POLYMER COMPOSITIONS

Abstract

The invention relates to novel a high-volume swelling hydrogel which comprises a plurality of pores which are defined by an interpenetrating network, and/or a semi-interpenetrating network and/or simple cross-linked arrangement of a plurality of one or more species of hydrophilic polymers, optionally together with one or more biocompatible polymers and optionally together with one or more plasticising agents, characterised in that at least some of the pores are at least partially collapsed and/or flattened, and further characterised in that the interpenetrating network and/or semi-interpenetrating network and/or cross-linked arrangement which defines the collapsed and/or flattened pores is substantially unbroken. The invention also relates to a process for preparing such hydrogels, and to their use as an appetite suppressant.

Claims

1. A dosage regimen comprising the step of administering to a patient, suffering from one or more medical conditions selected from obesity and diabetes, a first dose of a product formulation, which is retained in the stomach of the treated patient for at least one day, the first dose comprising one or more compressed hydrogels in an amount which will swell to fill up to 80% of the volume of the treated patient's stomach.

2. The dosage regimen according to claim 1 comprising administering to the patient a second dose of a product formulation, which is retained in the stomach of the treated patient for at least one day, the second dose comprising one or more compressed hydrogels in an amount which will swell to maintain up to 80% of the volume of the treated patient's stomach to be filled.

3. The dosage regimen according to claim 2 further comprising administering one or more further doses of a product formulation, at time intervals of at least 12 hours, which are retained in the stomach of the treated patient for at least one day, the one or more further doses comprising one or more compressed hydrogels.

4. The dosage regimen according to claim 1 further comprising a step of administering the treated patient with at least 100 ml of water during and after ingestion of the first dose.

5. The dosage regimen according to claim 4 further comprising a step of administering the treated patient with at least 300 kcal of foodstuffs during and after ingestion of the first dose.

6. The dosage regimen according to claim 1 wherein the orally acceptable product formulation is retained within the treated patient's stomach for up to 7 days.

7. The dosage regimen according to claim 1 wherein the orally acceptable product formulation is retained within the treated patient's stomach for up to 30 weeks.

8. The dosage regimen according to claim 1 wherein the one or more compressed hydrogels are superporous hydrogels.

9. The dosage regimen according to claim 8 wherein the orally acceptable product formulation further comprises one or more non-superporous hydrogels.

10. The dosage regimen according to claim 8 wherein the orally acceptable product formulation further comprises one or more superporous hydrogels that have not been treated with a compressive force.

11. The dosage regimen according to claim 1 wherein the first dose of the orally acceptable product formulation is administered in an amount which will swell upon ingestion to fill up to 60% of the volume of the treated patient's stomach.

12. The dosage regimen according to claim 1 wherein the first dose of the orally acceptable product formulation is administered in an amount which will swell upon ingestion to fill up to 50% of the volume of the treated patient's stomach.

13. The dosage regimen according to claim 2 wherein the second dose of the orally acceptable product formulation is administered in an amount which will swell upon ingestion to maintain up to 60% of the volume of the treated patient's stomach to be filled.

14. The dosage regimen according to claim 3 wherein the time intervals are at least 24 hours.

15. The dosage regimen according to claim 3 wherein the time intervals are at least 48 hours.

16. The dosage regimen according to claim 1 wherein the one or more compressed hydrogels swell to a diameter 25 mm within 30 minutes of ingestion.

17. The dosage regimen according to claim 1 wherein the one or more compressed hydrogels swell to a diameter >30 mm within 10 minutes of ingestion.

18. An orally acceptable product formulation comprising a plurality of discrete core and shell regions such that the one or more core regions are surrounded by the one or more shell regions, wherein the one or more shell regions comprise a first component and the one or more core regions comprise a second component; wherein the first component comprises one or more compressed hydrogels and the second component comprises one or more non-superporous hydrogels.

19. The orally acceptable product formulation according to claim 18 wherein the one or more compressed hydrogels are superporous hydrogels.

20. The orally acceptable product formulation according to claim 19 wherein the one or more core regions further comprise one or more superporous hydrogels that have not been treated with a compressive force.

Description

DESCRIPTION OF THE DRAWINGS

[0091] The invention will now be described with reference to the representations in the following Figures, in which:

[0092] FIG. 1 shows a first example product formulation which includes a string of hydrogel beads;

[0093] FIG. 2 shows a second example product formulation which includes hydrogel beads wrapped in a membrane or mesh;

[0094] FIG. 3 shows a third example product formulation which includes a core/shell arrangement of the hydrogel components; and

[0095] FIG. 4 shows a graph of volume swelling ratio against time for a number of AAm/alginate high-volume swelling hydrogel samples that have been subjected to a range of plasticising conditions.

[0096] FIG. 5 shows a fourth example product formulation.

DETAILED DESCRIPTION

[0097] Referring to FIG. 1, this depicts an elongate capsule 10 having a capsule casing 12 which surrounds three hydrogel beads 14, 16 and 18 which are linked together using a thread 20. Hydrogel beads 14 and 16 are made from one or more slow swelling non-superporous hydrogel material, whereas hydrogel bead 18 is made from one or more high-volume swelling hydrogel material.

[0098] FIG. 2 shows a similar elongate capsule 22 to that shown in FIG. 1, except that the three hydrogel beads 14, 16 and 18 are wrapped in a stretchable or initially folded membrane or mesh 24, in place of the thread 20.

[0099] FIG. 3 shows an elongate capsule 26, which contains a core shell arrangement of hydrogel components, the shell 28 being made from a high-volume swelling hydrogel material, and the core 30 being made from a slow swelling non-superporous hydrogel material.

[0100] FIG. 5 shows an oval shape blob 40 (35 mm-45 mm major axis and 10-15 mm minor axis), which represents a partially hydrogel material which will comprise a swollen flexible high-volume fast swelling superporous hydrogel according to the present invention. The gel is flexible and coated with acid-dissolvable polymers or expandable membrane or mesh 38.

[0101] The following process is according to the present invention and is used to prepare the high-volume swelling hydrogels as detailed in Table 1.

[0102] Process for the Preparation of High-Volume Swelling Superporous Hydrogels Comprising Chitosan (CS) and Poly(N-Vinyl-2-Pyrrolidone) (PVP)

[0103] Ingredients: [0104] Chitosan (CS) dissolved in 0.1M acetic acid (2% w/v). [0105] Poly (N-vinyl-2-pryrolidone) (PVP) dissolved in distilled water (4% w/v). [0106] 0.4-2 wt. % glutaraldehyde (GTA) crosslinker in distilled water

[0107] Various ratios of the two solutions containing CS and PVP are mixed together (volume ratio of CS solution:PVP solution ranges 5:1 to 1:2), and different amounts of 0.4% GTA (volume ratio of GTA solution:CS solution ranges from 1:0.5 to 1:100) as a cross linking agent of CS is added to the CS/PVP blend as detailed in Table 2 below.

[0108] Gelation generally commences upon addition of the cross-linking agent to the mixture of CS and PVP solutions and is left to continue until the mixture in the mould/petri dish/reaction vessel is no longer able to move upon tilting. The higher the concentration, the faster the rate of gelation, typically 0.4% requires up to 12 hours to reach full gelation, whereas 1.2% achieves full gelation in about 10 minutes.

[0109] The sample is then covered and left to complete the crosslinking at room temperature over a period of 5-24 h.

[0110] Pores of a suitable size may be then created in the gelled sample. This can be achieved by freezing the gelled material in a conventional freezer or in an ultra-low temperature freezer (20 C to 86 C). The rapid cooling of ultra-low temperature freezer will result in a sample with a desirably smooth surface. Freeze-dryer can then be used to dry the frozen sample for 24-48 h to thereby create pores.

[0111] Depending on composition ratio, freezing process and freeze drying temperature, the pore size ranges from approximately 100 um to 1 mm.

[0112] The gelled SPH sample is then plasticised by treating it in a steamed chamber for 0.5 to 2 hours; typically this is a closed containing which contains a small water bath of 40-80 C. The gelled SPH sample is then treated with a compressive force so that its thickness is compressed (dramatically reduced) to to 1/10.sup.th of its original dimension and it is made into a flat sheet; this dramatic reduction serves to render a much higher volume potential which upon contacting the swelling media, will boost both the swelling rate and the swelling volume ratio. The flat sheet is rolled into a swirl, and the rolled sample state can be fixed by cooling down to room temperature. The rolled sample is then washed in acetone for 10-24 h and left in the vacuum desiccator to dry for 24-48 h.

TABLE-US-00002 TABLE 1 Volume Volume of 2% w/v of 4% w/v Compression CS PVP Concentration ratio (initial dissolved dissolved and Volume of Volume thickness over in 0.1M in GTA:CS glutaraldehyde of GTA final acetic acid distilled molecular in distilled added compressed SAMPLE (ml) water (ml) ratio water (ml) thickness) 1 20 10 1:10 0.4% 6.25 1 2 20 10 1:10 0.4% 6.25 8 3 20 10 1:10 1.2% 2.08 7 4 30 10 1:10 0.4% 9.38 1 5 30 10 1:10 0.4% 9.38 5 6 30 10 1:10 1.2% 3.126 4.5

[0113] Method of Testing

[0114] The rate of swelling and increase in swelling volume ratio for the gelled samples detailed in Table 1 above were tested as follows:

[0115] The swelling media used is simulated gastric fluid (SGF), which per litre contains 2 g sodium chloride, 7 ml hydrochloric acid, various amount of pepsin with an activity of 500 per mg protein from 0 g to 15 g) and the solvent is distilled water. The dimension and the mass of the dry samples will be measured prior to the rolling of the sample. The sample will then be put into SGF media for swelling tests. The measurements of the size and mass of the swollen sample will be made at 30 seconds, 5 min, 30 min and 1 hour and 24 h, 48 h etc. (consecutively once every day to test the its degradation property in SGF). In details, samples will be taken out of the media, and drain until no water dripping down from the sample before the weighing on the scale.

[0116] Results

[0117] The rate of swelling and the swelling volume ratio (SR.sub.v=V.sub.sV.sub.d/V.sub.d where V.sub.s represents the volume of SPH sample after immersion in SGF, and V.sub.d is the volume of the SPH sample prior to immersion) for each of the above samples were measured to be as detailed in Table 2 below:

TABLE-US-00003 TABLE 2 RATE OF SWELLING (VOLUME SWELLING MAXIMUM SWELLING RATIO IN THE SWELLING WEIGHT SAMPLE FIRST 5 MINUTES) VOLUME RATIO RATIO 1 1.4 2.5 33.4 2 14.0 15.3 33.6 3 11.6 12.6 24.9 4 3.15 3.21 33.2 5 10.5 12.7 33.8 6 8.0 8.4 23.4

[0118] All samples that have been compressed and rolled (2, 3, 5, 6) can open up and flatten into their unmodified state immediately when attaching the swelling media. The samples generated in this method have a superfast swelling rate and can open up automatically in 5-in SGF with a volume swelling ratio of 14-15.

[0119] The results demonstrate that a high-volume swelling hydrogel number 2, provides particularly good results.

[0120] Discussion of the Results

[0121] It is noted that the theoretical extent of improvement of volume swelling ratio will depend on the volume portion of the pores (pore density); the more porous the material the greater the effect will be on increasing swelling volume. The water content in the initial sample has a linear correlation to the maximum swelling volume. This is again because the initial water content determines the volume of pores that can be created within the device system. The water content is controlled by both by the composition of both samples, the concentration of PVP and GTA.

[0122] Method of Preparing a High-Volume Swelling Super Porous Hydrogel and a Non-Super Porous Hydrogel from a Basic Hydrogel Composition Comprising Acrylamide and Alginate Starting Materials.

[0123] The Acrylamide (0.5-4.0M), Alginate (0.08-1.2M), N,N-bis(acryloyl)cystamine (0.3-8.0 mM), Ammonium persulfate (1.2-40.0 mM), Tetramethylethylenediamine (1.2-40.0 mM) are dissolved and mixed together in distilled or deionized water. The mixture is then poured into moulds of a desired shape and size and incubated at 50-60 C. for 30 min to 2 hours and then left at room temperature for 24-48 hours to allow for the reaction (formation of the hydrogel) to go to completion. The set samples are then removed from the moulds and soaked in calcium chloride (10%-40% w/v) for 1 minutes to 1 hour with vigorous stirring. The treated samples are then washed intensively to get rid of any unreacted residual starting materials, loosely covered and dried slowly at room temperature.

[0124] Completely dried samples of the resulting basic hydrogel are used directly as a mechanically strong slow swelling non-super porous hydrogel.

[0125] Partially dried samples of the resulting basic hydrogel are converted into a high-volume swelling hydrogel using the following further treatment steps. Firstly, a sample of the basic hydrogel is treated using a freeze-drying process to obtain a super porous hydrogel, by freezing a sample of the basic hydrogel at 20 C. to 86 C. for 5-24 hours and then transferred to the freeze-drying chamber to complete the lyophilization under vacuum for 24-48 hours. The resulting freeze-dried samples (super porous hydrogel) are then plasticised by treating with steam in the water bath at temperature of 40-70 C. for 20-60 min. Finally, the high volume-swelling hydrogel is compressed at the preferred swelling direction in order to minimise the initial volume of the sample and to maximise its swelling capacity.

[0126] Experiment to Determine the Optimum Plasticising Conditions for Making High Volume Swelling Superporous Hydrogels of the Present Invention

[0127] Five samples of initial hydrogel (Acrylamide (AAm)/Alginate) were prepared using the general composition detailed in Table 3 below.

TABLE-US-00004 TABLE 3 AAm Alginate MBA APS/TEMED CaSO.sub.4 100 mM AAm:Alginate 6:1 w/w 0.1 mM 0.5 mM 1.8 mM

[0128] An amount of water was then added to each sample before it was freeze dried; the amount of water and freeze drying conditions for each sample is detailed below in Table 4.

TABLE-US-00005 TABLE 4 #0- #5- #10- #15- #20- #0- #5- #10- #15- #20- Sample # 20C 20C 20C 20C 20C 50C 50C 50C 50C 50C #15 H.sub.2O 87.5% 89.6% 90.3% 91.3% 92.1% 87.5% 89.6% 90.3% 91.3% 92.1% 91.3% content (w/w) Freeze- 20 20 20 20 20 50 50 50 50 50 drying temperature ( C.)

[0129] The resulting plasticised AAm/Alginate samples were then compressed by the ratio 2:16 and as demonstrated in FIG. 4, the plasticising conditions have a profound impact on the volume and rate of swelling with the samples #20-20C (92.1% by wt of water and freeze drying at 20 C.) and #20-50C (92.2%/wt of water and freeze drying at 50 C.) providing the most favourable high-volume swelling superporous hydrogels.

CONCLUSIONS AND ADVANTAGES OF THE PRESENT INVENTION

[0130] The fast rate of swelling and excellent high swelling volume achieved by the hydrogel materials of the present invention yield hydrogels and hydrogel-containing compositions which may solve the conventional conflict between volume swelling ratio and swelling rate. [0131] These advantages are particularly seen when hydrogel materials, preferably superporous hydrogel materials, are compressed and rolled after plasticization by water vapour. [0132] Tablets comprising/made using the hydrogel materials of the present invention can be taken without the supervision of a doctor and are therefore truly procedure-less. [0133] The polymer formulation can be easily designed to ensure that the resulting high-volume swelling hydrogel stays in the stomach for predetermined and/or a wide range of time. [0134] The formulation of the high-volume swelling hydrogel can be designed to be chemically degradable in the stomach over a predetermine period of time, for example 7 days. Patients can add in more pills or take less pills to customized the strength and duration of the weight control process. [0135] The weight control process can be terminated by FDA-approved chemicals or natural food resources. For example, 10 mg/ml or higher pepsin is found to degrade CS-PVP semi interpenetrating network SPH. For a material which expands 15 folds of its dry volume, the amount of water will be around 93.3% by volume, and such a material will exhibit relatively low mechanical properties which are expected to allow the modified SPH material to be broken down by stomach movement. However, it is likely that the precise termination chemical and mechanism will be different depending on the chemical formulation of the high-volume swelling hydrogel. [0136] The remaining pores that have not been filled up with water of the swollen high-volume swelling hydrogel will enhance the retentive properties of the hydrogel while keeping it floating just below the surface of the gastric fluids. Further, the mechanical properties of the hydrogel are designed to allow it to withstand the gentle movement of the upper stomach without over-pushing the stomach walls thereby avoiding unnecessary discomfort to the patient. A stomach retentive dosage form is a form of design, the aim of which is to make a pill that will stay in the stomach for a desired period without passing out of the duodenum. It is reported that the device that cannot pass into the duodenum should have a size of either 20*50 mm or a diameter of 30 mm. For this to be possible, the stomach retentive dosage form needs to be: [0137] Expandable system (which swells in the stomach fluid immediately to a size that cannot pass out of the stomach or into the duodenum) [0138] Floating system (floating at the top of the stomach to prevent exiting the stomach) [0139] Open-up system (opens up to a larger size, usually, from a folded shape, in order to reach the size that is larger than the diameter of duodenum) [0140] The invention in this patent actually meet all these criterions. We aim to make a device that is originally 20*50 mm, with a thickness of 10 mm. Then by compressing to a size around 20*50*1 mm and roll it into a shape that can be put into a capsule. When opening up and expanding, it should have a much larger size (approx. 20*70*12) than the criterion and it will also float.