FORMULATIONS COMPRISING POLYETHYLENE GLYCOL

Abstract

The present invention concerns a solid formulation for oral administration as a solid comprising polyethylene glycol and a further solid such as mannitol. The formulation may be used to prevent gastrointestinal disorders such as constipation in healthy subjects. In some embodiments, the solid formulation is chewable or suckable.

Claims

1. A solid formulation for oral administration as a solid, comprising: (a) 60-90% w/w polyethylene glycol (PEG) having an average molecular weight within the range 2,000 to 10,000 Da; and (b) 14-40% w/w of mannitol.

2. A solid formulation of claim 1 comprising 82 to 84% w/w PEG.

3. A solid formulation of claim 1 comprising 15 to 20% w/w of mannitol.

4. A solid formulation of claim 1 wherein the mannitol is granular mannitol.

5. A solid formulation of claim 1 wherein the PEG has an average molecular weight of between 3,000 and 4,100 Da.

6. A solid formulation of claim 1, comprising: (a) 70-90% w/w polyethylene glycol (PEG) having an average molecular weight within the range 2,000 to 10,000 Da; (b) 15-20% w/w of mannitol; (c) 0-2.0% w/w lubricant; and (d) 0-2.0% w/w flavouring.

7. A solid formulation of claim 1, comprising PEG and mannitol in a weight ratio of PEG:mannitol=3:1 to 9:1.

8. A solid formulation of claim 1 comprising a lubricant in an amount of 2.0% w/w or less.

9. A solid formulation of claim 8 wherein the lubricant is present in an amount of 0.2 to 0.8% w/w.

10. A solid formulation of claim 8 wherein the lubricant is present in an amount of 0.5% w/w.

11. A solid formulation as claimed in claim 8 wherein the lubricant is magnesium stearate.

12. A solid formulation of claim 1 comprising a flavouring.

13. A solid formulation as claimed in claim 12, wherein the flavor is peppermint or raspberry/lemon flavouring

14. A solid formulation of claim 1 that is substantially free from electrolytes.

15. A solid formulation of claim 14 that is substantially free from sodium chloride, potassium chloride, bicarbonates sulphates or phosphates.

16. A solid formulation of claim 1 that has a mass of 1.0 to 5.0 g.

17. A solid formulation as claimed in claim 16 that has a mass of 2.0 to 3.5 g and comprises: (a) 1.20-3.15 g polyethylene glycol (PEG) having an average molecular weight within the range 2,000 to 10,000; (b) 0.30-1.40 g mannitol.

18. A solid formulation as claimed in claim 1 that comprises; (a) 2273 to 2284 mg polyethylene glycol (PEG) having an average molecular weight within the range 3,000 to 4,000 Da; (b) 420 to 446 mg of mannitol; (c) 13.5 to 13.75 mg magnesium stearate; and (d) 11 to 42 mg flavour.

19. A method of softening the stool for ease of defecation and allowing regular gastrointestinal transit, in a subject, comprising administering a solid formulation as claimed in claim 1 to the subject, wherein the subject consumes a sufficient amount of formulation to receive up to 6 g or thereabout per day of PEG.

20. The method of claim 19 wherein the subject is healthy.

21. A chewable or suckable solid formulation for oral administration as a solid comprising; (a) 2.0 to 3.5 g PEG having an average molecular weight of 3000 to 4000 Da; (b) 300 to 500 mg of mannitol; (c) optional flavouring which if present is in an amount of 5 to 75 mg; (d) optional lubricant which if present is in an amount of 5 to 25 mg.

22. A chewable or suckable solid formulation as claimed in claim 21, comprising 2.1 to 2.5 g PEG.

23. A chewable or suckable solid formulation as claimed in claim 21, comprising 420 to 450 mg of mannitol.

24. A chewable or suckable solid formulation as claimed in claim 21, wherein the lubricant is magnesium stearate.

25. A method of softening the stool for ease of defecation and allowing regular gastrointestinal transit, comprising administering a solid formulation as claimed in claim 21.

26. A pack comprising a plurality of units of solid formulations comprising (a) 60-90% w/w polyethylene glycol (PEG) having an average molecular weight within the range 2,000 to 10,000 Da; and (b) 14-40% w/w of mannitol; or (a) 2.0 to 3.5 g PEG having an average molecular weight of 3000 to 4000 Da; (b) 300 to 500 mg of mannitol; (c) optional flavouring which if present is in an amount of 5 to 75 mg; (d) optional lubricant which if present is in an amount of 5 to 25 mg.

27. A pack as claimed in claim 25, wherein the solid formulation comprises 2.1 to 2.5 g PEG.

28. A pack as claimed in claim 25, wherein the solid formulation comprises 420 to 450 mg of mannitol.

29. A pack as claimed in claim 25, wherein the solid formulation comprises magnesium stearate as the lubricant.

Description

EXAMPLES

Example 1: Comparison of PEG Tablets without Mannitol with PEG Tablets Including Mannitol

[0124] The tablets described in Table 1a were prepared. The materials were dispensed and then bag blended. The unit formula amounts were compressed on a Manesty D machine at normal manufacturing speed and with a standard stainless steel punch and die with flat 22 mm diameter and beveled edge and PTFE inserts. The properties of the tablets were noted and they are given in Table 1b below. In the tables, * denotes comparative examples.

[0125] It is seen in Tables 1a and 1b that tablet 1A, made up only of PEG, stuck to the punches and were capped and chipped. It was possible to reduce the capping and chipping to an extent by including magnesium stearate, as seen in tablets 1B, 1C and 1D. However, tablets including magnesium stearate had a poor taste, and the hardness was poor, particularly with the higher amounts of magnesium stearate in tablets 1C and 1D. In contrast, tablet 1E that includes mannitol had a better taste, good hardness and was well manufactured with only minimal capping.

[0126] It is seen that addition of mannitol provides a tablet that has good processing characteristics with only 0.5% w/w of magnesium stearate lubricant. It is also seen that a pleasant taste is achieved in the tablet containing mannitol, something not achieved in the tablets lacking mannitol.

TABLE-US-00001 TABLE 1a Composition of Tablets 1A to 1E Tablet 1A* Tablet 1B* Tablet 1C* Tablet 1D Tablet 1E Unit 5 kg bag Unit 5 kg bag Unit 5 kg bag Unit 5 kg bag Unit 5 kg bag Component formula blend formula blend formula blend formula blend formula blend PEG average 3000 mg 5.00 kg 2985 mg 4.98 kg 2700 mg 4.50 kg 2400 mg 4.00 kg 2535 mg 4.23 kg MW 3000-4000 (100%) (99.5%)   (90%) (80%) Mannitol — — — — — — — —  450 mg 0.75 kg  (15%) Magnesium — —  15 mg 0.03 kg  300 mg  0.5 kg  600 mg 1.00 kg  15 mg 0.03 kg Stearate  (0.5%) (10.0%) (20%) (0.5%) Total wt 3000 mg 3000 mg 3000 mg 3000 mg 3000 mg

TABLE-US-00002 TABLE 1b Properties of Tablets 1A to 1E Ease of Capping, Poor Some Unable Slight Manu- chipping hardness capping. to form capping facture and sticking and weight. Difficult to tablet to punches Difficult to compress. compress. Taste Poor taste Poor taste Poor taste Better taste Hardness 6.37-13.59 kg 2.47-5.60 kg 0.7-1.8 kg 0.4-6.1 kg

Example 2: Comparison of Tablets Containing Different w/w % of Mannitol

[0127] The tablets described in Table 2 were prepared by combining the dry ingredients and compressing in a punch and die machine. For tablets 2A to 2C, the machine was a Manesty 16 punch D machine with a standard stainless steel punch and die with flat 22 mm diameter and beveled edge with PTFE and vulcalon inserts from I Holland Ltd. For tablets 2D and 2E, the unit formula amounts were compressed on a Manesty D machine at normal manufacturing speed and with a standard stainless steel punch and die with flat 22 mm diameter and beveled edge. The properties of the tablets were noted and they are given in Table 2b below. In the tables, * denotes comparative example.

[0128] Tablet 2A had an acceptable taste. However, the tablets were prone to sticking to the tableting machine, and many tablets were capped or laminated, making them unusable. Tablet 2B contained the same flavouring as tablet 2A, but more mannitol (15.3% vs. 9.1% in 2A) and less flavouring (1.5% vs. 5.4%). Tablet 2B had an acceptable taste and there was no evidence of sticking to the tableting machine, or capping or laminating of the tablets. Tablet 2C contains similar amounts of PEG, mannitol and magnesium stearate to tablet 2B, but the flavouring is peppermint. It displays similar characteristics to tablet 2B. Tablet 2D contained no flavouring, and 10% mannitol. It displayed no capping or sticking and only a small amount of chipping. Tablet 2E contained no flavouring, and 40% mannitol. It displayed good manufacturing characteristics. Tablets 2D and 2E had a bland taste as compared with tables 2A to 2C. This is most likely because of the absence of flavouring. The taste was, however, not unpleasant. Tablets 2F to 2H all displayed good manufacturing characteristics and an acceptable taste.

[0129] It is seen that a tablet containing from 59.5 to 89.5% w/w PEG (in particular 82.7 or 82.9% w/w PEG) and 10 to 40% /w mannitol (in particular 15.3 or 16.2% w/w mannitol) has better ease of manufacture characteristics than a tablet containing 85.0% PEG and 9.1% mannitol.

TABLE-US-00003 TABLE 2a Composition of Tablets 2A to 2E Tablet 2A* Tablet 2B Tablet 2C Tablet 2D Unit 5 kg bag Unit 5 kg bag 255 kg Unit 5 kg bag 255 kg Unit 5 kg bag Component formula blend formula blend batch formula blend batch formula blend PEG av. MW 2339 mg  4.25 kg 2273.7 mg 4.144 kg 211 kg  2284 mg 4.155 kg 212 kg  2685 mg 4.48 kg 3000-4000 (85.0%)  (82.7%) (82.9%) (89.5%)   Mannitol 250 mg 0.45 kg 420.75 mg 0.765 kg 39 kg   446 mg 0.810 kg 41 kg   300 mg 0.50 kg (9.1%) (15.3%) (16.2%) (10%) Magnesium 13.75 mg   0.03 kg  13.75 mg 0.025 kg 1 kg 13.75 mg  0.025 kg 1 kg  15 mg 0.03 kg Stearate (0.5%)  (0.5%)  (0.5%) (0.5%)  Flavouring 150 mg 0.27 kg  41.8 mg 0.075 kg 4 kg  11 mg 0.020 kg 1 kg — — (5.4%)  (1.5%)  (0.4%) (raspberry- (raspberry- (peppermint) lemon) lemon) Total wt 2752.75 mg    2749.3 mg 2754.75 mg   3000 mg Tablet 2E Tablet 2F Tablet 2G Tablet 2H Unit 5 kg bag 5 kg bag 5 kg bag Component formula blend Unit formula blend Unit formula blend Unit formula 5 kg bag blend PEG av. MW 1785 mg 2.98 kg 2270 mg 3.96 Kg 2045 mg 3.705 Kg 1900 mg 3.46 Kg 3000-4000 (59.5%)   (79%)   (74%)  (69%) Mannitol 1200 mg 0.75 kg  574 mg  1.0 Kg  690 mg  1.25 Kg  827 mg  1.5 Kg   (40%)   (20%)   (25%)  (30%) Magnesium  15 mg 0.03 kg  14 mg 0.025 Kg   14 mg 0.025 Kg  14 mg 0.025 Kg  Stearate  (0.5%) (0.49%) (0.5%) (0.5%) Flavouring — —  11 mg 0.02 Kg  11 mg  0.02 Kg  11 mg 0.02 Kg (Peppermint) (peppermint) (Peppermint) (0.38%) (0.4%) (0.4%) Total wt 3000 mg 2870 mg  5.0 Kg 2760 mg  5.0 Kg 2756 mg  5.0 Kg

TABLE-US-00004 TABLE 2b Properties of Tablets 2A to 2E Ease of Some capping, Reliable Reliable Some Good Manufacture chipping and manufacture with manufacture with chipping control, sticking minimal capping, minimal capping, of tablets, but good to punches chipping or chipping or sticking acceptable. appearance sticking at at 255 kg scale. Weight 255 kg scale. No sticking or and hardness Good weights capping; good weight consistent and hardness and hardness control; throughout batch good appearance at 5 kg scale. at 5 kg scale. Taste Acceptable taste Acceptable taste Acceptable taste Bland Bland Hardness Not measured 8.95-14.29 kg 6.34-9.19 kg 4.42-7.34 kg 5.96-10.2 kg (measured (measured for 5 kg batch) for 5 kg batch) Properties of Tablets 2F to 2H Ease of Appearance Appearance Appearance Manufacture of tablet of tablet of tablet good, no capping good, no capping good, no capping Taste Acceptable taste Acceptable taste Acceptable taste Hardness 6.28-14.4 Kg 5.12-7.5 Kg 7.27 Kg-10.15 Kg

Example 3: Comparison of Tablets Containing Mannitol and Different w/w % of Magnesium Stearate

[0130] The tablets described in Table 3a were prepared. The materials were dispensed and then bag blended. The unit formula amounts were compressed on a Manesty D machine at normal manufacturing speed and with a standard stainless steel punch and die with flat 22 mm diameter and beveled edge and PTFE inserts. The properties of the tablets were noted and they are given in Table 3b below. In the tables, * denotes comparative example.

[0131] It is seen in Tables 3a and 3b that tablets containing PEG and 15% w/w mannitol and 0.2%, 0.5% or 5.0% w/w magnesium stearate have good manufacturing properties and acceptable taste.

TABLE-US-00005 TABLE 3a Composition of Tablets 3A to 3C Tablet 3A Tablet 3B Tablet 3C 5 kg bag 5 kg bag 5 kg bag Component Unit formula blend Unit formula blend Unit formula blend PEG average MW 2544 mg 4.24 kg 2400 mg  4.0 kg 2535 mg 4.23 kg 3000-4000 (84.8%) (80%) (84.5%) Mannitol  450 mg 0.75 kg  450 mg 0.75 kg  450 mg 0.75 kg   (15%) (15%)   (15%) Magnesium Stearate   6 mg 0.01 kg  150 mg 0.25 kg  15 mg 0.03 kg  (0.2%)  (5%)  (0.5%) Flavouring — — — — — — Total wt 3000 mg 3000 mg 3000 mg

TABLE-US-00006 TABLE 3b Properties of Tablets 3A to 3C Ease of Tablets good, Tablets good Slight Manufacture no capping capping Taste Bland taste Bland taste, Better taste slightly artificial Hardness 5.4-11.0 kg 4.42-7.34 kg 0.4-6.1 kg

Example 4: Comparison of Various Flavours of PEG+Mannitol Tablets

[0132] Tablets analogous to the tablets of Example 2 with a variety of flavourings 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 22 mm diameter and beveled edge with PTFE and vulcalon inserts from I Holland Ltd.

[0133] The tablets were provided to a panel of tasters. They were asked to taste each of the tablets and score them with an emphasis on the flavour, scoring from 1 (unpleasant) to 5 (pleasant). There were 22 tasters and their scores were summed together. It was found that peppermint flavoured tablets (score=65) and lemon-raspberry flavoured tablets (score=87) were preferred over lemon-lime flavoured tablets (score=37) and orange flavoured tablets (score=23).

Example 5: Comparison of Tablets Containing Various Other Solids

[0134] Tablets containing solids other than mannitol were prepared in the same manner as the tablets of Example 2 supra. The composition and properties of these tablets are noted in Table 5a and 5b below.

TABLE-US-00007 TABLE 5A Comparison of Alternative Solids Tablet 5A Tablet 5B Tablet 5C Unit amount/ Unit amount/ Unit amount/ Component 5 Kg blend 5 Kg blend 5 Kg blend PEG av. 2276 mg/4.145 Kg 2279 mg/4.145 Kg 2280 mg/4.145 Kg MW   (83%)   (83%) 3000-4000 Solid Sorbitol Lactose/Starch.sup.1 Xylitol  445 mg/0.81 Kg  446 mg/0.81 Kg  446 mg/0.81 Kg (16.2%) (16.2%) Magnesium  14 mg/0.025 Kg  14 mg/0.025 Kg  14 mg/0.025 Kg Stearate (0.51%) (0.51%) (0.51%) Flavouring  11 mg/0.02 Kg  11 mg/0/02 Kg  11 mg/0.02 Kg (0.40%) (0.40%) (0.40%) Total wt 2746 mg/5.0 Kg 2753 mg/5.0 Kg 2750 mg/5.0 Kg .sup.1Lactose/starch compound, StarLac ® (Roquette Pharma, Northants, UK) is a spray-dried compound consisting of 85% alpha-lactose monohydrate (Ph. Eur./USP-NF) and 15% maize starch (Ph. Eur./USP-NF) dry matter.

TABLE-US-00008 TABLE 5b Properties of Tablets 5A to 5C Ease of Tablet appearance Tablet appearance Tablet appearance Manufacture good, no capping good, no capping good, no capping Taste Tasted ok but lacked Good hardness, Tasted ok, but enhanced mouth feel tasted bland tablet too soft of mannitol tablets Hardness 6.97-10.09 Kg 4.13-9.4 Kg 4.67-7.99 Kg

Example 6—Comparison of Tablets Containing Further Various Solids

[0135] Tablets containing solids other than mannitol were prepared in the same manner as the tablets of example 2 supra. The composition and properties of these tablets are noted in Table 6a and 6b below.

TABLE-US-00009 TABLE 6a Comparison of alternative solids Tablet 6A Tablet 6B Tablet 6C Unit amount/ Unit amount/ Unit amount/ Component 5 Kg blend 5 Kg blend 5 Kg blend PEG av. MW 2279 mg/4.145 Kg 2279 mg/4.145 Kg  2263 mg/4.145 Kg 3000-4000 (82.9%) (82.9%) (82.9%) Solid Lactose Dextratel Cellulose2  445 mg/0.810 Kg  440 mg/0.800 Kg   442 mg/0.810 Kg (16.2%) (16.0%) (16.2%) Magnesium  14 mg/0.025 Kg  14 mg/0.025 Kg  13.6 mg/0.025 Kg Stearate  (0.5%) (0.50%)  (0.5%) Flavouring  11 mg/0.020 Kg  11 mg/0.020 Kg   11 mg/0.020 Kg  (0.4%)  (0.4%)  (0.4%) Total wt 2750 mg/5.0 Kg 2746 mg/4.99 Kg  2730 mg/5.0 Kg .sup.1Emdex ®, available from JRS Pharma, Rosenberg, Germany. .sup.2Avicel ®, microcrystalline cellulose, available from FMC biopolmers, Philadelphia, USA.

TABLE-US-00010 TABLE 6b Properties of Tablets 6A to 6C Ease of Tablet appearance Tablet appearance Tablet appearance Manufacture good, no capping, good, some good, no capping hardness good capping Taste Taste ok, but Pleasant taste Taste unpleasant very bland but quite soft Hardness 5.2-13.6 Kg 5.4-11.9 Kg 7.1-13.4 Kg