GASTRORETENTIVE GEL FORMULATIONS

Abstract

The present invention provides a gastric retentive gel composition comprising: (a) a hydrophobic or amphiphilic liquid gelled with an organogelator; (b) an active agent; and (c) a hard wax or wax-like additive, for controlled delivery of the active agent to or through the upper gastrointestinal tract, in particular to or through the stomach. The gel composition forms a stable, floating and coherent raft in the gastric environment, and is not directly expelled from the stomach as a result of gastric emptying. The active agent is released from the composition in a controlled manner for absorption or local action.

Claims

1. A gastric retentive gel composition comprising: (a) a hydrophobic or amphiphilic liquid gelled with an organogelator; (b) an active agent; and (c) a hard wax or wax-like additive.

2. The gel composition of claim 1, wherein (a) comprises an organogel, lipogel or oleogel, and (b) and (c) are dispersed, solubilized or suspended in the gel.

3. The gel composition of claim 1, having a density less than the density of gastric fluid (approximately 1.004-1.1 g/ml).

4. The gel composition of claim 1, wherein the hard wax or wax-like additive is selected from triglycerides, mono- and diglycerides, natural or synthetic waxes, fat or wax alcohols, fatty acids, esters of fatty alcohols and fatty acids, fatty acid amides, or hardened fats or oils.

5. The gel composition of claim 1, wherein the hard wax or wax-like additive is selected from a semi-synthetic glyceride base comprising saturated C8-18 triglyceride fatty acids; a mixture of triglycerides, diglycerides and monoglycerides; a mixture of glycerides and esters of polyethylene glycol; mono- and diglycerides, glycerol monostearate; hydrogenated castor oil; a glyceryl stearate; hydrogenated palm oil; triglyceride of behenic acid; glyceryl behenate behenoyl polyoxyl-8 glycerides); glyceryl distearate; a glyceryl stearate; 114—trimyristate; 116—tripalmitate; 118—tristearate, and equivalents of any of the foregoing.

6. The gel composition of claim 1, wherein (c) is provided in a quantity between about 5-200% by weight of (a).

7. The gel composition of claim 1, wherein the organogelator comprises an ethylcellulose polymer, preferably an ethylcellulose polymer having a viscosity grade of about 50 centipoise (cP) or less; or wherein the organogelator comprises polyethylene, polyethyleneoxide propyleneoxide, gum such as xanthan gum, guar gum or locust bean gum, polyacrylic acid or polyacrylic-methacrylic acid such as ammonio methacrylate copolymer, shellac resin, polyvinyl acid, carboxyvinyl polymer such as carbomers, or block copolymer ethyleneoxide-co-propyleneoxide including poloxamers.

8. The gel composition of claim 1, wherein the hydrophobic or amphiphilic liquid comprises an oil or a modified oil.

9. The gel composition of claim 1, wherein the hydrophobic or amphiphilic liquid comprises a glyceride such as a mono-, di- or tri-glyceride, or wherein the hydrophobic or amphiphilic liquid is selected from propyleneglycol monocaprate, propyleneglycol dicaprylocaprate, oleoyl macrogol 6 glycerides, propyleneglycol monolaurate, glyceryl monolinoleate, glycerol mono oleate, polyglyceryl 3 dioleate, a medium chain triglyceride, and equivalents thereof.

10. The gel composition of claim 1, wherein a weight/weight (w/w) ratio of organogelator to hydrophobic or amphiphilic liquid in component (a) is up to about 15:85 (15% organogelator).

11. The gel composition of claim 1, wherein the w/w ratio of organogelator to hydrophobic or amphiphilic liquid in (a) is between about 1:99-5:95 (1-5% organogelator), preferably between about 3:97-5:95 (3-5% organogelator); or is about 4:96 (4% organogelator) or less.

12. The gel composition of claim 1, wherein (a) comprises a hydrophobic or amphiphilic liquid gelled with an ethylcellulose polymer with a viscosity grade of about 50 cP, and the w/w ratio of the ethylcellulose polymer to the hydrophobic or amphiphilic liquid is about 4:96 (4% ethylcellulose polymer).

13. The gel composition of claim 1, wherein the active agent comprises a pharmaceutical drug, a nutritional supplement, a marker such as a diagnostic marker, or an imaging agent, or wherein the active agent is selected from active pharmaceuticals, prodrugs of active pharmaceuticals, active biologicals, antibiotics, antifungals, antitoxins, antigens, therapeutics, preventive therapeutics, analgesics, nutritional supplements, imaging agents, fluid stabilizers, or any combination thereof.

14. The gel composition of claim 1, wherein the active agent is suitable for administration to or through the upper part of the gastrointestinal tract, in particular to or through the stomach.

15. The gel composition of claim 1 wherein the active agent is an analgesic such as paracetamol; or an antibiotic such as amoxicillin; or a receptor agonist or antagonist such as alfuzosin HCl, atenolol or losartan; or an anti-viral drug such as acyclovir; or a beta blocker such as propranolol.

16. The gel composition of claim 1, wherein the active agent comprises up to about 50% by weight of the gel composition.

17. The gel composition of claim 1, wherein the active agent comprises at least about 25% by weight of the gel composition.

18. The gel composition of claim 1, wherein the active agent is formulated as a powder, as pellets including coated pellets, as particles, nanoparticles or granules, or as a liquid or gel; or wherein the active agent is formulated for controlled, sustained or modified release such as capsules, pellets, non pareils, microballoons, microspheres or beads.

19. The gel composition of claim 1, wherein (a) comprises ethylcellulose 50cPs gelled with propyleneglycol dicaprylocaprate, glycerol mono oleate or glyceryl monolinoleate in a w/w ratio of about 4:96 (4% w/w organogelator), and (c) comprises mono- and diglycerides, glycerol monostearate, a mixture of glycerides and esters of polyethylene glycol, a semi-synthetic glyceride base comprising saturated C8-18 triglyceride fatty acids.

20. The gel composition of claim 1, wherein (b) comprises paracetamol, amoxicillin or alfusozine.

21. The gel composition of claim 1, comprising: 15-90% w/w, or preferably 30-80% w/w, hydrophobic or amphiphilic liquid; 0.2-15% w/w, or preferably 1-4% w/w, organogelator; 0.1-50% w/w, or preferably 10-50% w/w, active agent; and 2-70% preferably 10-60% w/w, hard wax or wax-like additive; wherein the sum of these percentages is 100%.

22. (canceled)

23. A dosage form which is a sachet, bottle, tube, dosing syringe, or a bottle with a dosing pump, comprising the composition of claim 1.

24. A dosage form which is a single dose sachet containing a predetermined quantity of the composition of claim 1 or a bottle, tube or syringe that is configured to dispense a predetermined quantity of the composition of claim 1, wherein the predetermined quantity represents a dose of the active agent.

25. A method for administering an active agent to or through the upper gastrointestinal tract, in particular the stomach, of a human or animal patient, comprising orally administering to the patient a gel composition according to claim 1 which comprises said active agent.

26. (canceled)

27. (canceled)

28. (canceled)

29. The method of claim 25, wherein the patient is in a non-fasting state.

30. (canceled)

Description

EXAMPLES

[0085] The present disclosure may be further comprehended by reference to the specific examples and figures below, which are purely exemplary and are not limiting in scope.

[0086] FIG. 1 illustrates the results of a dissolution test performed on the composition of example 1.

[0087] FIG. 2 illustrates the results of a dissolution test performed on the composition of example 2.

[0088] FIG. 3 illustrates the results of a dissolution test performed on the composition of comparative example 3 (no hard wax additive).

[0089] FIG. 4 illustrates the results of a dissolution test performed on the composition of comparative example 4 (no polymer).

[0090] FIG. 5 illustrates the results of a dissolution test performed on the composition of comparative example 5 (no hard wax additive).

[0091] FIG. 6 illustrates the results of a dissolution test performed on the composition of comparative example 6 (no hard wax additive).

[0092] FIG. 7 illustrates the results of a dissolution test performed on the composition of example 7.

[0093] FIG. 8 illustrates the results of a dissolution test performed on the composition of example 8.

[0094] FIG. 9 shows the dissolution profile of the composition of example 12 in acetate buffer (pH 4.5) plus 0.2% sodium lauryl sulfate (experiment performed in duplicate).

[0095] FIG. 10 illustrates a floating/buoyancy test performed on the composition of example 12 in water (experiment performed in duplicate).

EXAMPLE 1: AMOXICILLIN POWDER+MAISINE-4% ETC50CP-SUPPOCIRE AM

[0096] Component (a): Maisine-4% Etc50Cp:

[0097] Maisine 35-1 batch 126879, Gattefosse (FR)

[0098] Ethylcellulose Type ECN 50 batch 41796, Pharm Hercules

[0099] Warm up Maisine to 90° C. whilst stirring with a magnetic stirrer. Add 4% ethylcellulose and stir until the ethylcellulose dissolves completely.

[0100] Component (c): Suppocire AM

[0101] Suppocire AM Pellets batch 2E0905-2, Gattefosse SAS (FR)

[0102] Warm up 20 g of Maisine-4% Etc50Cp and 4 g of Suppocire AM to 37° C. while stirring. The compound is elastic.

[0103] Component (b): Amoxicillin Powder

[0104] Amoxicillin trihydrate powder batch WJAN1506

[0105] Weigh 12.00 g of Maisine-4% Etc50Cp+Suppocire AM preparation and add 6.888 g of Amoxicillin trihydrate.

[0106] The resulting oleogel composition is buoyant in gastric fluid and capable of holding together as a raft in the gastric environment.

[0107] A dissolution test was performed using apparatus 2 (paddle), rotation speed 100 rpm, temperature 37° C. in 1000 mL of distilled water. The sample for the dissolution test was prepared by weighing 3.148 g of the AMX oleogel (containing Amoxicillin-Maisine-4% Etc50Cp+Suppocire AM) directly onto greaseproof paper.

[0108] The composition was found to float at the surface of the dissolution medium, forming a continuous large and thin raft around the paddle shaft. The amount of drug released was determined by UV detection at 275 nm.

[0109] The results of the dissolution test are shown in FIG. 1. As will be seen, controlled sustained drug release was attained with a T50% of 4 hours. The results showed moderate variability.

EXAMPLE 2: AMOXICILLIN POWDER+MAISINE-4% ETC50CP-SUPPOCIRE AML

[0110] Component (a): Maisine-4% Etc50Cp:

[0111] Maisine 35-1 batch 126879, Gattefosse (FR)

[0112] Ethylcellulose Type ECN 50 batch 41796, Pharm Hercules

[0113] Warm up Maisine to 90° C. whilst stirring with a magnetic stirrer. Add 4% ethylcellulose and stir until the ethylcellulose dissolves completely.

[0114] Component (c): Suppocire AML

[0115] Suppocire AML Pellets batch 9E0303-2, Gattefosse SAS (FR)

[0116] Warm up 20 g of Maisine-4% Etc50Cp and 10 g of Suppocire AML to 37° C. while stirring. The compound is elastic.

[0117] Component (b): Amoxicillin Powder

[0118] Amoxicillin trihydrate powder batch WJAN1506

[0119] Weigh 12.00 g of Maisine-4% Etc50Cp+Suppocire AML preparation and add 6.888 g of Amoxicillin trihydrate.

[0120] A dissolution test was performed as in Example 1. The composition was found to float at the surface of the dissolution medium, forming a continuous large and thin raft around the paddle shaft.

[0121] The results of the dissolution test are shown in FIG. 2. As will be seen, controlled sustained drug release was attained with a T50% of 3 hours. The results showed low variability (small error bars) and hence good reproducibility. The small amount of lecithin contained in Suppocire AML allows faster dissolution and drug release as compared with the formulation containing Suppocire AM (Example 1).

COMPARATIVE EXAMPLE 3: AMOXICILLIN POWDER+MAISINE-4% ETC50CP

[0122] (No hard wax additive included)

[0123] Component (a): Maisine-4% Etc50Cp:

[0124] Maisine 35-1 batch 126879, Gattefosse (FR)

[0125] Ethylcellulose Type ECN 50 batch 41796, Pharm Hercules

[0126] Warm up Maisine to 90° C. whilst stirring with a magnetic stirrer. Add 4% ethylcellulose and stir until the ethylcellulose dissolves completely.

[0127] Component (b): Amoxicillin Powder

[0128] Amoxicillin trihydrate powder batch WJAN1506

[0129] Weigh 12.00 g of Maisine-4% Etc50Cp and add 6.888 g of Amoxicillin. The compound is creamy and yellow.

[0130] A dissolution test was performed using apparatus 2 (paddle), rotation speed 100 rpm, temperature 37° C. in 1000 mL of distilled water with blank subtraction. In the dissolution medium, the formulation does not hold together as a continuous integral raft, but spreads out at the surface of the dissolution medium in multiple “small flakes” and releases its drug content very rapidly. The amount of drug released was determined by UV detection. The sample for the dissolution test was prepared by weighing 3.148 g of Amoxicillin (POWDER)-Maisine-4% Etc50Cp directly onto greaseproof paper.

[0131] The results are shown in FIG. 3. As will be seen, the drug was rapidly released from the formulation with a T50% of only 1 hour. The results were highly variable as indicated by the size of the error bars, demonstrating poor reproducibility.

COMPARATIVE EXAMPLE 4: AMOXICILLIN POWDER+MAISINE-SUPPOCIRE AM

[0132] (No polymer included hence this is not an oleogel formulation)

[0133] Maisine 35-1

[0134] Suppocire AM, Gattefosse (FR)

[0135] Amoxicillin trihydrate powder batch WJAN1506

[0136] Warm up 5 g of Suppocire AM at temperature>37° C. and add while stirring 18 g of Maisine. Weigh 12.00 g of the resulting composition and add 6.888 g of Amoxicillin trihydrate.

[0137] A dissolution test was carried out according to the previous examples. In the dissolution medium, the formulation does not hold together as a continuous integral raft, but breaks apart, spreads out and floats in multiple small flakes, releasing its drug content very rapidly.

[0138] The results of the dissolution test are shown in FIG. 4. As will be seen, the drug was rapidly released from the formulation with a T50% of less than 1 hour.

COMPARATIVE EXAMPLE 5: AMOXICILLIN POWDER+MAISINE-10% ETC50CP

[0139] (No hard wax additive included)

[0140] Component (a): Maisine-10% Etc50Cp:

[0141] Maisine 35-1 batch 126879, Gattefosse (FR)

[0142] Ethylcellulose Type ECN 50 batch 41796, Pharm Hercules

[0143] Warm up Maisine to 90° C. whilst stirring with a magnetic stirrer. Add 10% ethylcellulose and stir until the ethylcellulose dissolves completely.

[0144] Component (b): Amoxicillin Powder

[0145] Amoxicillin trihydrate powder batch WJAN1506

[0146] Weigh 12.00 g of Maisine-10% Etc50Cp and add 6.888 g of Amoxicillin.

[0147] A dissolution test was performed using apparatus 2 (paddle), rotation speed 100 rpm, temperature 37° C. in 1000 mL of distilled water with blank subtraction. The amount of drug released was determined by UV detection. The sample for the dissolution test was prepared by weighing 3.148 g of Amoxicillin (POWDER)-Maisine-10% Etc50Cp directly onto greaseproof paper.

[0148] The formulation does not spread out at the surface of the dissolution medium but sinks to the bottom of the vessel. The resulting dissolution rate is extremely slow with drug strongly entrapped in the agglomerated formulation. The results of the dissolution test are shown in FIG. 5.

COMPARATIVE EXAMPLE 6: AMOXICILLIN POWDER+MAISINE-10% ETC100CP

[0149] (No hard wax additive included)

[0150] Component (a): Maisine-10% Etc100Cp: Maisine 35-1 batch 126879, Gattefosse (FR) Ethylcellulose Type ECN 100 batch 42324, Pharm Hercules

[0151] Warm up Maisine to 90° C. whilst stirring with a magnetic stirrer. Add 10% ethylcellulose and stir until the ethylcellulose dissolves completely.

[0152] Component (b): Amoxicillin Powder

[0153] Amoxicillin trihydrate powder batch WJAN1506

[0154] Weigh 12.00 g of Maisine-10% Etc100Cp and add 6.888 g of Amoxicillin.

[0155] A dissolution test was performed using apparatus 2 (paddle), rotation speed 100 rpm, temperature 37° C. in 1000 mL of distilled water with blank subtraction. The amount of drug released was determined by UV detection. The sample for the dissolution test was prepared by weighing 3.148 g of Amoxicillin (POWDER)-Maisine-10% Etc100Cp directly onto greaseproof paper.

[0156] The formulation does not spread out at the surface of the dissolution medium but sinks to the bottom of the vessel. The resulting dissolution rate is extremely slow with drug strongly entrapped in the agglomerated formulation. The results of the dissolution test are shown in FIG. 6.

EXAMPLE 7: AMOXICILLIN POWDER-MAISINE-4% ETC 50CP+GELUCIRE 43/01

[0157] Component (a): Maisine-4% Etc50Cp:

[0158] Maisine 35-1 batch 126879, Gattefosse (FR)

[0159] Ethylcellulose Type ECN 50 batch 41796, Pharm Hercules

[0160] Warm up Maisine to 90° C. whilst stirring with a magnetic stirrer. Add 4% ethylcellulose and stir until the ethylcellulose dissolves completely.

[0161] Component (c): Gelucire 43/01

[0162] Gelucire 43/01 batch 1E5203-2-2, Gattefosse SAS (FR)

[0163] Warm up 12.5 g of Maisine-4% Etc50Cp and 3.5 g of Gelucire 43/01 to 45° C. while stirring. The compound is elastic.

[0164] Component (b): Amoxicillin Powder

[0165] Amoxicillin trihydrate powder batch WJAN1506

[0166] Weigh 12.00 g of Maisine-4% Etc50Cp+Gelucire 43/01 preparation and add 6.888 g of Amoxicillin trihydrate.

[0167] A dissolution test was performed as in Example 1. The composition floats at the surface of the dissolution medium forming a continuous large and thin raft around the paddle shaft.

[0168] The results of the dissolution test are shown in FIG. 7. As will be seen, controlled sustained drug release was attained with a T50% of 2 hours and a T80% at 5 hours.

EXAMPLE 8: APAP (PARACETAMOL) MAISINE-4% ETC 50-GELUCIRE 43/01

[0169] Component (a): Maisine-4% Etc50Cp:

[0170] Maisine 35-1 batch 126879, Gattefosse (FR)

[0171] Ethylcellulose Type ECN 50 batch 41796, Pharm Hercules

[0172] Warm up Maisine to 90° C. whilst stirring with a magnetic stirrer. Add 4% ethylcellulose and stir until the ethylcellulose dissolves completely.

[0173] Component (c): Gelucire 43/01

[0174] Gelucire 43/01 batch 1E5203-2, Gattefosse SAS (FR)

[0175] Warm up 12.5 g of Maisine-4% Etc50Cp and 3.5 g of Gelucire 43/01 to 45° C. while stirring. The compound is elastic.

[0176] Component (b): Paracetamol Powder

[0177] Paracetamol powder batch 6088902V768

[0178] Weigh 12.00 g of Maisine-4% Etc50Cp+Gelucire 43/01 preparation and add 2.4 g of APAP (paracetamol).

[0179] A dissolution test was performed as in Example 1. The composition floats at the surface of the dissolution medium forming a continuous large and thin raft around the paddle shaft. The results of the dissolution test are shown in FIG. 8. As will be seen, controlled sustained drug release was attained with a T50% of 2 hours. T80% is achieved within 6.5 hours.

[0180] The formulations of examples 1-8 are summarized in Table 6. As will be seen, the oleogel formulations comprising a hard wax additive (Suppocire AM, Suppocire AML or Gelucire 43/01) showed significantly improved sustained release dissolution characteristics as compared with the non-oleogel formulations and the oleogel formulations without a hard wax additive. The buoyancy and integrity of the formulations was also improved.

TABLE-US-00006 TABLE 6 % Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 AMX 36.47 36.47 36.47 36.47 36.47 36.47 36.47 APAP 16.67 Maisine 50.83 40.66 60.99 49.72 57.75 57.75 47.64 62.49 Ethylcellulose 50 cp 2.12 1.69 2.54 6.35 1.99 2.61 Ethylcellulose 100 cp 6.35 Suppocire AM 10.59 13.81 Suppocire AML 21.15 Gelucire 43/01 13.90 18.23 T 50% (h) 4 3 1 40 min Nd Nd 2 2 FIG. 1 FIG. 2 FIG. 3 FIG. 4 FIG. 5 FIG. 6 FIG. 7 FIG. 8 Buoyancy Floats Floats Floats Floats Does not float Does not float Floats Floats in dissolution medium Consistency in Forms a raft Forms a raft Breaks into Breaks into Agglomerates Agglomerates Forms a Forms a dissolution medium flakes flakes and sinks and sinks raft raft

EXAMPLES 9 TO 13: PRAZIQUANTEL-LABRAFAC-ETC 50-GELUCIRE 43/01

[0181] Examples 9, 12 and 13 illustrate the present invention, whilst Examples 10 and 11 are comparative, lacking a hard wax additive and an organogelator respectively. These examples all utilize Praziquantel as active ingredient. Details of Examples 9-12 are summarized in Table 7.

TABLE-US-00007 TABLE 7 Ex11 Ex10 No Ingredients (%) Ex 9 No hard wax organogelator Ex12 Praziquantel 32.95 38.80 33.61 33.27 Labrafac PG 49.96 58.84 50.98 50.46 Aqualon N50 (Etc 50) 2.00 2.36 — 1.02 Gelucire 43/01 15.00 — 15.41 15.25 Buoyancy water OK NO NO OK Buoyancy buffer OK NO NO OK

[0182] Flavouring agents and sweeteners can be added to the formulation to make it more palatable. Example 13 provides a formulation containing Praziquantel that has been flavoured to hide the bitter taste of this active ingredient. The formulation of this composition is summarised in Table 8, and the manufacturing process is described in Table 9.

TABLE-US-00008 TABLE 8 Quantity Ingredients Ex 13 % per unit Trade name Chemical name Function w/w (g) Praziquantel Praziquantel Active ingredient 25.86 1.200 EP Labrafac PG Propylene glycol Oil phase 53.87 2.500 dicaprylocaprate Aqualon N50 Ethylcellulose Organogelator 1.94 0.090 50 cP Gelucire 43/01 Hard fat Hardening agent 14.01 0.650 Orange Flavouring agent 0.38 0.018 Grapefruit Mint Flavouring agent 0.06 0.003 Masking agent Taste masking 0.63 0.029 Sucralose Sweetener 3.25 0.151 Total per unit 4.641 (stick pack)

[0183] A dissolution test was performed on the composition of example 12 using USP Apparatus 2 (paddle), rotation speed 100 rpm, temperature 37° C. in 900 mL of acetate buffer (pH 4.5) plus 0.2% sodium lauryl sulfate. The amount of drug released was determined by UV detection. The system is extracted from the stick pack and dropped in the dissolution vessel for testing. The system is floating at the surface of the dissolution fluid for at least the duration of the test. The dissolution profile of the composition of example 12 is illustrated in FIG. 9. Its buoyancy in distilled water after stick pack extraction is illustrated in FIG. 10.

EXAMPLE 14: ALFUZOSIN PELLETS FOR OLEOGEL PREPARATION

[0184] The active agent in the compositions of the present disclosure may be included in the form of a powder, as in the examples above. Other formulations are however possible, including sustained or delayed release formulations. A pellet formulation for alfuzosin is prepared as below:

Alfuzosine Pellet Centesimal Formula

[0185]

TABLE-US-00009 % Core Alfuzosin HCl 3.50 Compritol 888ATO - glyceryl behenate 10.51 Avicel -microcrystalline cellulose 3.50 PVP plasdone K29-32 1.63 Mounting blend Methocel K100M - HPMC 20.77 PVP plasdone K29-32 2.79 Compritol 888 ATO -glyceryl behenate 20.77 Coatings 1- Opadry YS -HPMC 3 cps 6.35 2- Surelease - EC 21.08 3- Opadry YS -HPMC 3 cps 9.09 100.00

[0186] The components are introduced into the bowl of a fluid bed rotogranulator, then initial core formation is obtained by spraying water while agglomerates are formed by the twisting plate.

[0187] Then ingredients for mounting are added to the cores and agglomeration is obtained again by spraying water while agglomerates are shaped by the twisting plate. 3 successive coating layers are applied to the pellets thus obtained, a first one based on HPMC 3 cps (weight gain of 10%), the second one based on Ethylcellulose polymer (weight gain of 30%) and finally another HPMC based layer (weight gain of 10%).

[0188] The finished pellets are then ready to be added to an oleogel base formulation according to the present disclosure.