/or increasing stool frequency, preventing dehydration of the stool, softening the stool for ease of defaecation or preventing constipation in a healthy subject. For example may be subject of more than 50 years of age, for example more than 60, 65 or 70 years of age.

|E 11 0 4 80 In an alternative embodiment, a solid formulation of the invention is for use as a medicament. For example, the medicament may be for the treatment of a gastrointestinal disorder, for example constipation, faecal impaction, faecal retention or other gastrointestinal disorder. The medicament may be for therapeutically softening the stool, therapeutically increasing stool weight and/or therapeutically increasing stool frequency in a subject in need thereof. Accordingly, the invention provides a method of therapeutically softening the stool, therapeutically increasing stool weight, therapeutically increasing stool frequency, or treating constipation, faecal impaction, faecal retention or another gastrointestinal disorder in a subject in need thereof comprising administering a solid formulation of the invention to the subject.

IE 1 1 0 4 8 0 Examples Example: Tablets of the invention The tablets described in Table 1 were prepared by combining the dry ingredients and compressing in a punch and die machine. The machine was a Manesty 16 punch D machine with a standard stainless steel punch and die with flat 22mm diameter and beveled edge with PTFE and vulcalon inserts from I Holland Ltd.

Table 1- Composition of Tablets of the Invention Component Tablets of the invention Unit formula A 5kg bag blend Unit formula B 5kg bag blend PEG av. MW 3000- 4000 2284mg (82.9%) 4.155kg 2273.7mg (82.7%) 4.144kg Mannitol 446mg(16.2%) 0.810kg 420.75 mg (15.3%) 0.765kg Magnesium Stearate 13.75mg(0.5%) 0.025kg 13.75mg (0.5%) 0.025kg Flavouring llmg(0.4%) (peppermint) 0.020kg 41.8mg(1.5%) (raspberry-lemon) 0.075kg Total wt 2754.75mg 2749.3mg Table 2 - Properties of Tablet of the Invention Unit Formula A Unit Formula B Ease of Manufacture No sticking or capping; good weight and hardness control; good appearance Good weights and hardness throughout batch Taste Acceptable teste Acceptable taste Hardness 6.34-9.19kg 8.95-14.29kg IE 1 1 0 4 80

Claims

CLAIMS:

1. A solid formulation for oral administration as a solid, comprising: (a) about 82 to 84% w/w polyethylene glycol (PEG) having an average molecular weight within the range 3,000 to 4,000 Da: (b) about 14 to 17% w/w mannitol; (c) about 0.5% w/w magnesium stearate; and (d) flavouring.

2. A solid formulation as claimed in claim 1 comprising; (a) about 2284mg of PEG; (b) about 446mg mannitol; (c) about 13.75mg magnesium stearate; (d) about 11 mg flavouring or (a) about 2273.7mg of PEG; (b) about 420.75 mg of mannitol; (c) about 13.75mg of magnesium stearate; (d) about 41,8mg flavouring.

3. A solid formulation as claimed in claim 1 or claim 2 in the form of a tablet, preferably in the form of a chewable or sucltable tablet.

4. A solid formulation as claimed in any of claims 1 to 3 for use as a medicament, preferably for use in the treatment or prevention of gastrointestinal disorders in a subject.

5. Use of a solid formulation as claimed in any of claims 1 to 3 for nontherapeutically maintaining gastrointestinal health in a subject. ANNE RYAN & CO. AGENTS FOR THE APPLICANT