Topical bioadhesive formulations

Abstract

The present invention relates to topical bioadhesive formulations comprising low viscosity, non-liquid crystalline, mixtures of: a) at least one neutral diacyl lipid and/or at least one tocopherol; b) at least one phospholipid; c) at least one biocompatible, oxygen containing, low viscosity organic solvent; wherein at least one bioactive agent is dissolved or dispersed in the low viscosity mixture and wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid. The invention additionally relates to a method of delivery of an active agent comprising administration of a preformulation of the invention, a method of treatment comprising administration of a preformulation of the invention and the use of a preformulation of the invention in a method for the manufacture of a medicament.

Claims

1. A bioadhesive pre-formulation comprising a low viscosity mixture of: a) at least one neutral lipid component comprising a polar head group linked to at least one non-polar tail group by an ester, and optionally at least one tocopherol; b) at least one phospholipid; c) at least one biocompatible, oxygen containing organic solvent selected from alcohols, amides, sulfoxides and mixtures thereof; optionally including at least one bioactive agent which is dissolved or dispersed in the low viscosity mixture, wherein the weight ratios of components a:b are from 85:15 to 35:65; wherein the weight of component c) relative to the total weight of the a-b-c mixture is 2 to 30 wt. %; and wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid and/or body surface.

2. A pre-formulation as claimed in claim 1 wherein said polar head group is a polyol.

3. A pre-formulation as claimed in claim 2 wherein the polyol is selected from glycerol, diglycerol or a sugar moiety.

4. A pre-formulation as claimed in claim 3 wherein the sugar moiety is selected from an inositol or glucosyl based moiety.

5. A pre-formulation as claimed in claim 1 wherein the polar head group is an esterified polyol.

6. A pre-formulation as claimed in claim 1 wherein the neutral lipid component comprises a fatty acid ester of a polyol.

7. A pre-formulation as claimed in claim 6 wherein the neutral lipid component comprises a fatty acid ester of a sugar.

8. A pre-formulation as claimed in claim 1 wherein the neutral lipid component a) comprises at least one C6 to C32 alkyl or alkenyl group.

9. A pre-formulation as claimed in claim 1 wherein the neutral lipid component comprises at least one non-polar tail group selected from caproyl (C6:0), capryloyl (C8:0), capryl (C10:0), lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoly (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2), linolenoyl (C18:3), arachidonoyl (C20:4), behenoyl (C22:0) and lignoceroyl (C24:9) groups.

10. A pre-formulation as claimed in claim 1 wherein the neutral lipid component comprises a sugar head group, and at least one fatty acid tail group selected from caproyl (C6:0), capryloyl (C8:0), capryl (C10:0), lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoly (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2) and linolenoyl (C18:3) groups.

11. A pre-formulation as claimed in claim 1 wherein the neutral lipid component comprises a sugar head group, and at least one fatty acid tail group selected from palmitoyl (C16:0), phytanoly (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2) and linolenoyl (C18:3) groups.

12. A pre-formulation as claimed in claim 1 wherein component a) comprises two apolar tail groups.

13. A pre-formulation as claimed in claim 1 further comprising a drug agent selected from drugs which act on cells and receptors, peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulation system, endocrine and hormone system, blood circulatory system, synoptic sites, neuroeffector junctional sites, the immunological system, the reproductive system, the skeletal system, autacoid system, the alimentary and excretory systems, the histamine system, and the central nervous system.

14. The pre-formulation as claimed in claim 1 wherein said tocopherol is present and is selected from vitamin E, salts thereof and analogues thereof.

15. A pre-formulation as claimed in claim 1 wherein said liquid crystalline phase structure is bioadhesive.

16. A pre-formulation as claimed in claim 1 wherein component b) is phosphatidylcholine.

17. A pre-formulation as claimed in claim 1 having a viscosity of 0.1 to 5000 mPas.

18. A pre-formulation as claimed in claim 1 having a molecular solution, L2 and/or L3 phase structure.

19. A pre-formulation as claimed in claim 1 having 35 to 60% by weight a), 20 to 50% by weight b) and 10 to 20% by weight c).

20. A pre-formulation as claimed in claim 1 wherein component c) is selected from an alcohol, ethanol, dimethylacetamide, N-methyl pyrrolidone and dimethylsulfoxide.

21. A pre-formulation as claimed in claim 1 wherein said active agent is selected from corticosteroids, nonsteroidal anti-inflammatory compounds, local inhibitors of inflammatory pathways, phospholipase inhibitors, antioxidants, antiinfectives, cytokines and cytokine inducers/supressors.

22. A pre-formulation as claimed in claim 1 which is administrable by rinsing, spraying, gargling, as a patch, by suppository or by enema.

23. A topical pre-formulation as claimed in claim 1 for dermatological administration which forms a bioadhesive, controlled release product, wherein the active agent is selected from UV absorbing agents.

24. A method of delivery of a bioactive agent to a human or non-human animal body, this method comprising administering a pre-formulation as claimed in claim 1.

25. A method of treatment or prophylaxis of a human or non-human animal subject comprising administration of a pre-formulation as claimed in claim 1.

26. A method as claimed in claim 25 for the treatment of inflammation and/or irritation at a body surface and/or in a body cavity.

27. The method as claimed in claim 26 wherein said inflammation is caused by Crohn's disease, ulcerative collitus or oral mucositis.

28. Method for the treatment of oral mucositis in a human or animal subject comprising administration of a pre-formulation as claimed in claim 1, said composition comprising 40 to 60 wt % GDO, 20 to 35% PC, 5 to 25% ethanol, and 1 to 8% benzydamine, or a derivative thereof.

29. The pre-formulation as claimed in claim 1 further comprising a UV absorbing agent.

Description

(1) The Invention will now be further illustrated by reference to the following non-limiting Examples and the attached Figures, in which;

(2) FIG. 1 shows the cumulative release of methylene blue (MB) from a depot formulation comprising PC/GDO/EtOH (45/45/10 wt %) when injected into excess water;

(3) FIG. 2 demonstrates the non-linear decrease of pre-formulation viscosity upon addition of N-methyl pyrolidinone (NMP) and EtOH;

(4) FIG. 3 displays the in vitro release in excess aqueous phase of chlorhexidine from a depot formulation comprising PC/GDO/EtOH (36/54/10 wt %) containing 50 mg chlorhexidine/g of formulation, corresponding to 5% drug load.

EXAMPLES

Example 1: Availability of Various Liquid Crystalline Phases in the Depot by Choice of Composition

(5) Injectable formulations containing different proportions of phosphatidyl choline (PCEpikuron 200) and glycerol dioleate (GDO) and with EtOH as solvent were prepared to illustrate that various liquid crystalline phases can be accessed after equilibrating the depot precursor formulation with excess water.

(6) Appropriate amounts of PC and EtOH were weighed in glass vials and the mixture was placed on a shaker until the PC completely dissolved to form a clear liquid solution. GDO was then added to form an injectable homogenous solution.

(7) Each formulation was injected in a vial and equilibrated with excess water. The phase behaviour was evaluated visually and between crossed polarizes at 25 C. Results are presented in Table 1.

(8) TABLE-US-00001 TABLE 1 Formulation PC (wt %) GDO (wt %) EtOH (wt %) Phase in H.sub.2O A 22.5 67.5 10.0 L.sub.2 B 28.8 61.2 10.0 I.sub.2 C 45.0 45.0 10.0 H.sub.II D 63.0 27.0 10.0 H.sub.II/L.sub. L.sub.2 = reversed micellar phase I.sub.2 = reversed cubic liquid crystalline phase H.sub.II = reversed hexagonal liquid crystalline phase L.sub. = lamellar phase

Example 2: In Vitro Release of a Water-Soluble Substance

(9) A water-soluble colorant, methylene blue (MB) was dispersed in formulation C (see Example 1) to a concentration of 11 mg/g formulation. When 0.5 g of the formulation was injected in 100 ml water a stiff reversed hexagonal H.sub.II phase was formed. The absorbency of MB released to the aqueous phase was followed at 664 nm over a period of 10 days. The release study was performed in an Erlenmeyer flask at 37 C. and with low magnetic stirring.

(10) The release profile of MB (see FIG. 1) from the hexagonal phase indicates that this (and similar) formulations are promising depot systems. Furthermore, the formulation seems to give a low initial burst, and the release profile indicates that the substance can be released for several weeks; only about 50% of MB is released after 10 days.

Example 3: Viscosity in PC/GDO (6:4) or PC/GDO (3:7) on Addition of Solvent (EtOH, PG and NMP)

(11) A mixture of PC/GDO/EtOH was manufactured according to the method in Example 1. All, or nearly all, of the EtOH was removed from the mixture with a rotary evaporator (vacuum, 40 C., 1 h) and the resulting solid mixture were weighed in glass vial after which 2, 5, 10 or 20% of a solvent (EtOH, propylene glycol (PG) or n-methyl pyrrolidone (NMP)) was added. The samples were allowed to equilibrate several days before the viscosity was measured at a shear rate of 0.1 s.sup.1 with a Physica UDS 200 rheometer at 25 C.

(12) This example clearly illustrates the need for solvent with certain depot precursors in order to obtain an injectable formulation (see FIG. 2). The viscosity of solvent-free PC/GDO mixtures increases with increasing ratio of PC. Systems with low PC/GDO ratio (more GDO) are injectable with a lower concentration of solvent.

Example 4: Composition and In Vitro Phase Study

(13) The formulations were manufactured according to the method described in Example 1 with compositions according to Table 2. An active substance (peptide), salmon calcitonin (sCT), was added to each formulation to a concentration of 500 g sCT/g formulation. The formulations were designed as homogenous suspensions for parenteral administration (mixing required shortly prior to use since the drug is not completely dissolved in the PC/GDO/EtOH system).

(14) The phase study in this example is performed in excess of rat serum at 37 C. in order to simulate an in vivo situation. Table 2 shows that the same phases as those in water are formed (compare Table 1).

(15) TABLE-US-00002 TABLE 2 PC GDO OA EtOH Phase in Formulation (wt %) (wt %) (wt %) (wt %) rat serum E 18 72 10 L.sub.2 F 36 54 10 I.sub.2 G 34 51 5 10 I.sub.2 H 54 36 10 H.sub.II I 72 18 10 H.sub.II/L.sub. OA = Oleic Acid

Example 5: Sterile Filtration of Formulations with Reduced Viscosity

(16) To lower the viscosity with various solvents is sometimes necessary in order to obtain an injectable formulation and to be able to administrate the system with a regular syringe (see Example 3). Another important effect from the viscosity-lowering solvent is that the formulations can be sterile filtrated.

(17) Formulations E to I in Example 4 were studied in a sterile filtration test by using a 0.22 m filter (before addition of the active substance). Formulations E to H were successfully filtrated, but formulation I failed since the viscosity was too high. An aseptic manufacturing procedure was therefore needed for this formulation.

Example 6: Preparation of Depot Precursor Compositions with Various Solvents

(18) Depending on composition of the formulation and the nature and concentration of active substance certain solvents may be preferable.

(19) Depot precursor formulations (PC/GDO/solvent (36/54/10)) were prepared by with various solvents; NMP, PG, PEG400, glycerol/EtOH (90/10) by the method of Example 1. All depot precursor compositions were homogeneous one phase solutions with a viscosity that enabled injection through a syringe (23Gi.e. 23 gauge needle; 0.6 mm30 mm) After injecting formulation precursors into excess water a liquid crystalline phase in the form of a high viscous monolith rapidly formed with NMP and PG containing precursors. The liquid crystalline phase had a reversed cubic micellar (I.sub.2) structure. With PEG400, glycerol/EtOH (90/10) the viscosification/solidification process was much slower and initially the liquid precursor transformed to a soft somewhat sticky piece. The difference in appearance probably reflects the slower dissolution of PEG400 and glycerol towards the excess aqueous phase as compared to that of EtOH, NMP and PG.

Example 7: Preparation of Depot Composition Containing Benzydamine

(20) Benzydamine is a non-steroidal antiinflammatory drug and is extensively used as a topical drug in inflammatory conditions.

(21) 1 g of a depot formulation containing 1.5 mg benzydamine was prepared by dissolving the active substance in a mixture of PC/GDO/EtOH (36/54/10) prepared as described in Example 1. The depot composition was stable against crystallization during storage at 25 C. for at least two weeks. Equilibration of the formulation precursor with excess water resulted in a high viscous monolithic liquid crystalline phase (I.sub.2 structure).

Example 8: Robustness of the Behaviour of the Formulation Against Variations in the Excipient Quality

(22) Depot precursor formulations were prepared with several different GDO qualities (supplied by Danisco, Dk), Table 3, using the method of Example 1. The final depot precursors contained 36% wt PC, 54% wt GDO, and 10% wt EtOH. The appearance of the depot precursors was insensitive to variation in the quality used, and after contact with excess water a monolith was formed with a reversed micellar cubic phase behaviour (I.sub.2 structure).

(23) TABLE-US-00003 TABLE 3 Tested qualities of GDO. GDO Monoglyceride Diglyceride Triglyceride quality (% wt) (% wt) (% wt) A 10.9 87.5 1.6 B 4.8 93.6 1.6 C 1.0 97.3 1.7 D 10.1 80.8 10.1 E 2.9 88.9 8.2 F 0.9 89.0 10.1

Example 9: Preparation of Depot Composition Containing Saturated PC (Epikuron 200SH)

(24) Depot precursor formulations were prepared with various amounts PC comprising saturated hydrocarbon chains by addition of Epikuron 200SH directly to a mixture of PC/GDO/EtOH, prepared as for Example 1. The formulations are shown in Table 4. All precursor formulations were homogenous one phase samples in RT, while they became more viscous with increasing amount Epikuron 200SH. Injecting the depot precursor into excess water gave a monolith comprising a reversed miceller cubic (I.sub.2) structure. Monoliths formed from samples containing higher amounts of Epikuron 200SH became turbid, possibly indicating segregation between Epikuron 200SH and the other components upon exposure to water and formation of the I2 phase.

(25) TABLE-US-00004 TABLE 4 Depot composition containing saturated PC Saturated PC, PC EtOH Formulation Epikuron 200SH (% wt) (% wt) GDO (% wt) (% wt) G1 3.9 34.6 51.9 9.6 G2 7.0 33.5 50.2 9.3 G3 14.3 30.8 46.3 8.6

Example 10: Bioadhesive Spray of Depot Precursor Formulation

(26) A pump spray bottle was found to be a convenient way to apply the formulation topically, e.g. to the skin or the oral mucosa.

(27) A depot precursor formulation prepared as in Example 1 (36% wt PC, 54% wt GDO, and 10% wt EtOH) was sprayed with a pump spray bottle onto the skin and oral mucosa. A film with solid mechanical properties formed shortly after application.

Example 11: Robustness of a Topical Film

(28) After applying the depot precursor formulation, as described in Example 10, (36% wt PC, 54% wt GDO, and 10% wt EtOH) to the skin, the applied formulation was exposed to flushing water (10 L/min) for 10 minutes. The formulation showed excellent bioadhesive properties and resistance against rinsing and no loss of the formulation could be discerned.

Example 12: Formation of Cubic Phase with Solid Properties after Exposure of Depot Precursor Formulation to Air

(29) After exposing a depot precursor formulation prepared as described in Example 1 (36% wt PC, 54% wt GDO, and 10% wt EtOH) to air (RT, relative humidity 40%) for at least 3 hours, a solid cubic phase was formed. This formation of a cubic phase structure demonstrates that a topical film will acquire bulk non-lamellar depot properties after application without the need for direct exposure to excess aqueous fluid.

Example 13: Formulation to Treat Periodontitis or Perimplantitis

(30) In order to treat periodontitis or perimplantitis an antibacterial formulation is injected in the periodontal pocket, and a prolonged effect of the formulation is normally desired.

(31) 100 nL of a formulation as prepared in Example 1, with the addition of the antibiotic chlorohexidine (PC/GDO/EtOH/chlorhexidine (35/53/10/2)), is injected via a syringe into a rat peridontal pocket. The injected composition is observed to transform from the low viscous formulation, and which initially spreads out to fill voids, to form a solid mass by uptake of gingival fluids. An antibacterial depot system is thus provided.

(32) Chlorhexidine remains at clinically effective levels (MIC 125 g/ml) in the GCF of the periodontal pockets for over 1 week. The depot system is completely degraded by enzymes within 7 to 10 days and does not need to be removed.

Example 14: Alternate Antibacterial Formulation to Treat Periodontitis or Perimplantitis

(33) An alternate antibacterial formulation was provided by a formulation prepared as described in Example 1 and containing the antibacterial detergent Gardol (Glycine, N-methyl-N-(1-oxododecyl)-, sodium salt) (PC/GDO/EtOH/Gardol (34/51/10/5)). This formulation is injected into the rat periodontal pocket.

(34) Gardol is observed to remain at clinically effective levels in the GCF of the periodontal pockets for a prolonged period (several days). The depot system is completely degraded by enzymes within 7 to 10 days and did not need to be removed.

Example 15: Adhesion of the Formulation to High Energy Surfaces

(35) In order to treat perimplantitis, adhesion not only to biological surfaces but also to high energy surfaces such as a gold or titanium implant is important. It is also important that the formulation adheres to ceramic and plastic surfaces.

(36) A formulation (PC/GDO/EtOH (36/54/10)) as prepared in Example 1 was applied to various surfaces in the oral cavity. The composition showed excellent adhesion to ceramic, plastic, gold, as well as to a normal tooth surface and could not be rinsed away by excess aqueous fluid. The depot resulting from the composition stayed at the site in the oral cavity where it was applied for at least 6 h.

Example 16: Bioadhesive Sustained Release Formulation of Sodium Fluoride for Use on the Teeth

(37) Fluoride containing compounds are often needed to oppose caries attack and a bioadhesive formulation precursor with depot effect was prepared as indicated in Example 1 from a mixture of PC/GDO/EtOH/sodium fluoride (35/53/10/2). The formulation was a dispersion of sodium fluoride since it could not be dissolved in the precursor. The liquid formulation was applied to the teeth with the aid of a brush. By uptake of saliva the formulation solidified and formed a depot providing sustained release of sodium fluoride for an extended period (several hours).

Example 17: Oral Cavity Spray Depot Composition

(38) To be suitable as a topical depot system in the oral cavity the mechanical properties of the system was adjusted by decreasing the PC/GDO ratio.

(39) A mixture containing PC/GDO/EtOH (27/63/10) was prepared according to Example 1. A drop of patent blue was added to visualize the formulation after application. About 300 l of the formulation was sprayed into the oral cavity with pump spray bottle. Shortly after application the formulation viscosified/solidified since it underwent a phase transformation by uptake of aqueous fluid (saliva) and loss of solvent (EtOH). The formulation had excellent bioadhesion to keritinized surfaces such as the hard palate and the gum. Here the film lasted for several hours despite saliva secretion and mechanical wear by the tongue. At soft mucosal surfaces the duration was much shorter (minutes).

Example 18: Oral Cavity Liquid Depot Composition

(40) To be suitable for application with a pipette to the oral cavity the solidification/viscosification of the formulation has to be delayed relative to the spray formulation. This is to allow the formulation to be conveniently distributed with the tongue to a thin film in the oral cavity after application.

(41) Propylene glycol (PG) and EtOH were added to a formulation prepared as in Example 1, to the final composition PC/GDO/EtOH/PG (24/56/10/10). 300 l of the formulation was conveniently applied with a pipette to the oral cavity and distributed with the tongue to a thin film in the oral cavity. After about 20 seconds the viscosification of the formulation started since it underwent a phase transformation by uptake of aqueous fluid (saliva) and loss of solvent (EtOH and PG). After about one minute the solidification/viscosification appeared to be finished. The formulation had excellent bioadhesion to keritinized surfaces such as the hard palate and the gum. Here the film lasted for several hours despite saliva secretion and mechanical wear by the tongue. At soft mucosal surfaces the duration was much shorter (minutes).

Example 19: Bioadhesive Depot for Nails

(42) The mixture in Example 18 was sprayed to the nail bed and in between the toes. The formulation solidifies/viscosifies slowly by uptake of aqueous fluids (cf. sweat). The solidification can be speeded up by adding water after spray application. The formulation had excellent bioadhesive properties and had a duration for several hours.

Example 20: Loading Capacity of the Bioactive Agent Benzydamine in the Formulation Precursors

(43) Formulations with compositions as specified in Table 5 were prepared using the method in Example 1. An excess amount of benzydamine (50 mg) was added to 0.5 g of the formulations. The vials were placed on a shaker at 15 C. for three days after which the solutions were filtered through a filter (0.45 m) to get rid of crystals of undissolved benzydamine. The benzydamine concentration in each formulation was determined with reversed phase gradient HPLC and UV detection at 306 nm and the results are given in Table 5.

(44) TABLE-US-00005 TABLE 5 Composition GDO/ Benzydamine PC (Lipoid S100)/EtOH concentration in formulation 67.5/22.5/10 3.4% 63/27/10 3.2% 58.5/31.5/10 3.3% 60/20/20 4.0% 56/24/20 4.5% 52/28/20 4.3%

Example 21: Compositions Containing PC and Tocopherol

(45) Depot precursor formulations were prepared with several different PC/-tocopherol compositions using the method of Example 1 (PC was first dissolved in the appropriate amount of EtOH and thereafter -tocopherol was added to give clear homogenous solutions).

(46) Each formulation was injected in a vial and equilibrated with excess water. The phase behaviour was evaluated visually and between crossed polarizes at 25 C. Results are presented in Table 6.

(47) TABLE-US-00006 TABLE 6 -tocopherol PC Ethanol Phase in excess H.sub.2O 2.25 g 2.25 g 0.5 g H.sub.II 2.7 g 1.8 g 0.5 g H.sub.II/I.sub.2 3.15 g 1.35 g 0.5 g I.sub.2 3.6 g 0.9 g 0.5 g I.sub.2/L.sub.2

Example 22: In Vitro Release of Water-Soluble Disodium Fluorescein

(48) A water-soluble colorant, disodium fluorescein (Fluo), was dissolved in a formulation containing PC/-tocopherol/Ethanol (27/63/10 wt %) to a concentration of 5 mg Fluo/g formulation. When 0.1 g of the formulation was injected in 2 ml of phosphate buffered saline (PBS) a reversed micellar (I.sub.2) phase was formed. The absorbency of Fluo released to the aqueous phase was followed at 490 nm over a period of 3 days. The release study was performed in a 3 mL vial capped with an aluminium fully tear off cap at 37 C. The vial was placed on a shaking table at 150 rpm.

(49) The release of Fluo from the PC/-tocopherol formulation (see Table 7) indicates that this (and similar) formulations are promising depot systems. Furthermore, the absence of a burst effect is noteworthy, and the release indicates that the substance can be released for several weeks to months; only about 0.4% of Fluo is released after 3 days.

(50) TABLE-US-00007 TABLE 7 % release (37 C.) Formulation 24 h 72 h PC/-tocopherol/EtOH: <0.1* 0.43 27/63/10 wt % *Release below detection limit of the absorbance assay

Example 23: Formulations of the Analgesic/Antiinflammatory Benzydamine

(51) Formulations were prepared as in Example 1 by mixing benzydamine with a mixture of GDO, PC, ethanol and optionally PG/AP in the following proportions.

(52) TABLE-US-00008 Formulation BZD GDO PC EtOH PG AP 1 3.0 53.3 28.7 10.0 5.0 0.01 2 3.0 53.3 28.7 15.0 0 0.01 3 3.0 57.4 24.6 10.0 5.0 0.01 4 3.0 49.2 32.8 10.0 5.0 0.01 where BZD is benzydamine, EtOH is ethanol, PC is LIPOID S100 soybean phosphatidylcholine, GDO is glycerol dioleate, PG is propylene glycol, and AP is ascorbyl palmitate.

(53) All formulations are low viscosity liquids which generate liquid crystalline phase compositions upon exposure to aqueous conditions.

Example 24: Fentanyl Nasal Formulation

(54) Formulations were prepared as in Example 1 by mixing the narcotic analgesic fentanyl with a mixture of GDO, PC, ethanol and optionally PG in the following proportions.

(55) TABLE-US-00009 Formulation Fentanyl PC GDO EtOH PG 1 0.05 34 51 10 5 2 0.05 36 54 10 3 0.05 42 43 10 5 4 0.05 45 45 10 5 0.15 34 51 10 5 6 0.15 36 54 10 7 0.05 30 45 15 10 8 0.15 30 45 15 10 where EtOH is ethanol, PC is LIPOID S100 soybean phosphatidylcholine, GDO is glycerol dioleate, and PG is propylene glycol

(56) All formulations are low viscosity liquids suitable for administration by nasal spray, which generate liquid crystalline phase compositions upon exposure to aqueous conditions.

Example 25: Diazepam Nasal Formulation

(57) Formulations were prepared as in previous examples by mixing the benzodiazepine antianxiety agent diazepam with a mixture of GDO, PC, ethanol and optionally PG in the following proportions.

(58) TABLE-US-00010 Formulation Diazepam PC GDO EtOH PG 1 5 32 48 10 5 2 5 34 51 10 3 10 37 38 10 5 4 10 40 40 10 5 10 30 45 10 5 6 10 32 48 10 7 10 26 39 15 10 8 10 30 45 15 where EtOH is ethanol, PC is LIPOID S100 soybean phosphatidylcholine, GDO is glycerol dioleate, and PG is propylene glycol

(59) All formulations are low viscosity liquids suitable for administration by nasal spray, which generate liquid crystalline phase compositions upon exposure to aqueous conditions.

Example 26: Acne Formulations with Clindamycin

(60) Formulations were prepared as in previous examples by mixing the semisynthetic antibiotic clindamycin (free base or salt) with a mixture of GDO, PC, ethanol and PG in the following proportions (by weight).

(61) TABLE-US-00011 Formulation Clindamycin HCl PC GDO EtOH PG 1 1 30 54 10 5 2 2 29 54 10 5 3 1 34 50 10 5 4 2 33 50 10 5

(62) TABLE-US-00012 Formulation Clindamycin base PC GDO EtOH PG 5 1 30 54 10 5 6 2 29 54 10 5 7 1 33 54 2 10 8 2 32 54 2 10

(63) The resulting preformulations are low viscosity liquids which, after application resistant to water, sweat, etc. The formulation are applied locally on the skin as a gel or by spraying and are bioadhesive with good film-forming properties.

Example 27: Further Examples of Viscosity in PC/GDO Mixtures on Addition of Co-Solvent

(64) Mixtures of PC/GDO and co-solvent were prepared according to the methods of Example 1 and Example 3 in the proportions indicated in the table below. The samples were allowed to equilibrate for several days before viscosity measurements were performed using a Physica UDS 200 rheometer at 25 C.

(65) TABLE-US-00013 PC/GDO EtOH/ Glycerol/ H.sub.2O/ Viscosity/ Sample (wt/wt) wt % wt % wt % mPas 1 50/50 3 1900 2 50/50 5 780 3 50/50 7 430 4 50/50 8 300 5 50/50 10 210 6 50/50 15 100 7 45/55 3 1350 8 45/55 5 540 9 45/55 7 320 10 45/55 8 250 11 45/55 10 150 12 45/55 15 85 13 40/60 3 740 14 40/60 5 400 15 40/60 7 240 16 40/60 8 200 17 40/60 10 130 18 40/60 15 57 19 40/60 10 8 * 10.sup.6 20 40/60 3 2.5 * 10.sup.8 21 40/60 5 4 * 10.sup.7

(66) This example further illustrates the need for a solvent with viscosity lowering properties in order to obtain injectable formulations. The mixtures containing glycerol (sample 19) or water (samples 20 and 21) are too viscous to be injectable at solvent concentrations equivalent to the samples containing EtOH (compare with samples 13, 14 and 17).

Example 28: Sunscreen Formulations

(67) Formulations were prepared as in Example 1 by mixing each of several UV absorbing/scattering agents with a mixture of GDO, PC, and ethanol in the following proportions (by weight)

(68) TABLE-US-00014 Formu- Tioveil Spectraveil Solaveil Tioveil lation PC GDO EtOH CM FIN CT-100 50 MOTG 1 38 42 5 15 2 38 42 5 15 3 37 38 5 15 5 Where TIOVEIL CM (Uniqema) comprises Cyclomethicone (and) Titanium Dioxide (and) Dimethicone Copolyol (and) Aluminium Stearate (and) Alumina, SPECTRAVEIL FIN (Uniqema) comprises Zinc Oxide (and) C12-15 Alkyl Benzoate (and) Polyhydroxystearic Acid, SOLAVEIL CT-100 (Uniqema) comprises C12-15 Alkyl Benzoate (and) Titanium Dioxide (and) Polyhydroxystearic Acid (and) Aluminum Stearate (and) Alumina, and TIOVEIL 50 MOTG (Uniqema) comprises Titanium Dioxide (and) Caprylic/Capric Triglyceride (and) Mineral Oil (and) Polyhydroxystearic Acid (and) Aluminum Stearate (and) Alumina.

(69) The resulting formulation precursors show low viscosity upon formulation and are readily applied by pump spray. Upon contact with body surfaces a resilient UV protective layer is formed.

Example 29: Chlorhexidine Periodontal Depots

(70) Formulations were prepared as in Example 1 by mixing the antiinfective agent chlorhexidine digluconate with a mixture of GDO, PC, and ethanol in the following proportions (by weight)

(71) TABLE-US-00015 TABLE Chlorhexidine digluconate depot formulation compositions. Chlorhexidine Formulation digluconate PC GDO EtOH A 5 34 51 10 B 5 36 54 5 C 7 33 50 10 D 10 32 48 10 E 15 30 45 10

(72) The chlorhexidine depot preformulations have low viscosity and are easily administered to the periodontal pocket. The compositions provide better distribution and spreading of the active substance throughout the periodontal pocket when compared to current products, such as Periochip.

(73) The depot formed after application gives protection against re-infection of the pocket. The depot also has excellent bioadhesive properties and sticks to mucosal, teeth and bone surfaces.

(74) Release of chlorhexidine digluconate from 250 mg Formulation A (see above) in 0.9% aqueous NaCl (500 ml) was studied. The formulation was held in a cylindrical metal cup which was placed in a teflon holder at the bottom of a standard USP release bath. The contact area between the formulation and surrounding saline solution was 2.4 cm.sup.2, and the solution was stirred by paddle at 100 rpm.

(75) The release curve shown in FIG. 3 demonstrates the sustained and essentially uniform release of chlorhexidine from the formulation over a period of 24 hours.

Example 30: Topical Formulation with a NSAID

(76) Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID). It belongs to the phenylacetic acid group and is used in inflammatory conditions of various etiologies, degenerative joint disease and many other painful conditions. A formulation for topical administration containing diclofenac sodium was prepared by first preparing a placebo formulation.

(77) Composition of Placebo Formulation

(78) TABLE-US-00016 Excipient Abbreviation Concentration (%) Phosphatidyl choline SPC 45.0 (from soy bean) Glycerol dioleate GDO 45.0 Etanol 99.5% EtOH 10.0

(79) Diclofenac sodium to a concentration of 5% was dissolved in the placebo formulation. The resulting oily liquid was slightly yellowish, transparent, and had a low viscosity.

Example 31: Formation of Liquid Crystalline Phase

(80) One drop of the diclofenac sodium containing formulation in Example 30 was added to 3 ml aqueous saline solution with a pipette. A cohesive liquid crystalline phase formed.

Example 32: Formation of Rigid Film In Situ

(81) One drop of the diclofenac sodium containing formulation in example 30 was applied to the skin on the arm of a healthy volunteer and smeared out to a thin film covering an area of about 2-4 cm.sup.2. Shortly after application the liquid formulation transformed to a much more rigid film by uptake of small amounts of water from the skin and/or the air.

Example 33: Improving Spray Pattern by Lowering Viscosity

(82) A placebo formulation with the composition as given in the Table in Example 30 was filled in a standard pump-spray bottle. After priming the pump with formulation the formulation could be applied to the skin with a sub-optimal spray-pattern. By diluting the formulation further with EtOH the viscosity of the formulation decreased and at an EtOH concentration corresponding to about 25% the formulation could be applied as a mist to the skin. Spaying the formulation to the skin on the arm of a healthy volunteer resulted in formation of a rigid film after evaporation of EtOH and uptake of small amounts of water from the skin and/or the air.

Example 34: Improving Spray Pattern by Using a Compression Pump Device

(83) A placebo formulation with the composition as given in the Table in Example 30 was filled in a standard compression pump bottle. This device gave a good mist/aerosol and spray pattern. Spaying the formulation to the skin on the arm of a healthy volunteer resulted in formation of a rigid film after uptake of small amounts of water from the skin and/or the air.

Example 35: Use of Pressure Driven Device

(84) A placebo formulation with the composition as given in the Table in Example 30 was filled in a pressure driven spray-device either with a hydrocarbon propellant or with HFC-134a as propellant, respectively. Both propellants were found to form low-viscous homogeneous mixtures with the formulation. Spaying the formulation to the skin on the arm of a healthy volunteer resulted in rapid formation of a rigid film after uptake of small amounts of water from the skin and/or the air.

Example 36: Spraying Formulation with Very Low Concentration of EtOH

(85) A formulation with the composition as given in the table below was prepared by evaporating EtOH from the placebo formulation with the composition as given in the Table in Example 30 with the aid of a rotary evaporator (vacuum, 40 C.). The resulting formulation had a high viscosity but when mixed with propellant (hydrocarbon propellant or HFC-134a) and filled in a spray bottle the formulation could be sprayed to the skin on the arm of a healthy volunteer where a rigid film formed after uptake of small amounts of water from the skin and/or the air.

(86) Composition of Placebo Formulation

(87) TABLE-US-00017 Excipient Abbreviation Concentration (%) Phosphatidyl choline SPC 49.0 (from soy bean) Glycerol dioleate GDO 49.0 Etanol 99.5% EtOH 2.0

Example 37: Targeting to Different Surfaces by Varying the Composition of the Formulation

(88) By varying the PC/GDO ratio in the formulation duration of the formulation at different places in the oral cavity could be adjusted. A formulation with the composition PC/GDO/EtOH (36/54/10) has a preference for adherance to hard surfaces, such as teeth, while a formulation with the composition PC/GDO/EtOH (27/63/10) was found to be better suited for the upper palate.

Example 38: Formation of a Liquid Crystalline Phase from Precursors with Various Solvent Mixtures

(89) To improve solubility of active substance in the precursors it may be useful to change solvent in the formulation. A number of different solvent mixtures were used in the formulation precursors (see Table) and their ability to form a liquid crystalline phase after contacting them with excess aqueous solution was investigated. One drop of each formulation was added to 3 ml aqueous saline solution with a pipette. Independent of the solvent (mixture) used a cohesive liquid crystalline phase formed.

(90) Composition of Formulations

(91) TABLE-US-00018 Excipients Composition (wt %) PC/GDO/EtOH 45/45/10 PC/GDO/EtOH/NMP 45/45/5/5 PC/GDO/EtOH/propylene-carbonate 45/45/5/5 PC/GDO/EtOH/dimethyl-isosorbide 45/45/5/5 PC/GDO/EtOH/dimethyl-acetamide 45/45/5/5 PC/GDO/EtOH/ethyl-acetate 45/45/5/5

Example 39Topical Formulation with Testosterone Enanthate

(92) A topical formulation containing 2% testosterone enanthate was prepared by mixing the components in the Table below. Shortly after applying the liquid formulation to the skin it transformed to a much more rigid film by uptake of small amounts of water from the skin and/or the air.

(93) Composition of Topical Formulation with Testosterone Enanthate

(94) TABLE-US-00019 Component Amount (g) Composition (wt %) Testosterone enanthate 0.060 2.00 Soy Phosphatidyl Choline 1.323 44.10 Glycerol Dioleate 1.323 44.10 Ethanol 0.294 9.80

LEGENDS TO FIGURES

(95) FIG. 1. Cumulative release of MB from a depot forming a reversed hexagonal H.sub.II phase.

(96) FIG. 2. Decrease in viscosity of the depot precursor on addition of solvents. PC/GDO (6/4) is a precursor to a reversed hexagonal H.sub.II phase and PC/GDO (3/7) is a precursor to a reversed cubic 12 phase.

(97) FIG. 3: Release of Chlorhexidine from formulation A, see Example 33.