Liquid depot formulations

[0001] The present invention relates to formulation precursors (preformulations) for the production of controlled release lipid compositions in situ. In particular, the present invention relates to pre-formulations in the form of low-viscosity mixtures (such as molecular solutions) of amphiphilic components and at least one biologically active ingredient that undergo at least one phase change when exposed to water-containing fluids, such as body fluids, by this forming a controlled release matrix that optionally exhibits bioadhesion.

[0002] Many biologically active agents, including pharmaceuticals, nutrients, vitamins and so on, have a specific "usefulness range". This means that there is a range of concentrations at which these agents give some observable biological effect. When in an appropriate part of the body (e.g. locally or as the serum concentration shows) the concentration falls below a certain level, no such beneficial effect can be attributed to such a measure. Similarly, in general, there is an upper concentration level above which no further benefit is obtained by increasing the concentration. In some cases, increasing the concentration above a certain level causes undesirable or even dangerous effects.

[0003] Some biologically active agents have a long biological half life and / or a wide range of utility, and thus may be administered sporadically, maintaining the useful biological concentration for a significant period of time (e.g. 6 hours to several days). In other cases, the removal rate is high and / or the usefulness range is narrow, and therefore regular (or even continuous) doses in small amounts are required to maintain biological concentration within this range. This can be particularly difficult when non-oral routes of administration are indicated (e.g. parenteral administration). In addition, under certain circumstances, such as implant insertion (e.g., artificial joints or dental implants), the correct site of action may no longer be available for repeated administration. In such cases, a single administration must ensure the activity of the agent at the therapeutic level throughout the period during which this activity is needed.

[0004] Various methods have been used and proposed for the sustained release of biologically active agents. Such methods include orally administered slow release compositions, such as coated tablets, formulations designed for gradual absorption, such as transdermal patches, and slow release implants, such as "sticks" implanted under the skin.

[0005] One method proposed for the gradual release of a bioactive agent is the so-called "depot" injection. In this method, the biologically active agent is formulated with carriers, providing a gradual release of the active agent over a period of hours or days. They are often based on a decomposing matrix that gradually disperses in the body, releasing the active agent.

[0006] The most common recognized depot injection method is based on a polymer depot system. Typically, it is a biodegradable polymer such as poly (lactic acid) (PLA) and / or poly (lactic acid-co-glycolic acid) (PLGA) and may be in the form of a solution in an organic solvent, a prepolymer mixed with initiator, encapsulated polymer particles or polymer microspheres. The polymer or polymer particles bind the active agent and are gradually broken down, releasing the agent by slow diffusion as the matrix is ​​absorbed. Examples of such systems include those described in patents US 4938763, US 5480656 and US 6113943, which can provide active agents for a period of

EP 1 768 650 B1 up to several months. However, these systems have a number of limitations including the complexity of manufacture and the difficulty of sterilization (especially microspheres). A noticeable drawback is also local irritation caused by lactic and / or glycolic acid, which is released at the injection site. Also often, the procedure for making a dose for injection from a powder precursor is complicated.

[0007] From a drug delivery point of view, polymer depot compositions also have the disadvantage of being able to contain only relatively low amounts of drugs and have a "burst / lag" release profile. The nature of the polymer matrix, especially when applied as a solution or prepolymer, causes the initial burst of released drug as soon as the composition is administered. This is followed by a period of low release, while the matrix begins to break down, and finally the release rate increases to the desired sustained release profile. This burst / delay release profile may cause that the concentration of active agent in vivo immediately after administration rises above the utility interval, and then during the delay period falls below the utility interval before reaching a sustained useful concentration. Of course, from a utilitarian and toxicological point of view this burst / delay release profile is undesirable and can be dangerous. It may also limit the achievement of a balanced concentration due to the danger of harmful effects occurring during the "peak".

[0008] Previous depot systems have solved the problem of rapid burst of released drug. In particular, the use of hydrolyzed poly (lactic acid) and the inclusion of poly (lactic acid) -poly (ethylene glycol) block copolymers to obtain the "low-discharge" polymer system described in US Patent 6,113,943 and US Patent 6,113,945 has been proposed. Such systems provide improved release profiles, but the burst / delay effect remains, and they do not solve other disadvantages, such as irritation caused by the use of polymers giving acidic decomposition products.

[0009] US Patent 5,807,573 proposes a depot system as an alternative to the more recognized polymer-based depot systems. A lipid-based system consisting of diacylglycerol, phospholipid and optionally water, glycerin, ethylene glycol or propylene glycol is proposed in order to obtain a "L2" reverse micellar or liquid crystalline phase liquid delivery system. Because this depot system is made of physiologically well-tolerated diacylglycerols and phospholipids, and does not produce lactic acid or glycolic acid as degradation products of polymeric systems, there is less of a tendency to cause inflammation at the injection site when using this system. However, the liquid crystal phases have a high viscosity and the L2 phase may also be too viscous to be easily used. The authors of US Pat. No. 5,807,573 also do not provide any in vivo assessment of the release profile of the formulation, and therefore it is uncertain whether a "burst" profile is obtained or not.

[0010] The use of non-lamellar (non-laminar) phase structures (such as liquid crystal phases) for the delivery of biologically active agents is now relatively well established. Such structures arise when the amphiphilic compound is exposed to the solvent because the amphiphilic compound has both polar and nonpolar groups that aggregate to form polar and nonpolar regions. These areas can effectively dissolve both polar and nonpolar compounds. In addition, many of the structures formed by amphiphilic compounds in polar and / or non-polar solvents have

A very significant polar / nonpolar border area at which other amphiphilic compounds can adsorb and stabilize. The amphiphilic compounds can also be formulated to protect active agents, at least to some extent, against agents present in aggressive biological environments, including enzymes, and thereby provide beneficial regulation of stability and release of the active agent.

[0011] The phenomenon of forming non-laminar regions is well known in the phase diagrams of an amphiphilic compound / water, an amphiphilic compound / oil and an amphiphilic compound / oil / water. Such phases include liquid crystalline phases such as regular phase P, regular D, regular G and hexagonal, which are liquid at the molecular level, but exhibit significant long range ordering, and the L3 phase, which includes a multiple bonded continuous network of layer sheets duplicates that are non-laminated but do not have long range ordering as for liquid crystal phases. Depending on their curvature of the amphiphilic sheets, these phases can be described as normal (average curvature towards the non-polar region) or inverted (average curvature towards the polar region).

[0012] The non-layered liquid crystalline phases and L3 are thermodynamically stable systems. That is, they are not simply a metastable state that will separate and / or transform into layers, film phases or the like, but are a thermodynamically stable form of the lipid / solvent mixture.

[0013] While the efficacy of known lipid depot formulations is high, there are certain aspects in which their effectiveness is not so excellent. In particular, the proposed regular liquid crystal phases are relatively sticky in nature. This makes administration using a normal syringe difficult and possibly painful for the patient, and prevents filter sterilization because the composition cannot be passed through the necessary membrane with fine pores. As a result, the compositions must be manufactured under highly sterile conditions, which contributes to the complexity of manufacture. When L2 phases are used, they generally have a lower viscosity, but can still cause feeding difficulties and give access only to a small area of ​​the phase diagram. Specifically, the solvents used in known lipid formulations have only a limited effect on reducing the viscosity of the mixture. For example, water will cause the formation of a highly viscous liquid crystalline phase, and solvents such as glycerin and glycols have a high viscosity and do not provide any very favorable decrease in the viscosity of the composition. Glycols are also typically toxic or poorly tolerated in vivo and may cause irritation when applied topically.

[0014] In addition, known low lipid compositions of L2 phase lipids can only contain relatively low levels of many biologically active agents due to their limited solubility in the components of the mixture in the absence of water. In the presence of water, however, the formulations take the form of a highly viscous liquid crystal regular phase. It would be a clear advantage to obtain a depot system that could be injected at low viscosity and enabled the release of the biologically active agent at the required concentration simultaneously with a smaller volume of the depot composition.

[0015] Known lipid depot compositions practically allow access to only certain phase structures and compositions because other mixtures are either too highly viscous to be administered (such as those having high phospholipid concentrations) or carry the risk of separation into two or more separate phases ( such as the L2 phase in equilibrium with the phospholipid-rich phase). In particular, phospholipid concentrations above

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50% are impossible to achieve by known methods and from the phase diagram shown in US Pat. No. 5,807,573 it appears that the desired regular phase is stable at no more than 40% phospholipid. As a result, in practice it was not possible to produce depot compositions with high phospholipid concentration or having a hexagonal liquid crystal phase structure.

[0016] The inventors have found that by providing a preformulation containing certain amphiphilic components, at least one biologically active agent and a biologically tolerated solvent, especially in a low viscosity phase such as a molecular solution, a preformulation can be made that does not have many of the disadvantages of previous depot formulation. In particular, such a pre-formulation is easily prepared, it can be sterilized by filtration, it has a low viscosity (which allows easy and less painful administration), allows the incorporation of a biologically active agent at a high level (thus allows the use of a smaller amount of composition) and / or in vivo forms the desired non-layered depot composition having a controlled "burst" or "no burst" release profile. The compositions are also made of substances that are non-toxic, biologically tolerated and biodegrade. In addition, the pre-formulation is useful for producing depot compositions after parenteral administration, as well as after non-parenteral (e.g. topical) administration to body cavities and / or body surface or other sites.

[0017] In a first aspect, the invention relates to a pre-formulation comprising a low viscosity mixture:

a) at least one neutral diacyl lipid and / or tocopherol;

b) at least one phospholipid;

c) at least one biocompatible (preferably oxygen-containing) organic solvent; wherein at least one biologically active agent is dissolved or dispersed in a low viscosity mixture, and wherein, upon contact with the aqueous fluid, the pre-formulation forms, or can form, at least one liquid crystal phase structure.

[0018] Generally, the aqueous fluid will be a body fluid such as mucosal fluid, tears, sweat, saliva, gastric juice, extravascular fluid, extracellular fluid, interstitial fluid or plasma, and in contact with the aqueous body fluid the preformulation will form a phase structure liquid crystal when contacted with a surface, area or body cavity (e.g. in vivo). In general, the pre-formulation of the invention will not contain any significant amount of water prior to administration.

[0019] In a second aspect, the invention relates to a method of delivering a biologically active agent to the body of a human or non-human animal (preferably a mammal), which method comprises administering (preferably parenterally) a pre-formulation containing a low viscosity mixture:

a) at least one neutral diacyl lipid and / or tocopherol;

b) at least one phospholipid;

c) at least one biocompatible (preferably oxygen-containing) organic solvent; and at least one biologically active agent is dissolved or dispersed in a low viscosity mixture, whereby it forms at least one liquid crystalline phase structure upon contact with the aqueous fluid in vivo after administration. Preferably, the pre-formulation administered in such a manner is a pre-formulation of the invention as described herein.

[0020] A method of administration appropriate to the above method of the invention will be that appropriate to the disease state being treated and the bioactive agent used. Therefore

The parenteral depot drug will be prepared by parenteral (e.g. subcutaneous or intramuscular) administration, while the bioadhesive non-parenteral depot composition (e.g. topical) can be produced by applying to the surface of the skin, mucous membranes and / or nails, to the ocular, nasal, oral or internal surfaces, or into cavities such as nasal, anal, vaginal or cheek cavities, into the periodontal pocket or cavities produced after extraction natural or implanted structure or before implant insertion (e.g., joint, stent, cosmetic implant, tooth, tooth filling or other implant).

[0021] In a further aspect, the present invention also relates to a process for preparing a liquid crystal composition (especially a depot composition) comprising exposing a pre-formulation comprising a low viscosity mixture:

a) at least one neutral diacyl lipid and / or tocopherol;

b) at least one phospholipid;

c) at least one biocompatible (preferably oxygen-containing) organic solvent; and at least one biologically active agent dissolved or dispersed in a low viscosity mixture on the action of the aqueous fluid (particularly in vivo and / or especially body fluid as indicated herein). Preferably the preformulation administered is the preformulation of the present invention as described herein. Exposure to the fluid "in vivo" may of course occur inside the body or in the body cavity, or it may occur on a body surface, such as the surface of the skin, depending on the nature of the composition.

[0022] The liquid crystal composition produced in this way is preferably bioadhesive as described.

[0023] In yet another aspect, the invention relates to a method of producing a pre-formulation useful for administering a biologically active agent to a subject (preferably a mammal), the method comprising forming a low viscosity mixture

a) at least one neutral diacyl lipid and / or tocopherol;

b) at least one phospholipid;

c) at least one biocompatible (preferably oxygen-containing) organic solvent; and dissolving or dispersing at least one biologically active agent in a low viscosity mixture, or in at least one of the components a, b or c before forming the low viscosity mixture. Preferably, the pre-formulation thus formed is the formulation of the invention described herein.

[0024] In a still further aspect, the present invention relates to the use of a low viscosity mixture:

a) at least one neutral diacyl lipid and / or tocopherol;

b) at least one phospholipid;

c) at least one biocompatible (preferably oxygen-containing) organic solvent; wherein the at least one biologically active agent is dissolved or dispersed in a low viscosity mixture for producing a pre-formulation for use for sustained administration of the active agent, wherein the pre-formulation has the ability to form at least one liquid crystal phase structure upon contact with an aqueous fluid.

[0025] As used herein, the term "low viscosity mixture" indicates a mixture that can be easily administered to a subject and in particular easily administered with a normal syringe and needle kit. This can be demonstrated, for example, by the ability to dispense from a 1ml disposable syringe through a 22 awg (or size 23) needle under manual pressure. In a particularly preferred embodiment, the low viscosity mixture should be a mixture capable of passing through a normal filter sterilization membrane, such as a 0.22 μm syringe filter. In other preferred embodiments, a similar functional definition of useful viscosity can be defined as the viscosity of a pre-formulation that can be sprayed using a compressor or a pressure spray device using conventional spray equipment. A typical range of suitable viscosities could be, for example, 0.1 to 5000 mPas, preferably 1 to 1000 mPas at 20 ° C.

[0026] It has been observed that by adding small amounts of low viscosity solvent as indicated herein, a very significant change in viscosity can be provided. For example, as indicated in Figure 2, the addition of only 5% solvent can reduce the viscosity 100 times, and the addition of 10% can reduce the viscosity up to 10,000 times. In order to achieve this non-linear synergistic effect, when lowering viscosity, it is important to use a solvent with sufficiently low viscosity and appropriate polarity. Such solvents include the solvents described below.

[0027] Particularly preferred examples of low viscosity mixtures are molecular solutions and / or isotropic phases such as L2 and / or L3 phases. As described above, L3 means a non-laminar phase composed of joined sheets that has some phase structure but does not have a long range ordering specific to the liquid crystal phase. Unlike liquid crystal phases, which are usually highly viscous, L3 phases have lower viscosities. Of course, mixtures of the L3 phase and molecular solution and / or L3 phase particles suspended in a bulk molecular solution of one or more components are also useful. The L2 phase is the so-called "reversed micellar" phase or microemulsion. The most preferred low viscosity mixtures are molecular solutions, L3 phases and mixtures thereof. L2 phases are less preferred, except in the case of swollen L phases₂as described below.

[0028] The present invention provides a pre-formulation comprising components a, b, c and at least one biologically active agent as indicated herein. One of the significant advantages of the pre-formulations of the invention is that components a and b can be formulated in a wide range of proportions. In particular, the pre-formulations of the present invention can be prepared and used having a ratio of phospholipid to neutral diacyl lipid and / or tocopherol much higher than previously possible without the risk of phase separation and / or unacceptably high viscosities in the preformulation. The weight ratios of components a: b can therefore reach around 5:95, and even up to 95: 5. Preferred ratios could usually be from 90:10 to 20:80, and more preferably from 85:15 to 30:70. In one preferred embodiment of the invention, the proportion of component b is greater than component a. This means that the weight ratio a: b is below 50:50, e.g. 48:52 to 2:98, preferably, 40:60 to 10:90 , and more preferably 35:65 to 20:80.

[0029] The amount of component c in the pre-formulations of the invention will be at least sufficient to produce a low-viscosity mixture (e.g., molecular solution, see above) of components a, b and c, and will be easily determined by standard methods for any particular combination of components. Phase behavior alone can be analyzed by techniques such as visual observation combined with polarized light microscopy, nuclear magnetic resonance, and cryotransmission electron microscopy.

EP 1 768 650 B1 (cryo-TEM) looking for solutions, L2 or L3 phases, or liquid crystal phases. Viscosity can be measured directly by standard methods. As described above, in practice a suitable viscosity is one that allows effective syringe transfer, and in particular sterilization by filtration. As described herein, this can be easily assessed. The highest amount of component c incorporated will depend on the particular pre-formulation application, but generally the desired properties will be provided by any amount forming a low viscosity mixture (e.g., molecular solution, see above) and / or a solution of sufficiently low viscosity. Since administering unnecessarily large amounts of solvent to the subject is usually undesirable, the amount of component c will typically be limited to no more than ten times (e.g. three times) the lowest amount required to obtain a low viscosity mixture, preferably no more than five times, and most preferably no more than twice that amount. The composition of the present invention may, however, contain more solvent than would be acceptable in a composition for direct administration, because the process by which the active agents are slowly released (e.g. the formation of liquid crystal coatings as described herein) also serves to delay the passage of solvent from the composition. As a result, the solvent is released for some time (e.g. minutes or hours) instead of immediately, making it better tolerated by the body.

[0030] Higher proportions of solvent can also be used for non-parenteral (e.g. topical) applications, especially on body surfaces, where the solvent will be lost by evaporation instead of being absorbed into the body. In such applications, you can use up to one hundred times the least amount of solvent (e.g. up to 95% by weight of the composition, preferably up to 80% by weight and more preferably up to 50% by weight), especially if ultimately a very thin non-parenteral depot layer is desired.

[0031] The compositions of the invention formulated as (non-parenteral) aerosol spray compositions (e.g. for topical or systemic delivery of the active agent) may also contain a propellant. Such compositions may also contain a high proportion of solvent component c) as considered above, since a significant amount of solvent will evaporate when the composition is dispensed.

[0032] Useful propellants are volatile compounds that will mix with the composition of the invention under the pressure of a spray dispenser, without producing high viscosity mixtures. Of course, they should have acceptable biocompatibility. Useful propellants will be easily identified by simple tests, and examples include hydrocarbons (especially C hydrocarbons₁ to C.₄), carbon dioxide and nitrogen. Volatile fluorinated hydrocarbons such as HFC 134, 134a, 227ea and / or 152a may also be useful.

[0033] Generally, the weight of component c will typically be about 0.5 to 50% of the total weight of the abc solution. This proportion is preferably (especially for injectable depots) 2 to 30%, and more preferably 5 to 20% by weight.

[0034] Component "a" as indicated herein is a neutral lipid containing a polar group as "head" and non-polar groups as a "tail". In general, the lipid parts forming the head and tail will be linked by an ester moiety, but this attachment may occur through an ether, amide, carbon-carbon bond or other attachment. Preferred polar head groups are nonionic and include polyols such as glycerol, diglycerol and sugars (such as inositol and glucosyl based moieties); and polyol esters,

Such as acetate or succinate esters. Preferred polar groups are glycerol and diglycerol, especially glycerol.

[0035] In one preferred aspect, component a is a diacyl lipid that has two non-polar "tail" groups. This is usually preferred as opposed to the use of mono-acyl ("lyso") lipids because they are usually less tolerated in vivo. Two non-polar groups may have the same or different number of carbon atoms and may be saturated or unsaturated independently of each other. Examples of non-polar groups include C groups₆-C₃₂ alkyl and alkenyl, which are typically present as esters of long chain carboxylic acids. They are often described by reference to the number of carbon atoms and the number of unsaturations in the carbon chain. Thus, CX: Z indicates a hydrocarbon chain having X carbon atoms and Z unsaturations. Examples especially include caprooyl (C6: 0), capryloyl (C8: 0), caprinoyl (C10: 0), lauroyl (C12: 0), myristoyl (C14: 0), palmitoyl (C16: 0), phytanoyl (C16: 0), palmitoleoyl (C16: 1), stearoyl (C18: 0), oleoyl (C18: 1), elaidoyl (C18: 1), linoleoyl (C18: 2), linolenoyl (C18: 3), arachidonoyl (C20: 4 ), behenoil (C22: 0) and lignoceroil (C24: 9). Thus, typical non-polar chains are based on fatty acids of natural lipid esters containing caproic, caprylic, capric, lauric, myristic, palmitic, phytanic, palmitol, stearic, oleic, elaidic, linoleic, linolenic, arachidonic, behenic or lignoceric acids suitable alcohols. Preferred non-polar chains are palmitic, stearic, oleic and linoleic acids, especially oleic acid.

[0036] The diacyl lipid, when used as all or part of the component "a", may be synthetic or may come from purified and / or chemically modified natural sources such as vegetable oils. Mixtures of any number of diacyl lipids can be used as component a. Most preferably this component will contain at least a portion of diacylglycerol (DAG), especially glycerol dioleate (GDO). In one preferred embodiment, component a consists of DAG. It can be a single DAG or a DAG mixture. A highly preferred example is DAG containing at least 50%, preferably at least 80%, and even containing essentially 100% GDO.

[0037] An alternative or additional highly preferred class of compounds for use as all or part of component a are tocopherols. The term "tocopherol," as used herein, is used to refer to a non-ionic tocopherol lipid, often known as vitamin E, and / or any suitable salts and / or analogues thereof. Useful analogs will be those that provide phase preservation, no toxicity, and phase change when exposed to the aqueous fluids that characterize the compositions of the present invention. Such analogues usually will not form liquid crystal phase structures as a pure compound in water. The most preferred tocopherol is tocopherol as such with the structure shown below. Of course, especially when it is purified from a natural source, it may contain a small proportion of "pollution" other than tocopherol, but it will not be sufficient to change favorable phase behavior or lack of toxicity. Typically, the tocopherol will contain no more than 10% of compounds other than tocopherol analogues, preferably no more than 5%, and most preferably no more than 2% by weight.

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[0038] In another preferred embodiment of the invention, component a) consists essentially of tocopherols, in particular tocopherol as shown above.

[0039] A preferred combination of constituent substances for component a) is a mixture of at least one DAG (e.g. GDO) with at least one tocopherol. Such mixtures contain 2:98 to 98: 2 by weight tocopherol: GDO, e.g. from 10:90 to 90:10 tocopherol: GDO, and especially from 20:80 to 80:20 these compounds. Mixtures of tocopherol with other DAGs are also useful.

[0040] The component "b" in the present invention is at least one phospholipid. As with component a, this component contains a polar head group and at least one non-polar tail group. The difference between components a and b lies mainly in the polar group. The non-polar portions may therefore conveniently be derived from fatty acids or the corresponding alcohols considered above for component a. Typically, the phospholipid will contain two non-polar groups, although one or more constituent substances of this component may have one non-polar moiety. When more than one non-polar group is present, they may be the same or different.

[0041] Preferred polar head phospholipid groups include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol. Phosphatidylcholine (PC) is most preferred. In a preferred embodiment, component b) therefore contains at least 50% PC, preferably at least 70% PC, and most preferably at least 80% PC. Component b) may consist essentially of PC.

[0042] The phospholipid portion, even more preferably than any diacylolipid portion, may be from a natural source. Useful sources of phospholipids include eggs, heart (e.g. beef), brain, liver (e.g. beef) and plant sources, including soy. Such sources may provide one or more constituents of component b, which may contain any mixture of phospholipids.

[0043] Since the pre-formulations of the invention are to be administered to a subject for the controlled release of an active agent, preferably components a and b are biocompatible. For this reason, it is preferable to use, for example, diacyl lipids and phospholipids instead of mono-acyl (lyso) compounds. A notable exception to this is the tocopherol described above. Although it has only one alkyl chain, it is not a "lyso" lipid in the sense of convention. The nature of tocopherol as a well-tolerated essential vitamin obviously makes it highly useful in terms of biological compatibility.

[0044] Furthermore, most preferably the lipids and phospholipids of components a and b occur naturally in nature (whether they come from a natural source or are of synthetic origin). Naturally occurring lipids tend to cause less inflammation and body reaction. Not only is it more convenient for the patient, but it can increase the residence time of the depot composition, especially in the case of parenteral depots, because less activity of the immune system is induced at the application site. In some cases, however, it may be advantageous to include in components a and / or b

Part of a non-naturally occurring lipid. This may be, for example, an "ether lipid" in which the head and tail groups are connected by an ether bond instead of an ester linkage. Such non-naturally occurring lipids can be used, for example, to change the rate of degradation of the resulting depot composition by having greater or less solubility or sensitivity to degradation mechanisms present at the site of release of the active agent. Although all proportions are within the scope of the present invention, generally at least 50% of each component a and b will be naturally occurring lipids. They will preferably constitute at least 75% and may constitute substantially up to 100%.

[0045] Two particularly preferred combinations of components a and b are GDO with PC and tocopherol with PC, especially in the range of 30-90 wt. GDO / tocopherol, 10-60 wt. PC and 1-30% solvent (especially ethanol, NMP and / or isopropanol).

[0046] In addition to the amphiphilic components a and b, the pre-formulations of the invention may also contain additional low levels of additional amphiphilic components. In one embodiment of the invention, the pre-formulation contains up to 10% (based on the weight of components a and b) of a charged amphiphilic compound, particularly an anionic amphiphilic compound such as a fatty acid. Preferred fatty acids for this purpose include caproic, caprylic, capric, lauric, myristic, palmitic, phytanic, palmitolyl, stearic, oleic, elaidic, linoleic, linolenic, arachidonic, behenic or lignoceric acids, or the corresponding alcohols. Preferred fatty acids are palmitic, stearic, oleic and linoleic acids, especially oleic acid. Particularly preferably, this component is used in combination with a cationic peptide active agent (see below). The combination of anionic lipid and cationic peptide is believed to give a particularly advantageous sustained release composition. In part, this may be due to increased protection of the peptide against in vivo degradative enzymes.

[0047] The "c" component of the pre-formulations of the invention is an oxygen-containing organic solvent. Since the pre-formulation is to produce a depot composition upon administration (e.g., in vivo) upon contact with an aqueous fluid, it is desirable that the solvent be tolerated by the subject and capable of mixing with the aqueous fluid, and / or diffusing or dissolving from the pre-formulation in the fluid. water. Therefore, solvents having at least moderate water solubility are preferred.

[0048] In a preferred version, the solvent is such that a relatively small addition to the composition containing a and b, i.e. less than 20%, or more preferably less than 10%, gives a large reduction in viscosity, by an order of magnitude or more. As described herein, the addition of a 10% solvent can give a viscosity reduction of two, three or even four orders of magnitude compared to a non-solvent composition, even if the composition is a solution or an L phase₂ solvent-free or unsuitable solvent such as water (special case considered below) or glycerol.

[0049] Typical solvents useful for use as component c include at least one solvent selected from the group consisting of alcohols, ketones, esters (including lactones), ethers, amides and sulfoxides. Examples of useful alcohols include ethanol, isopropanol and glycerol formal.

[0050] Monohydric alcohols are more preferred than diols and polyols. When diols or polyols are used, it is preferably combined with at least an equal amount of monohydric or other alcohol

Preferred solvent. Examples of ketones include acetone, and propylene carbonate. Useful ethers include diethyl ether, glycofurol, diethylene glycol monoethyl ether, dimethyl isobarbide, and polyethylene glycols. Useful esters include ethyl acetate and isopropyl acetate, and dimethyl sulfide is a useful sulfide solvent. Useful amides and sulfoxides include dimethylacetamide (DMA), N-methylpyrrolidone (NMP), 2-pyrrolidone, and dimethyl sulfoxide (DMSO). Less preferred solvents include dimethyl isosorbide, tetrahydrofurfuryl alcohol, diglyme and ethyl lactate.

[0051] Since the pre-formulations are to be administered to a live individual, it is necessary that the solvent component c must be sufficiently biocompatible. The degree of this biocompatibility will depend on the mode of administration and since component c can be any solvent mixture, some solvent may be present that is not acceptable in large quantities. In general, however, the solvent or mixture forming component c must not cause unacceptable reactions when administered to the bluebird. Such solvents will be hydrocarbons or preferably oxygen-containing hydrocarbons, both optionally with other substituents such as nitrogen-containing groups. Preferably component c contains little or no halogen substituted hydrocarbons since they show lower biocompatibility. When a halogenated solvent, such as dichloromethane or chloroform, is required, this proportion will usually be minimized. When the depot composition is to be formulated as non-parenteral, of course a larger range of solvents can be used than when the depot is to be parenteral.

[0052] Component c used in the present invention may be a single solvent or a mixture of suitable solvents, but generally low viscosity. This is important because one of the key aspects of the present invention is that it provides pre-formulations that have low viscosity and the main role of a useful solvent is to reduce this viscosity. This reduction will be a combination of the effect of lower solvent viscosity and the effect of molecular interactions between the solvent and the lipid composition. One of the inventors' observations is that the low viscosity oxygen-containing solvents described herein exhibit highly beneficial and unexpected intermolecular interactions with the lipid parts of the composition, thereby providing a non-linear decrease in viscosity when a small volume of solvent is added.

[0053] The viscosity of the "low viscosity" solvent component c (single solvent or mixture) should typically be no more than 18 mPas at 20 ° C. Preferably it sinks more than 15 mPas, more preferably not more than 10 mPas, and most preferably not more than 7 mPas at 20 ° C.

[0054] The solvent component c will generally be at least partially lost during the in vivo formation of the depot composition, or diluted by absorbing water from the surrounding air and / or tissue. Thus, preferably component c will be at least somewhat miscible with water and / or dispersible and should at least not repel water to such an extent as to prevent water absorption. Also in this regard, oxygen-containing solvents are preferred, with a relatively small number of carbon atoms (e.g. up to 10 carbon atoms, preferably up to 8 carbon atoms). Of course, when more oxygen atoms are present, the solvent will tend to maintain water solubility with more carbon atoms. The ratio of carbon atoms to heteroatoms (e.g., N, O, preferably oxygen) will therefore often be around 1: 1 to 6: 1, preferably 2: 1 to 4: 1. When a solvent is used

In a ratio outside of one of these preferred ranges, it will preferably be no more than 75%, preferably no more than 50%, in combination with a preferred solvent (such as ethanol). It can be used, for example, to reduce the evaporation rate of solvent from pre-formulations to control the rate of formation of the liquid crystal depot phase.

[0055] A further advantage of these pre-formulations is that a higher level of biologically active agent can be incorporated into the system. In particular, by proper selection of ac components (especially c), high levels of active agent can be dissolved or suspended in the pre-formulations. In general, the lipid components are relatively poorly dissolving in the absence of water, but in the presence of water they form too viscous phases to be easily administered. Higher proportions of biologically active agent can be included by using appropriate solvents as component c and this level will either dissolve in the depot composition as it forms in situ, or may form microdroplets or microcrystals that will gradually dissolve and release the active agent. Useful solvent selection will be possible through routine experimentation in accordance with the guidelines provided.

[0056] The pre-formulations of the present invention typically do not contain significant amounts of water. Since it is generally not possible to remove residual water from the lipid composition, it should be assumed that there is only such residual water that cannot be easily removed. This amount will generally be less than 1% by weight, preferably less than 0.5% by weight of the pre-formulation. In one preferred aspect, the pre-formulations of the invention do not contain glycerol, ethylene glycol or propylene glycol and contain no more than a residual water as described.

[0057] However, there is an embodiment of the present invention in which higher proportions of water can be tolerated. This is the case when water is present as part of the solvent component in combination with the additional water-miscible component c (single solvent or mixture). Up to 10 wt.% Can be present in this embodiment. water, provided that at least 3% by weight, preferably at least 5% and more preferably at least 7% by weight is also present. component c, which component c is miscible with water, and that the resulting pre-formulation remains non-viscous and therefore does not form a liquid crystal phase. Generally, the weight amount of component c) will be greater than the weight of water contained in the pre-formulation. The most useful solvents for use with water in this aspect of the invention include ethanol, isopropyl alcohol, NMP, acetone and ethyl acetate.

[0058] The pre-formulations of the present invention contain one or more biologically active agents (also described as "active agents"). The active agents can be any compounds having the desired biological or physiological effect, such as protein, drug, antigen, nutrient, cosmetic, flavoring, flavoring, diagnostic, pharmaceutical, vitamin, or dietetic agent, and will be formulated at sufficient to generate a concentration in vivo at a useful level (including local concentrations for topical compositions). In some circumstances, one or more components a, b and / or c may also be an active agent, although preferably the active agent should not be one of these ingredients. The most preferred active agents are pharmaceuticals, including drugs, vaccines and diagnostic agents.

[0059] Therapeutic agents that can be delivered with the help of the present invention include drugs that act on cells and receptors, peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, cardiovascular system, smooth muscles, cardiovascular system,

Endocrine and endocrine systems, circulatory system, synaptic sites, neuroefector junction sites, immune system, reproductive system, skeletal system, autacoid system, digestive and excretory systems, histamine system, and central nervous system.

[0060] Examples of drugs that may be provided by the composition of the present invention include, but are not limited to, antibacterial agents such as β-lactams or macrocyclic peptide antibiotics, antifungal agents such as polyene macrolides (e.g. amphotericin B) or azole antifungal agents, anticancer and / or antiviral drugs such as nucleoside analogues, paclitaxel and its derivatives, anti-inflammatory agents such as non-steroidal anti-inflammatory drugs and corticosteroids, cardiovascular drugs including cholesterol lowering agents and blood pressure, analgesics, antipsychotics and antidepressants including serotonin reuptake inhibitors, prostaglandins and derivatives, vaccines, and modulators of bone formation processes. Diagnostic agents include radionuclide labeled compounds and contrast media, including contrast enhancing agents in X-ray, ultrasound and magnetic resonance imaging. Nutrients include vitamins, coenzymes, dietary supplements, etc.

[0061] Particularly useful active agents include those that would normally have a short residence time due to rapid degradation or excretion, and those that have poor oral bioavailability. These include active agents based on peptides, proteins and nucleic acids, hormones and other agents occurring in nature in their native or modified forms. By administering such agents in the form of depot compositions made from the pre-formulations of the present invention, the agents are delivered at a sustained level over a period of time that may extend to days, weeks or even several months despite the high removal rates. This gives obvious advantages over the patient's durability and susceptibility to multiple dosing each day for the same period. In one preferred embodiment, the active agent therefore has a biological half life (at entry into the bloodstream) of less than 1 day, preferably less than 12 hours, and more preferably less than 6 hours. In some cases it can be as low as 1-3 hours or less. Useful agents are also those that have poor oral bioavailability relative to that achieved by injection, where the active agent also or alternatively has a bioavailability of less than 0.1%, especially less than 0.05% in oral formulations.

[0062] Peptide and protein based active agents include drugs for humans and animals selected from the group consisting of adrenocorticotropic hormone (ACTH) and fragments thereof, angiotensin and related peptides, antibodies and fragments thereof, antigens and fragments thereof, vestibular natriuretic peptides, bioadhesive peptides, bradykinins and related peptides, calcitonins and related peptides, protein fragments of receptors on cell surfaces, chemotactic peptides, cyclosporins, cytokines, dynorphins and related peptides, endorphins and fragments of P-lidotropin, enkephalin and related proteins, enzyme inhibitors, immunostimulatory peptides and polyamino acids, fragments of fibronectin and related peptides, gastrointestinal peptides, gonadotone-releasing hormone agonists and antagonists (GnRH), glucagon-like peptides, growth hormone releasing peptides, immunostimulatory peptides, insulins and insulin-like growth factors, interleukins, Luteinizing hormone releasing hormones (LHRH) and related peptides, melanocyte stimulating hormones and related peptides, peptides associated with nuclear localization signals, neurotensins and related peptides, peptides

Neurotransmitter, opiate peptides, oxytocins, vasopressins and related peptides, parathyroid hormone and fragments thereof, protein kinases and related peptides, somatostatin and related peptides, substance P and related peptides, growth factors transforming (TGF) and related peptides, tumor necrosis factor fragments, toxins and toxoids, and useful peptides such as anti-cancer peptides including angiostatin, antihypertensive peptides, anti-clotting peptides, and antibacterial peptides; selected from the group consisting of proteins such as immunoglobulins, angiogenins, bone morphogenetic proteins, chemokines, colony stimulating factors (CSF), cytokines, growth factors, interferons (type I and II), intereleins, leptins, leukemia inhibiting factors, stem cell factors growth factors and tumor necrosis factors.

A further significant advantage of the depot compositions of the present invention is that the active agents are released gradually over long periods of time, without the need for repeated dosing. The compositions are therefore highly useful in situations where it is difficult for the patient to be susceptible to treatment, where it is uncertain, or where the dose level is highly relevant, such as in the case of mood-altering agents that have a narrow therapeutic range, and agents administered to children or people, whose lifestyles are in conflict with reliable dosing regimens. Also for active agents affecting the lifestyle, where the inconvenience of repeated dosing could outweigh the benefit of using the active agent. Particular classes of active agents for which this aspect of the invention gives particular benefit include contraceptives, hormones, including contraceptive hormones, and especially hormones used in children, such as growth hormone, anti-addiction agents, supplements such as vitamins or mineral supplements. antidepressants and anticonvulsants.

[0063] Cationic peptides are particularly useful for use where part of the pre-formulation contains an anionic amphiphilic compound such as a fatty acid. In this embodiment, preferred peptides include octreotide, lanreotide, calcitonin, oxytocin, interferon beta and gamma, interleukins 4, 5, 7 and 8, and other peptides having an isoelectric point above pH 7, especially above pH 8.

In one preferred aspect of the present invention, the composition of the invention is such that phase I₂, or a mixed phase comprising phase I₂ forms when exposed to aqueous fluids and the polar active agent is included in the composition. Particularly useful polar active agents include peptide and protein active agents, oligonucleotides, and small water-soluble active agents, including those mentioned above. Of particular interest in this aspect are the octreotide peptide and other somatostatin-related peptides, alpha and beta interferons, glucagon-like peptides 1 and 2, luprorelin and other GnRH agonists, abarelix and other GnRH antagonists, interferon alpha and beta, zolendronate and ibandronates and other bisphosphonates as well as the polar active agent chlorhexidine (e.g., chlorhexidine digluconate or chlorhexidine dihydrochloride).

[0064] Particularly preferably, the present invention is used in combination with active protein / peptide agents, it is that aggregation of the active agent is inhibited. In one preferred embodiment, the present invention provides a depot precursor, and particularly a depot composition as described herein, comprising at least one peptide (e.g., antibody) or protein active agent, wherein no more than 5% of the active agent is in a concentrated form. Preferably no more than 3% is concentrated, and most preferably no more than 2% (especially less than 2%) is in concentrated form. This stabilization of the non-focused protein is highly beneficial from a high point of view

The effectiveness, low side effects and the predictable absorption profile. In addition, protein / peptide therapeutics are increasingly expected to have low levels of protein aggregation for marketing.

[0065] The amount of biologically active agent to be formulated with the pre-formulations of the present invention will depend on the useful dose and the period during which the depot composition prepared upon administration is intended to provide sustained release. Typically, the dose formulated for a particular agent will be about the equivalent of a normal daily dose multiplied by the number of days the formulation is expected to give release. Of course, this amount will have to be adjusted to take account of any harmful effects of the high dose at the start of treatment, and therefore this will usually be the highest dose used. The exact amount useful in any case will be easily determined by appropriate experimentation.

[0066] In one embodiment, the pre-formulations of the present invention will generally be administered parenterally. This administration will usually not be by intravascular administration, but preferably by subcutaneous, intracavitary or intramuscular injection. Typically, administration is by injection, which term is used herein to indicate any method in which the formulation passes through the skin, such as using a needle, catheter or needle-less injector.

[0067] In parenteral (especially subcutaneous) depot precursors, preferred active agents are agents useful for systemic administration, including antibacterial agents (including amikacin, monocycline and doxycycline), local and systemic anesthetics (including bupivacaine, tramadol, fentanyl, morphine, hydromorphone , methadone, oxycodone, codeine, aspirin, acetaminophen), nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, naproxen, keteprofen, indomethacin, sulindac, tolomethin, salicylic acid derivatives (such as salicylamide, diflunisal), Cox1 or Cox2 inhibitors (such as celecoxib, rofecoxib, valdecoxib), anti-cancer agents (including octreotide, lanreotide, buserelin, luprorelin, grerelinlin, , degarelix, fulvestrant, interferon alfa, interferon beta, darbepoetin alfa, epoetin alfa, beta, delta, and paclitaxel), antipsychotics (such as bromperidol, risperidone, olanzapine, iloperidone, paliperadone, pipothiazine and zuclopenthixol), antiviral agents, anticonvulsants (e.g. tiagabine topiramate or gabapentin) or nicotine, hormones (such as testosterone and testosterone undecanoate, medroxyprogesterone, estradiol), growth hormones (and human hormones) growth (such as granulocyte and macrophage colony stimulating factor).

[0068] In an alternative embodiment, the formulations of the present invention may form non-parenteral depots where the active agent is slowly released on the surface of the body. In this embodiment, it is particularly important that the pre-formulations of the invention and / or the liquid crystal depot compositions made therefrom should preferably be bioadhesive (body adherent). This means that the compositions should coat the surface, respectively the surface to which it is applied and / or on which they are formed, and should remain even when the surface is subjected to the flow of air or liquid and / or friction. Particularly preferably, the liquid crystal depot compositions prepared should be resistant to washing with water. For example, a small volume of depot precursor can be applied to body surfaces and exposed to a flow of five hundred times more water per minute for 5 minutes. After this action,

The composition may be biadhesive if less than 50% of the biologically active agent has been lost. Preferably this level of loss will be met when water in a volume of one thousand times, and more preferably 10,000 times that of the composition will flow for a minute, five, or preferably 10, minutes.

[0069] Although the non-parenteral depot compositions of the present invention may absorb some or all of the water needed to form the liquid crystal structure from the biological surface they contact, some additional water may also be absorbed from ambient air. In particular, when a thin layer with a high surface area is formed, then the affinity of the composition for water may be sufficient to form a liquid crystal phase structure in contact with water in the air. Thus, in this embodiment, the "aqueous fluid" discussed herein is, at least in part, air containing some moisture.

[0070] Non-parenteral depot compositions will typically be prepared by applying the pre-formulation topically to the body surface or to a natural or artificially created body cavity and / or to the surface of the implant. This administration can be done by direct administration of liquids such as spraying, dipping, washing, applying from a tampon or ball dispenser, injection into the body cavity (e.g., into an open cavity with or without a needle), brushing, instillation (especially into the eyes) ) and similar methods. Spraying using an aerosol or atomizer is a highly effective method, and of course requires that the viscosity of the pre-formulation is as low as possible, so it is well adapted to the composition of the invention. Non-parenteral depots can, however, be used for the administration of systemic agents, e.g. mucosal or transdermal.

[0071] Non-parenteral depots can also be used for application to surfaces, especially implants and materials that will be in contact with the body or body part or body fluid. Devices such as implants, catheters, etc. can therefore be treated e.g. by dipping or spraying with the pre-formulations of the invention that will form a resistant layer to reduce the possibility of infection. Anti-infectious agents are particularly suitable for this aspect.

[0072] Conditions particularly useful for the causal or symptomatic treatment of topical binge depot compositions of the present invention include skin conditions (such as soreness from any cause including cracks, scratches and skin conditions including eczema and herpes), eye diseases, genital soreness (including including genital infection such as genital herpes), infections and nail changes in the hands and / or legs (such as bacterial or fungal infections of the nails, such as onychomycosis or paronychia). Bioadhesive topical-type formulations can also be used to administer systemic active agents (e.g., treatments), particularly by routes of skin adsorption, oral, transdermal or rectal. A preferred example is the treatment of motion sickness, as is the administration of nicotine (e.g. in smoking cessation measures). When acceptable, "topical application" as defined herein includes systemic agents administered non-parenterally to a specific area of ​​the body.

[0073] Periodontal infections are particularly suitable for treatment with the compositions of the present invention. In particular, known compositions for treating periodontal infection are difficult to administer or are usually ineffective. The most commonly used depot composition for periodontal treatment involves the insertion into the periodontal space of a "scrap" of collagen from which the anti-infectious agent is released. This scrap is difficult to introduce, and it does not adapt to the shape and volume of the periodontal space, so that

Infection pockets can remain untreated. In contrast, the compositions of the present invention, used as low viscosity preformulation, can be easily and quickly injected into the periodontal space and will continue to flow, taking the exact shape of that space and filling the available space. The compositions then quickly absorb water to form a strong gel that is resistant to oral conditions. The only known prior approach to such injectable periodontal treatment has used relatively high viscosity dispersions that were difficult to apply and which were subject to undesirable phase separation. All of these drawbacks have been overcome as described in the compositions of the present invention. Anti-infectious agents, especially benzydamine, tramadol and chlorhexidine, are highly useful active agents for periodontal administration.

[0074] Non-parenteral depot compositions also provide significant advantages in combination with non-pharmaceutical active agents such as cosmetic active agents, fragrances, aromatic oils etc. Such non-pharmaceutical depots will retain important aspects of tissue adhesion and sustained release, resulting in prolonged cosmetic effects. , but can be easily applied by spraying or wiping. This further applies to agents that have both cosmetic and medical (especially prophylactic) benefits, such as sunscreen. Since topical depot compositions provide strong, water-resistant barriers that can dissolve high levels of active agents, they are especially useful for sunscreen filters and blockers in combination with ultraviolet (UV, e.g. UVa, UVb and / or UVc), especially when a high level of protection is desired. The compositions are also highly biologically compatible and can act to moisturize and soothe the skin while tanning. Compositions of the invention containing soothing agents such as aloe vera extract are also highly useful for soothing and moisturizing after exposure to sunlight, or for skin that is dry, inflamed or damaged due to, for example, irritation, burns or abrasions.

[0075] Active agents, particularly adapted for non-parenteral (e.g. topical) depot administration, which includes intra-oral, buccal, nasal, ocular, dermal, vaginal routes, include antibacterial agents such as chlorhexidine, chloramphenicol, triclosan , tetracycline, terbinafine, tobramycin, sodium fusidate, butenafine, metronidazole (the latter especially for treatment (e.g. symptomatic rosacea or certain vaginal infections), antiviral agents including acyclovir, antiinfectives such as bibrocatol, ciprofloxacin, levofloxacin, topical painkillers such as benzydamine, lidocaine, prilocaine, xylocaine, bupivacaine, fuplacaine, morphine, hydromorphone, methadone, oxycodone, codeine, aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs such as ibuprofen, flurbiprofen, naproxen, ketoprofen, fenoprofen, diclofenac, etodalac, diflunisal, oxaproxin, piroxicam, piroxicam, indometansin, sulindac, tolmetin, salicylic acids such as salicylamide and diflunisal, Cox1 or Cox2 inhibitors such as celecoxib, corticosteroid, and rextexekroxide (for example, methylaminolevulin hydrochloride, interferon alpha and beta), anticonvulsants (for example, tiagabine, topiramate or gabapentin), hormones (such as testosterone, and testosterone undecanoate, medroxyprogesterone, estradiol), growth hormones (like human growth hormone), and growth factors (like factor stimulating the growth of granulocyte and macrophage colonies), suppressants of the immune system response (cyclosporin, sirolimus, tacrolimus) , nicotine, and antiviral agents (e.g., acyclovir).

[0076] The inventors have found that some specific active agents produce highly effective depot compositions that include the following:

For long-acting depot products for injecting hydrophilic active agents:

i. octreotide (or other somatostatin analogues such as lanreotide for the treatment of carcinoid tumors and tumors producing vasoactive intestinal peptide and acromegaly). Subcutaneous depots forming, especially with GDO and PC, having a sustained release period of more than one month and showing less than 20% octreotide degradation within one month for a swollen depot in water at 37 ° C. Surprisingly good stability was observed, and was found to be better than for microspheres octreotide. Depot showed less than 5% degradation in product preformulation in eight weeks at 4 ° C.

ii. human growth hormone. For the treatment of growth disorders and growth hormone deficiencies. A subcutaneous depot forming, especially with GDO and PC, has a sustained release period of more than two weeks.

iii. interferon alfa, for the treatment of cancer and viral infections. Subcutaneous depots forming, especially with GDO and PC, have a sustained release period of more than one month.

iv. leuprolide. Depots forming having continuous delivery (preferably continuous delivery within the therapeutic compartment) for at least one month.

For long-acting depot products for injection of lipophilic / amphiphilic active agents:

i. risperidone ii. olanzapine iii. testosterone undecanoate

Depot-forming and up to iii have continuous delivery (preferably continuous delivery within the therapeutic compartment) for at least two weeks.

For topical bioadhesive controlled-release products, for oral administration (including buccal and periodontal):

i. benzydamine (local analgesic, anti-inflammatory agent), or other local analgesic, analgesic, anti-inflammatory agent, antibacterial agent, antifungal agent or combination thereof. The composition provides sustained action on the oral mucosa, in particular damaged, allergic, infected mucosa, e.g. in patients suffering from oral mucositis (caused e.g. by chemo- and radiation therapy). In particular for the treatment of stomatitis.

ii. tramadol (a painkiller). It gives a composition with sustained systemic analgesic effect.

iii. chlorhexidine gluconate (an antibacterial agent) for the treatment of periodontal and local infections. Particularly useful for long-term operation in the periodontal pocket. The compositions give depots releasing chlorhexidine for more than 1 hour, preferably more than 6 hours,

Most preferably more than 24 h when administered as a liquid which forms a bioadhesive gel in situ. A surface gel time of between 1 second and 5 minutes was observed.

Depot and up to iii depots have a high level of incorporation of active agent and a high degree of resistance to leaching. Liquid preformulations administered as an aerosol or liquid rinse in case i and ii, and a gel forming liquid in case iii in which the liquid is administered into the periodontal pocket, e.g. by injection.

For non-parenteral (e.g. topical or systemic) biadhesive controlled release products for nasal administration:

i. fentanyl (an analgesic) provides the relief of pain with a rapid onset and long duration of action when administered as an aerosol.

ii. diazepam (anxiolytic) provides a non-parenteral systemic nasal depot for a quick onset and long duration of action. Administered as an aerosol.

For topical, bioadhesive ophthalmic controlled release products:

i. diclofenac (NSAID) with a long duration of action. Administered as in situ phase forming liquid. ii. pilocarpine (parasympathomimetic agent, cholinergic agonist) for the treatment of glaucoma.

iii. Levocabastine Hydrochloride, ketotifen fumarate for eye drops, for long-lasting relief from allergic conjunctivitis, with long periods between repeated administrations.

iv. pilocarpine hydrochloride for the treatment of Sjogren's syndrome.

v. dexamethasone, (corticosteroid).

vi. chloramphenicol (primarily a bacteriostatic anti-infective agent).

vii. indomethacin (NSAID).

Depots and to vii formulated as aerosols of liquids or more preferably drops for direct application to the eye surface and providing a situdepot formation with high resistance to tear washout and abrasion by eye blinking / rubbing.

Other active agents useful for ophthalmic compositions include antihistamines, mast cell stabilizers, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids (e.g. for the treatment of allergic conjunctivitis), anti-glaucoma agents, including suppressive / suppressant agents (beta blockers: timolol, betaxolol, carteolol, levobunolol, etc., local carbonic anhydrase inhibitors: dorzolamide, brinzolamide, sympathomimetics: epinephrine, dipivefrin, clonidine apraclonidine, brimonidine), drainage agents (parasympathomimetics (cholinergic agonists): pilocarpine, prostaglandin analogues and related compounds: atanoprost, travoprost, bimatoprost, unoprostone).

For non-parenteral (e.g. local or systemic) controlled release bioadhesive products for dermatological administration:

i. acyclovir (antiviral agent). The composition produces a bioadhesive film forming product with long-lasting effects. Used as an aerosol or liquid.

ii. testosterone undecanoate (hormone deficiency), a bioadhesive film-forming composition with long-lasting effects.

EP 1 768 650 B1

They can be used as an aerosol or from a pump atomizer, or as a liquid.

[0077] Particularly useful applications of dermatological formulations are anti-infectious dermatological bioadhesive depots for protection in environments where contact with infectious agents is likely (e.g. human or veterinary surgery, work in a slaughterhouse, certain types of cleaning, etc.). Bioadhesive depots made from the compositions of the invention provide the user with strong and sustained protection. Compositions with anti-infectious agents may also be used in situations where the sterility of the skin of the user is important to the health of others, such as in the case of nurses or doctors visiting many patients in a hospital, where cross-infection must be avoided. Precoating with the composition of the present invention can serve to generate resistance against the collection of the infectious agent from one site and thus prevent its transfer to another.

[0078] The pre-formulations of the present invention form non-layered liquid crystal depot compositions when exposed to aqueous fluids, especially in vivo and in contact with body surfaces. The term "non-layered" as used herein means a normal or reversed liquid crystalline phase (such as a regular or hexagonal phase) or the L3 phase or any combination thereof. The term liquid crystal phase means all hexagonal liquid crystal phases, all regular liquid crystal phases and / or all mixtures thereof. The term "hexagonal phase," as used herein, means "normal" or "reversed" (preferably inverted) hexagonal phase, and the "regular" phase means any regular liquid crystalline phase, unless otherwise stated. By using the pre-formulations of the present invention, any phase structure present on the phase diagram of the components a and b with water can be produced. This is because pre-formulations can be made in a wider range of relative ingredient concentrations than previous lipid depot systems, without the risk of phase separation or obtaining highly viscous injectable solutions. In particular, the present invention relates to the use of phospholipid concentrations above 50% based on the total content of amphiphilic compounds. To allows access to the phases observed only at high phospholipid concentrations, especially the hexagonal liquid crystalline phases.

[0079] For many lipid combinations, only certain non-layered phases exist, or exist in any stable state. An unexpected feature of the present invention is that the compositions as described herein often exhibit non-laminar phases which for many other combinations of ingredients do not occur. Thus, in one particularly preferred embodiment, the present invention provides compositions having a combination of ingredients for which a phase I region exists₂ and / or L₂when diluted with an aqueous solvent. The presence or absence of such areas can be easily checked for any particular combination by simply diluting the composition with an aqueous solvent and testing the resulting phase structures by the methods described herein.

[0080] In a highly preferred embodiment, the compositions of the invention may form phase I on contact with water₂, or a mixed phase containing phase I₂. Phase I₂ is an inverted regular liquid crystal phase having discontinuous water regions. This phase has special advantages in the controlled release of active agents, and especially in combination with polar active agents, such as water-soluble active agents, since discontinuous polar domains prevent rapid diffusion of active agents. Depot precursors in the L phase₂ are highly effective in combination with the formation of phase I depot₂. This is because phase L₂ is the so-called "reversed micellar" phase having a continuous region

Hydrophobic surrounding separate polar cores. So L.₂ with hydrophilic active agents has similar advantages. In transient stages after contact with body fluid, the composition may contain multiple phases, as the formation of the initial surface phase will delay the passage of solvent into the depot core, especially at significant internal dose sizes of the depot composition. Without being limited to theory, it is believed that this transient surface phase formation, especially the liquid crystal surface phase, serves to significantly reduce the "ejection / delay" profile of the composition of the present invention by directly limiting the rate of exchange between the composition and the environment. Transient phases may include (usually in order from the outside to the center of the depot): H_II or

L_and, I2, L2, and liquid (solution). It is highly advantageous that the composition according to the invention can form at least two, and more preferably at least three of these phases simultaneously at transition stages after contact with water at physiological temperatures. In particular, it is highly preferred that one of the resulting phases, at least transiently, is phase I₂.

[0081] It is important to appreciate that the pre-formulations of the present invention have low viscosity. As a result, these pre-formulations cannot be in the state of some large volume liquid crystal phase, since all liquid crystal phases have a viscosity much higher than could be administered by a syringe or aerosol dispenser. The pre-formulations of the present invention will therefore be in a non-liquid state, such as a solution, phase L₂ or L₃and especially the solution or phase L₂. Phase L as used herein₂ preferably represents phase L₂ "swollen" containing more than 10 wt. solvent (component c) having a viscosity reducing effect. This is opposite to the L phase₂"concentrated" or "non-swollen", solvent-free or containing less solvent, or containing a solvent (or mixture) that does not provide a decrease in viscosity associated with the oxygen-containing low viscosity solvents described herein.

[0082] Upon administration, the pre-formulations of the present invention undergo a phase structure transition from a low viscosity mixture to a high viscosity (generally tissue adherent) depot composition. Usually it will be a transformation from a molecular mixture of the swollen L phase₂ and / or L₃ for one or more liquid viscosities (high viscosities) such as hexagonal or regular normal or reversed liquid crystalline phases or mixtures thereof. As indicated above, further phase transitions may also occur after administration. Of course, complete phase transformation is not necessary for the operation of the invention, but at least the surface layer of the administered mixture will form a liquid crystal structure. Generally, this transformation will be rapid at least for the surface area of ​​the formulation being administered (the part that is in direct contact with air, body surfaces and / or body fluids). This will most preferably end in a few seconds or minutes (e.g. up to 30 minutes, preferably up to 10 minutes, more preferably 5 minutes or less). The rest of the composition may change to a liquid crystal phase more slowly by diffusion and / or as the surface area disperses.

[0083] In one preferred embodiment, the invention relates to the pre-formulation described herein, at least part of which upon contact with the aqueous fluid forms the hexagonal liquid crystalline phase. The resulting hexagonal phase can gradually disperse, releasing the active agent, or it can in turn transform into a regular liquid crystalline phase, which in turn then gradually disperses. It is believed that the hexagonal phase will provide a more rapid release of the active agent, in particular a hydrophilic active agent, than the structure of the regular phase, especially phase I₂ and L.₂. So when the phase

If the hexagonal form is formed before the regular phase, this will result in the initial release of the active agent rapidly bringing the concentration to an effective level followed by a gradual release of the "maintenance dose" as the regular phase breaks down. In this way the release profile can be adjusted.

[0084] Not limited to theory, it is believed that upon exposure (e.g., to body fluids), the pre-formulations of the invention lose some or all of the organic solvent contained therein (e.g., by diffusion and / or evaporation) and absorb aqueous fluid from the body environment (e.g., humid air close to the body or in vivo environment), such that at least part of the formulation produces a non-layered structure, particularly a liquid crystal phase. In most cases, these non-layered structures are highly viscous and do not dissolve or disperse easily in vivo and are bioadhesive, and therefore do not rinse or wash off easily. In addition, because the non-laminar structure has large polar, non-polar and border regions, it is highly effective in dissolving and stabilizing many types of active agents and protecting them against degradation mechanisms. As much as a depot composition made from pre-formulation, it gradually decomposes over days, weeks or months, the active agent is gradually released and / or diffuses out of the composition. Since the environment inside the depot composition is relatively protected, the pre-formulations of the invention are highly useful for active agents with a relatively low biological half life (see above).

[0085] The inventors have surprisingly found that pre-formulations give depot compositions that have a very low "burst" effect on the release profile of the active agent. This is unexpected because it seemed that the low viscosity mixture (especially if it is a solution) of the pre-composition should rapidly lose the active agent when exposed to water. In fact, the pre-formulations of the invention showed significantly less initial "burst" than previous known polymer-based depot compositions. This is illustrated in the examples below and in the figures attached thereto. In one embodiment, the invention therefore provides injectable preformulations and resulting depot compositions in which the highest plasma concentration of active agent after administration is not greater than five times the mean concentration between 24 hours and 5 days after administration. This proportion is preferably not more than four times, and most preferably is not more than three times the average concentration.

[0086] In an additional aspect of the invention, the topical compositions can be used to create a physical barrier on body surfaces in the absence of any active agent. In particular, due to the very high adhesion of the composition to biological structures, "barrier" coatings created by spraying or applying liquids can be formed from the present compositions so as to reduce contact with potential infectious or irritating factors or to reduce surface body contamination. The strength of the composition and the resistance to washing give advantageous properties to such barriers that can be conveniently applied as a liquid or by spraying.

[0087] The invention will now be further illustrated with reference to the following non-limiting Examples and the attached Figures, of which:

Figure 1 shows the cumulative release of methylene blue (MB) from a depot formulation containing PC / GDO / EtOH (45/45/10 wt%) when it is injected into excess water;

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Figure 2 shows the non-linear decrease in viscosity of the pre-formulation with the addition of N-methylpyrrolidinone (NMP) and EtOH;

Figure 3 shows the plasma concentration (in rats) of salmon calcitonin (sCT) after subcutaneous injection of various PC / GDO / EtOH depot precursors containing 500 μg sCT / g of preparation;

Figure 4 shows the initial in vivo release (up to 48 hours) into plasma (in rats) of sCT from two different depot formulations after subcutaneous injection;

Figure 5 shows the plasma concentration (in rats) of octreotide (OCT) after subcutaneous injection of a depot formulation containing PC / GDO / EtOH (36/54/10% w / w) containing 5 mg OCT / g formulation, corresponding to 0.5 % drug content.

Figure 6 shows the plasma concentration (in rats) of octreotide (OCT) after subcutaneous injection of a depot formulation containing PC / GDO / EtOH (47.5 / 47.5 / 5.0% by weight) containing 30 mgOCT / g formulation, which corresponds to 3% of the drug content.

In Figure 7, the in vitro release to excess aqueous phase of chlorhexidine is depot formulation containing PC / GDO / EtOH (36/54/10 wt%) containing 50 mg chlorhexidine / g formulation, corresponding to 5% drug content.

Examples:

Example 1

Availability of depot products of various liquid crystal phases by selection of compositions [0088] To illustrate that after achieving equilibrium of depot precursor formulations with excess water, various liquid crystal phases can be achieved, injection formulations have been prepared containing various proportions of phosphatidylcholine ("PC" - Epicuron 200) and dioleate glycerol (GDO) as a solvent containing EtOH.

[0089] Appropriate amounts of PC and EtOH were weighed into glass vials, and the mixture was placed on a shaker until the PC was completely dissolved to obtain a clear liquid solution. GDO was then added to give a homogeneous injection solution.

[0090] Each of the formulations was injected into a vial and equilibrated with excess water. Phase behavior was assessed visually and between crossed polarizers at 25 ° C. The results are shown in Table 1.

TABLE 1

<td>formulation</td><td>PC (wt.%)</td><td>GDO (wt.%)</td><td>EtOH (wt.%)</td><td>Phase in H₂ABOUT</td>

<td>AND</td><td> 22,5</td><td> 67,5</td><td> 10,0</td><td>^l2</td>

<td>B</td><td> 28,8</td><td> 61,2</td><td> 10,0</td><td>^AND2</td>

<td>C</td><td> 45,0</td><td> 45,0</td><td> 10,0</td><td>^HII</td>

<td>D</td><td> 63,0</td><td> 27,0</td><td> 10,0</td><td>^^ α</td>

L₂= reverse micellar phase

AND₂= regular reversed liquid crystal phase H_II= reversed hexagonal liquid crystal phase L_α = lamellar phase

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Example 2

In vitro release of a water-soluble substance [0091] The water-soluble methylene blue (MB) dye 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 into 100 ml of water, a rigid reversed hexagonal H phase was formed_II. The absorbance of MB released into the aqueous phase was monitored at 664 nm for a period of 10 days. The release test was carried out in an Erlenmeyer flask at 37 ° C and slow magnetic stirring. The MB release profile (see Figure 1) from the hexagonal phase indicates that these (and similar) formulations are promising depot systems. In addition, the formulation appears to give a low initial burst, and the release profile indicates that the substance can be released for several weeks; after 10 days only about 50% MB is released.

Example 3

Viscosity in PC / GDO (6: 4) or PC / GDO (3: 7) with addition of solvent (EtOH, PG and NMP) [0092] A PC / GDO / EtOH mixture was prepared according to the method described in Example 1. All or almost all EtOH was removed from the mixture using a rotary evaporator (vacuum, 40 ° C, 1 h) and the resulting solid mixture was weighed in a glass vial, followed by the addition of 2, 5, 10 or 20% solvent (EtOH, propylene glycol (PG) or N- methylpyrrolidone (NMP)). The samples were allowed to equilibrate a few days before measuring the viscosity at a shear rate of 0.1 s^-1 using a Physica UDS 200 rheometer at 25 ° C.

[0093] This example clearly illustrates the need for solvent at certain depot precursors to produce an injectable formulation (see Figure 2). The viscosity of the solvent-free PC / GDO mixture increases with increasing PC content. Systems with a low PC / GDO ratio (more GDO) are injectable at a lower solvent concentration.

Example 4

Composition and in vitro phase study [0094] The formulation described in Table 2 was prepared according to the method described in Example 1. The active substance (peptide), salmon calcitonin (sCT), was added to each formulation to a concentration of 500 μg sCT / g formulation. The formulations were designed as homogeneous suspensions for parenteral administration (mixing is required shortly before use because the drug is not completely dissolved in the PC / GDO / EtOH system).

[0095] In this example, the phases are tested in excess rat serum at 37 ° C to simulate the situation in vivo. Table 2 shows that the same phases as in water are formed (compare Table 1).

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TABLE 2

<td>formulation</td><td>PC (wt.%)</td><td>GDO (wt.%)</td><td>OA (wt.%)</td><td>EtOH (wt.%)</td><td>Rat serum phase</td>

<td>E</td><td> 18</td><td> 72</td><td> -</td><td> 10</td><td>^l2</td>

<td>F</td><td> 36</td><td> 54</td><td> -</td><td> 10</td><td>^AND2</td>

<td>G</td><td> 34</td><td> 51</td><td> 5</td><td> 10</td><td>^AND2</td>

<td>H</td><td> 54</td><td> 36</td><td> -</td><td> 10</td><td>^HII</td>

<td>AND</td><td> 72</td><td> 18</td><td> -</td><td> 10</td><td>^^ α</td>

OA = Oleic acid

Example 5

Sterilization of formulations with reduced viscosity [0096] Reduction of viscosity using various solvents is sometimes necessary for the preparation of an injectable formulation and that the system can be administered with a simple syringe (see Example 3). Another important activity of the viscosity reducing solvent is that the formulations can be sterilized by filtration.

[0097] Formulations E to I in Example 4 were tested in a filtration sterilization test using a 0.22 µ ^ filter (before addition of active substance). Formulations E to H were successfully filtered, but formulation I was not useful because its viscosity was too high. Therefore, aseptic manufacturing procedure was necessary for this formulation.

Example 6

In vivo release study of subcutaneous depot formulation [0098] Formulations E to I described in Example 4 were used to study drug release in vivo in rats. The formulations were administered subcutaneously between the shoulder blades using a syringe (21G, 0.6 mm x 30 mm) and the dose of sCT was 500 μg / kg body weight. The release profile was monitored for a period of 13 days. The concentration of sCT in rat plasma samples was analyzed using a sandwich type immunoassay using a commercial kit from DSLabs.

[0099] Figure 3 shows the results (n = 4). Pure triglyceride based on sesame oil was chosen as the lipid reference system.

Example 7

In vivo initial phase release study [0100] Formulations F and G described in Example 6 were used in an in vivo study in rats designed to study the initial "burst effect". From Figure 4 (n = 8) it can be seen that none of the formulations tested has a serious burst effect.

Example 8: Preparation of depot precursor compositions with various solvents.

[0101] Certain solvents may be advantageous depending on the formulation composition and the nature and concentration of the active substance.

[0102] Depot precursor formulations (PC / GDO / solvent (36/54/10)) were prepared as described in Example 1 using various solvents: NMP, PG, PEG400, glycerol / EtOH (90/10) . All depot precursor compositions were homogeneous single-phase solutions with a viscosity that allowed injection with a syringe (23G - i.e., needle number 23; 0.6 mm x 30 mm). After injecting the formulation precursors into excess water, the NMP and PG containing precursors rapidly formed a liquid crystalline phase in the form of a highly viscous monolith. The liquid crystal phase had a regularly reversed micellar structure (I₂). In the case of PEG400, glycerol / EtOH (90/10), the viscosity / solidification process was much slower and the precursor, initially liquid, turned into a soft piece, rather sticky. The difference in appearance probably reflects the slower dissolution of PEG400 and glycerol in excess of the aqueous phase compared to EtOH, NMP and PG.

Example 9: Preparation of a human growth hormone (HGH) depot composition.

[0103] Human growth hormone (hGH) plays a key role in stimulating body growth and development, and is involved in muscle protein production and fat breakdown. Hormone deficiency has a detrimental effect on numerous body processes such as lipid profile, insulin status, physical performance, bone mineral density and quality of life. The targeted dose is estimated at 0.10 to 0.24 mg / kg body weight every 2 weeks. 1 ml depot formulation precursor was prepared for 2 weeks by mixing 10 mg hGH and 360 mg PC in 0.1 ml NMP in turn. 540 mg GDO was added to the mixture to obtain a low viscosity depot formulation precursor. Injection of the formulation precursor into excess water (23G syringe; 0.6 mm x 30 mm) gave a monolithic liquid crystal phase (structure I₂).

Example 10: Preparation of a depot composition containing a sparingly soluble active substance.

[0104] Risperidone is an antipsychotic agent belonging to the chemical class of benzisoxazole derivatives. It is a very strong dopamine blocker (antagonist); i.e., it inhibits dopamine receptors, is practically insoluble in water, and has log (P) = 3.49.

[0105] 1 g of depot formulation containing 50 mg of risperidone was prepared by dissolving the active substance in 0.7 g of a 95 wt. EtOH (99.5%) and 5% by weight acetic acid. In this solution, 0.34 g PC and 0.51 g GDO were subsequently dissolved, the solvent content was reduced, leaving 0.15 g of solvent (0.55 g evaporated under reduced pressure). The composition of the final homogeneous and clear depot formulation containing 50 mg risperidone is PC / GDO / solvent / risperidone (32/49/14/5). Injection of the formulation precursor into excess water (23G syringe; 0.6 mm x 30 mm) gave a monolithic liquid crystal phase (structure I₂). This means that this amount of active substance (5%) did not change the monolith formation and phase behavior after exposure to the aqueous environment. Example 11: Alternative preparation of a depot composition containing risperidone.

[0106] A risperidone depot precursor formulation could also be prepared using a 90 wt. EtOH (99.5%) and 10% by weight acetic acid.

[0107] 50 mg of risperidone were dissolved in 0.7 g of the solvent mixture, followed by 0.36 g of PC and 0.54 g of GDO in this solution. 0.60 g of the solvent mixture was evaporated under reduced pressure to a homogeneous and clear formulation precursor containing 50 mg risperidone (PC / GDO / solvent / risperidone (34/51/10/5)). Injection formulation precursor into

Excess water (23G syringe; 0.6 mm x 30 mm) gave a monolithic liquid crystal phase (structure I₂). This means that this amount of active substance (5%) did not affect the monolith production and phase behavior after exposure to the aqueous environment.

Example 12: Temperature stability of a depot composition containing a sparingly soluble active substance.

[0108] The risperidone depot precursor formulations described in Examples 10 and 11 were tested for storage stability against crystallization. Each formulation was stable at 25 ° C for at least two weeks and at + 8 ° C for at least one week.

Example 13: Preparation of depot compositions containing benzydamine.

[0109] Benzydamine is a non-steroidal anti-inflammatory drug and is widely used as a topical drug for inflammation.

[0110] 1 g of a depot formulation containing 1.5 mg of benzydamine was prepared by dissolving the active substance in a PC / GDO / EtOH mixture (36/54/10) prepared as described in Example 1. The depot composition was stable to crystallization upon storage at temperature 25 ° C for at least two weeks. Balancing the formulation precursor with excess water gave a highly viscous monolithic liquid crystal phase (structure I₂).

Example 14: Resistance of the preparation behavior to changes in excipient quality.

[0111] Depot precursor formulations were prepared using several different GDO species (supplied by Danisco, DK), Table 3, using the method of Example 1. Final depot precursors contained 36 wt. PC, 54 wt. GDO, and 10 wt. EtOH. The appearance of the depot precursors was insensitive to changes in the quality used, and after contact with excess water, a monolith formed, retaining a regular inverted micellar phase (structure I₂).

<td colspan="4">Table 3. Tested GDO species.</td>

<td>GDO species</td><td colspan="2">Monoglyceride (wt.%) Diglyceride (wt.%)</td><td>Triglyceride (wt%)</td>

<td>AND</td><td> 10,9</td><td> 87,5</td><td> 1,6</td>

<td>B</td><td> 4,8</td><td> 93,6</td><td> 1,6</td>

<td>C</td><td> 1,0</td><td> 97,3</td><td> 1,7</td>

<td>D</td><td> 10,1</td><td> 80,8</td><td> 10,1</td>

<td>E</td><td> 2,9</td><td> 88,9</td><td> 8,2</td>

<td>F</td><td> 0,9</td><td> 89,0</td><td> 10,1</td>

Example 15: Preparation of a depot composition containing saturated PC (Epikuron 200SH).

[0112] Depot precursor formulations were prepared using various amounts of PC containing saturated hydrocarbon chains by adding Epikuron 200SH directly to the PG / GDO / EtOH mixture prepared as for Example 1. The formulations are shown in Table 4. All precursor formulations were homogeneous single-phase samples in at room temperature, and they became more sticky with increasing amounts of Epikuron 200SH. Injection of the depot precursor into excess water gave a monolith containing the structure of a regular reversed phase micellar (I₂). Monoliths formed from samples containing

Higher amounts of Epikuron 200SH became turbid, presumably indicating separation between Epikuron 200SH and other components when exposed to water and phase I formation₂.

Table 4. Depot composition containing saturated PC

<td>formulation</td><td>Saturated PC, Epicuron 200SH (wt.%)</td><td>PC (wt.%)</td><td>GDO (wt.%)</td><td>EtOH (wt.%)</td>

<td>G1</td><td> 3,9</td><td> 34,6</td><td> 51,9</td><td> 9,6</td>

<td>G2</td><td> 7,0</td><td> 33,5</td><td> 50,2</td><td> 9,3</td>

<td>G3</td><td> 14,3</td><td> 30,8</td><td> 46,3</td><td> 8,6</td>

Example 16: Preparation of a depot precursor dispersion or solution of salmon calcitonin peptide.

[0113] By adding 500 mg sCT / g formulation to the PC / GDO / EtOH solution (36/54/10) obtained as in Example 1, a sCT dispersion was prepared.

[0114] In an alternative method, 500 μg of sCT was dissolved in an excess of EtOH, followed by PC and GDO. Then the solvent concentration was reduced (evaporation of EtOH) to form a homogeneous formulation (active drug in solution). The latter technique can be used to obtain high levels of drugs. By this method, precursor compositions corresponding to at least 1500 μg of dissolved sCT per gram of final depot precursor composition can be obtained.

Example 17: In vivo release study from a subcutaneous depot formulation.

[0115] The two sCT compositions described in Example 16 were administered in a rat model in vivo by subcutaneous injection (between the shoulder blades). It was found that the first depot precursor containing the dispersed sCT formed rather unstable initial plasma concentrations, and the second depot precursor containing the dissolved sCT gave much more stable initial plasma levels (see Table 5).

Table 5

<td>formulations</td><td>Coefficient of variance (% CV)</td>

<td>Dispersed: 500 μg sCT / g PC / GDO / EtOH (36/54/10)</td><td> 32-127</td>

<td>Dissolved: 500 μg sCT / g PC / GDO / EtOH (36/54/10)</td><td> 20-37</td>

Example 18: Preparation of a depot composition containing octreotide peptide.

[0116] Octreotide is the acetate salt of synthetic octapeptide and is similar to the hormone somatostatin. Octreotide reduces the production of substances such as growth hormone, insulin and glucagons. It is used to treat acromegaly, and to reduce facial and upper body vasomotor disorders, and watery diarrhea, caused by metastatic cancerous tumors (carcinoid syndrome) or cancers called vasoactive intestinal peptide (VIPoma) producing tumors.

[0117] 24 mg or 60 mg octreotide was dissolved in 0.1 g EtOH. In turn, 0.36 g PC and 0.54 g GDO were dissolved in this solution and a depot formulation precursor was obtained. Injection of the formulation precursor into excess aqueous phase (23G syringe; 0.6 mm x 30 mm) gave a monolithic liquid crystalline phase (structure I₂). i.e. octreotide (2.4% or 6.0%) did not change monolith formation and phase behavior after exposure to the aqueous environment.

[0118] In this example, the formulation of octreotide depot precursors was tested for storage stability. Each formulation was stable at 4-8 ° C for at least two weeks.

Example 19: In vivo release study of a subcutaneous octreotide containing depot formulation.

[0119] Release of octreotide drug in a rat model in vivo was monitored for 28 days. The formulations were administered subcutaneously between the shoulder blades using a syringe (23G, 0.6 mm x 25 mm). Rat plasma octreotide concentration was monitored over a period of 28 days (see Figure 5). The dose was 5 mg / kg and the volume was 1 ml / kg, which corresponded to the drug content of 0.5% octreotide in the depot formulation precursor (PC / GDO / EtOH (36/54/10)). From Figure 5 (n = 3) it can be seen that the formulation tested gives a release profile with essentially no burst effect.

[0120] Figure 5 shows plasma octreotide levels determined in a rat model after administration of an octreotide formulation precursor (0.5% octreotide).

Example 20: Distribution of depot formulation in rat.

[0121] Various volumes (1, 2, 6 ml / kg) of the depot precursor (36% by weight PC, 54% by weight GDO, and 10% by weight EtOH) were injected in the rat and removed again after a period of 14 days. It was found that after this time significant amounts of the preparations were still present subcutaneously in the rat, see Table 6.

Table 6. Average diameter of the monolith depot.

<td>Dose (ml / kg)</td><td>Average diameter, day 3 (mm)</td><td>Average diameter, day 14 (mm)</td>

<td>1 (n = 3)</td><td> 15,8</td><td> 12,5</td>

<td>2 (n = 3)</td><td> 18,5</td><td> 15,3</td>

<td>6 (n = 3)</td><td> 23,3</td><td> 19,3</td>

Example 21: In vitro monolith depot formation study after injection of a precursor of depot formulation between bone and periosteum.

[0122] The precursor (36 wt.% PC, 54 wt.% GDO, and 10 wt.% EtOH, prepared as described in Example 1) was injected with a syringe between the bone and the periosteum. It was observed that the composition spread to fill the voids, and after absorbing aqueous fluids formed a monolith that was bioadhesive, both to the bone and the periosteum.

Example 22: Bioadhesive aerosol depot precursor formulation.

[0123] A spray bottle has been found to be a convenient way to apply the formulation locally, e.g., to the skin or oral mucosa.

[0124] A depot formulation precursor prepared as in Example 1 (36 wt% PC, 54 wt% GDO, and 10 wt% EtOH) was sprayed using a spray bottle onto the skin and oral mucosa. Shortly after application, a film with mechanical properties of a solid was formed.

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Example 23: Local film resistance.

[0125] After applying the depot formulation precursor as described in Example 22, (36 wt.% PC, 54 wt.% GDO, and 10 wt.% EtOH) to the skin, the applied formulation was exposed to water rinse (10 L / min) for 10 minutes. The formulation showed excellent bioadhesive properties and resistance to rinsing, and no loss of formulation could be seen.

Example 24: Formation of a regular phase with solid phase properties after exposure to a depot formulation precursor.

[0126] After exposing the depot formulation precursor prepared as described in Example 1 (36 wt% PC, 54 wt% GDO, and 10 wt% EtOH) to air (room temperature, relative humidity 40%) for at least 3 hours, there was a regular regular phase. This formation of the regular phase structure shows that after application, the local film acquires the properties of the non-laminar depot mass without the need for direct exposure to excess aqueous fluid.

Example 25: A formulation for the treatment of periodontitis or perimplantitis.

[0127] To treat periodontitis or perimplantitis, the antibacterial formulation is injected into the periodontal pocket, and a prolonged effect of the formulation is normally desired.

[0128] 100 μL of the formulation as prepared in Example 1, with the addition of chlorhexidine antibiotic (PC / GDO / EtOH / chlorhexidine (35/53/10/2)), is injected with a syringe into the rat periodontal pocket. It is observed that the injected composition transforms from a low viscosity formulation, and which initially spills with filling the voids, creating a solid mass by the uptake of fluid from the gums. Thus, a depot system with an antibacterial agent is provided.

[0129] Chlorhexidine remains at clinically effective levels (MIC 125 μg / ml) in periodontal pocket GCF for more than 1 week. The depot system is completely broken down by enzymes within 7 to 10 days, and does not need to be removed.

Example 26: Alternative antibacterial formulation for the treatment of periodontitis or perimplantitis.

[0130] An alternative antibacterial formulation was obtained from the formulation prepared as described in Example 1 and containing Gardol (N-methyl-N- (1-oxododecyl) glycine sodium) detergent (PC / GDO / EtOH / GardOH (34/51/10 / 5)). This formulation is injected into the rat periodontal pocket.

[0131] It is observed that Gardol remains at clinically effective levels in GCF in periodontal pockets for a longer period (several days). The depot system is completely broken down by enzymes within 7 to 10 days, and does not need to be removed.

Example 27: Adhesion of the preparation to high energy surfaces.

[0132] For treating peri-implant inflammation, it is important not only to adhere to biological surfaces, but also to high-energy surfaces such as gold or titanium implant. It is also important that the formulation adheres to ceramic and plastic surfaces.

[0133] The formulation (PC / GDO / EtOH (36/54/10)) as prepared in Example 1 was applied to various oral surfaces. The composition showed excellent adhesion to ceramics, plastic, gold, as well as to the normal tooth surface and could not be rinsed off with excess aqueous fluid. The depot obtained from the composition remained in the mouth in the place where it was applied for at least 6 hours.

Example 28 Sustainable release bioadhesive formulation of sodium fluoride for use on teeth.

[0134] Fluoride-containing compounds are often needed to counteract caries attack, and the bioadhesive depot formulation precursor was prepared as indicated in Example 1 from the PC / GDO / EtOH / sodium fluoride mixture (35/53/10/2). The formulation was a dispersion of sodium fluoride, it could not be dissolved in the precursor. The liquid formulation was applied to the teeth with a brush. Through salivation, the formulation solidified and formed a depot, providing sustained release of sodium fluoride over a longer period (several hours).

Example 29: Oral spray depot composition.

[0135] The mechanical properties of the system were selected by reducing the PC / GDO ratio to obtain a useful oral depot system.

[0136] 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 μl of the formulation was sprayed into the mouth from the spray bottle. Shortly after application, the formulation increased viscosity / solidified as it was phase changed by uptake of aqueous fluid (saliva) and loss of solvent (EtOH). The formulation had excellent biological adhesion to calloused surfaces, such as the hard palate and gums. There, the film remained for several hours despite salivation and mechanical abrasion with the tongue. The duration on soft surfaces of mucous membranes was much shorter (minutes).

Example 30: Liquid oral depot composition.

[0137] In order for the formulation to be usable by pipette, the solidification / viscosity of the formulation must be delayed relative to the spray formulation. After application, this is to allow convenient spreading of the formulation with the tongue over a thin film in the mouth.

[0138] Propylene glycol (PG) and EtOH were added to the formulation prepared as in Example 1 to obtain the final PC / GDO / EtOH / PG composition (24/56/10/10). 300 μl of preparation was conveniently applied by pipette to the oral cavity and spread with the tongue over a thin layer in the oral cavity. After about 20 seconds the viscosity of the preparation began to increase, as it underwent a phase change by uptake of aqueous fluid (saliva) and loss of solvent (EtOH and PG). After about one minute, the solidification / viscosity seemed complete. The formulation had excellent biological adhesion to calloused surfaces, such as the hard palate and gums. There, the film remained for several hours despite salivation and mechanical abrasion with the tongue. The duration on soft surfaces of mucous membranes was much shorter (minutes).

EP 1 768 650 B1

Example 31: Biada nail depot [0139] The mixture described in Example 29 was sprayed onto the nail bed and between the toes of the legs. The formulation solidifies / increases viscosity slowly by the uptake of aqueous fluids (e.g. sweat). Solidification can be accelerated by the addition of water after spray application. The formulation had excellent bias adhesion and had a shelf life of several hours.

[0140] Example 32: Maximum content of the bioactive agent benzydamine in formulation precursors.

[0141] Using the method of Example 1, formulations were prepared as shown in Table 7. 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 μm) to get rid of crystals of undissolved benzydamine. The concentration of benzydamine in each formulation was determined by reverse phase gradient HPLC and UV detection at 306 nm, and the results are given in Table 7.

Table 7

<td>Composition GDO / PC (Lipoid S100) / EtOH</td><td>Benzydamine concentration in the formulation</td>

<td> 67,5/22,5/10</td><td> 3,4%</td>

<td> 63/27/10</td><td> 3,2%</td>

<td> 58,5/31,5/10</td><td> 3,3%</td>

<td> 60/20/20</td><td> 4,0%</td>

<td> 56/24/20</td><td> 4,5%</td>

<td> 52/28/20</td><td> 4,3%</td>

Example 33: Compositions containing PC and tocopherol [0142] Depot precursor formulations were prepared with several different PC / α-tocopherol compositions using the method of Example 1 (PC was first dissolved in the appropriate amount of EtOH, then α-tocopherol was added to obtain clear homogeneous solutions ).

[0143] Each of the formulations was injected into a vial and equilibrated with excess water. Phase behavior was assessed visually and between crossed polarizers at 25 ° C. The results are shown in Table 8.

Table 8

<td>α-Tocopherol</td><td>PC</td><td>Ethanol</td><td>Phase in excess of H2O</td>

<td>2.25 g</td><td>2.25 g</td><td>0.5 g</td><td>^HII</td>

<td>2.7 g</td><td>1.8 g</td><td>0.5 g</td><td>^hII^/and2</td>

<td>3.15 g</td><td>1.35 g</td><td>0.5 g</td><td>^AND2</td>

<td>3.6 g</td><td>0.9 g</td><td>0.5 g</td><td>^and2^{/ l}2</td>

Example 34: Composition containing octreotide [0144] 60 mg octreotide was dissolved in 0.1 g EtOH. In turn, 0.25 g PC and 0.59 g α-tocopherol were dissolved in this solution, and a depot formulation precursor was obtained. Injection of the formulation precursor into excess aqueous solution (phosphate buffered saline - PBS) gave a monolithic phase

Liquid crystal (structure I₂), which means that octreotide (6.0%) did not change monolith formation and phase behavior after exposure to the aqueous environment.

[0145] The octreotide depot precursor formulation in this Example was tested by testing crystallization stability during storage. The formulation was stable at 4-8 ° C for at least two weeks.

Example 35: In vitro release of a water-soluble disodium fluorescein salt [0146] A water-soluble dye, fluorescein disodium salt (Fluo), was dissolved in a formulation containing PC / α-tocopherol / ethanol (27/63/10% wt) to a concentration of 5 mg Fluo / g formulation. When 0.1 g of the formulation was injected into 2 ml of phosphate buffered saline (PBS), a reverse micellar phase was formed (I₂). The absorbance of Fluo released into the aqueous phase was monitored at 490 nm for a period of 3 days. The release test was carried out at 37 ° C in a 3 ml vial closed with a tear-off aluminum cap. The vial was placed on a shaker table at 150 rpm. The release of Fluo from the PC / α-tocopherol formulation (see Table 9) indicates that these (and similar) formulations are promising depot systems. In addition, no burst effect is preferred, and the release indicates that the substance can be released for several weeks to months, since only about 0.4% Fluo is released after 3 days.

Table 9

<td rowspan="2">formulation</td><td colspan="2">% release (37 ° C)</td>

<td>24 h</td><td>72 h</td>

<td>PCfa-tocopherol / EtOH: 27/63/10 wt.</td><td> &lt;0,1*</td><td> 0,43</td>

<td colspan="3">* Release below the detection limit of the absorbance determination</td>

Example 36: Benzydamine analgesic / anti-inflammatory formulations [0147] 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,

<td>formulation</td><td>BZD</td><td>GDO</td><td>PC</td><td>EtOH</td><td>PG</td><td>AP</td>

<td> 1</td><td> 3,0</td><td> 53,3</td><td> 28,7</td><td> 10,0</td><td> 5,0</td><td> 0,01</td>

<td> 2</td><td> 3,0</td><td> 53,3</td><td> 28,7</td><td> 15,0</td><td> 0</td><td> 0,01</td>

<td> 3</td><td> 3,0</td><td> 57,4</td><td> 24,6</td><td> 10,0</td><td> 5,0</td><td> 0,01</td>

<td> 4</td><td> 3,0</td><td> 49,2</td><td> 32,8</td><td> 10,0</td><td> 5,0</td><td> 0,01</td>

where BZD means benzydamine, EtOH means ethanol, PC means soybean phosphatidylcholine LIPOID S100, GDO means glyceryl dioleate, PG means propylene glycol, and AP means ascorbyl palmitate.

[0148] All formulations are low viscosity liquids that form liquid crystal phase compositions when exposed to aqueous conditions.

Example 37: Nasal Fentanyl Formulation [0149] Formulations were prepared as in Example 1 by mixing the fentanyl narcotic analgesic with a mixture of GDO, PC, ethanol and optionally PG in the following proportions.

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<td>formulation</td><td>Fentanyl</td><td>PC</td><td>GDO</td><td>EtOH</td><td>PG</td>

<td> 1</td><td> 0,05</td><td> 34</td><td> 51</td><td> 10</td><td> 5</td>

<td> 2</td><td> 0,05</td><td> 36</td><td> 54</td><td> 10</td><td> -</td>

<td> 3</td><td> 0,05</td><td> 42</td><td> 43</td><td> 10</td><td> 5</td>

<td> 4</td><td> 0,05</td><td> 45</td><td> 45</td><td> 10</td><td> -</td>

<td> 5</td><td> 0,15</td><td> 34</td><td> 51</td><td> 10</td><td> 5</td>

<td> 6</td><td> 0,15</td><td> 36</td><td> 54</td><td> 10</td><td> -</td>

<td> 7</td><td> 0,05</td><td> 30</td><td> 45</td><td> 15</td><td> 10</td>

<td> 8</td><td> 0,15</td><td> 30</td><td> 45</td><td> 15</td><td> 10</td>

where EtOH is ethanol, PC is soy phosphatidylcholine LIPOID S100, GDO is glycerol dioleate, and PG is propylene glycol.

[0150] All formulations are low viscosity liquids useful for administration as a nasal spray, which when exposed to aqueous conditions form liquid crystal phase compositions. Example 38: Diazepam nasal formulation [0151] Formulations were prepared as in the previous examples by mixing the benzodiazepine anxiolytic diazepam with a mixture of GDO, PC, ethanol and optionally PG in the following proportions.

<td>formulation</td><td>diazepam</td><td>PC</td><td>GDO</td><td>EtOH</td><td>PG</td>

<td> 1</td><td> 5</td><td> 32</td><td> 48</td><td> 10</td><td> 5</td>

<td> 2</td><td> 5</td><td> 34</td><td> 51</td><td> 10</td><td> -</td>

<td> 3</td><td> 10</td><td> 37</td><td> 38</td><td> 10</td><td> 5</td>

<td> 4</td><td> 10</td><td> 40</td><td> 40</td><td> 10</td><td> -</td>

<td> 5</td><td> 10</td><td> 30</td><td> 45</td><td> 10</td><td> 5</td>

<td> 6</td><td> 10</td><td> 32</td><td> 48</td><td> 10</td><td> -</td>

<td> 7</td><td> 10</td><td> 26</td><td> 39</td><td> 15</td><td> 10</td>

<td> 8</td><td> 10</td><td> 30</td><td> 45</td><td> 15</td><td> -</td>

where EtOH is ethanol, PC is soy phosphatidylcholine LIPOID S100, GDO is glycerol dioleate, and PG is propylene glycol.

[0152] All formulations are low viscous liquids useful for administration as a nasal spray, which when exposed to aqueous conditions form liquid crystal phase compositions. Example 39: Interferon alfa-2a [0153] Interferons (IFN) are used as therapy in many types of systemic cancers, often in combination with chemotherapy or radiation. Recent data suggest that IFN alpha is a multifunctional immunomodulatory cytokine with significant effects on the cytokine cascade, which has several anti-inflammatory functions. These newly identified immunoregulatory and anti-inflammatory functions may also be relevant in the treatment of diseases such as chronic viral hepatitis and help explain several of the mechanisms of IFN action.

[0154] A non-aqueous formulation precursor was prepared by dissolving PC (360 mg) and GDO (540 mg) in EtOH (100 mg). Interferon alfa-2a (4 mg) was dissolved in water (76 mg), and then this solution was added to the non-aqueous formulation precursor to obtain a low viscosity depot formulation precursor.

[0155] Injection of the depot precursor into excess water (23 G syringe; 0.6 mm x 30 mm) gave a monolithic liquid crystal phase (structure I₂).

Example 40: Leuprorelin (Leuprolide) [0156] Leuprorelin acetate (or leuprolide acetate) is a synthetic nonapeptide that is an analogue of the naturally occurring gonadotropic hormone (GnRH or LH-RH) which, when administered continuously (e.g. as depot formulation), inhibits secretion of gonadotropins from the pituitary gland and suppresses the formation of steroids in the testicles and ovaries. Leuprorelin is used to treat advanced prostate cancer.

[0157] A depot formulation precursor was prepared by dissolving 22.5 mg of leuprorelin acetate and 360 mg PC in 100 mg NMP in turn. 540 mg GDO was added to the mixture to obtain a low viscosity depot formulation precursor molecular solution. Injection of the formulation precursor into excess water (23G syringe; 0.6mm x 30mm) gave a monolithic liquid crystal phase (structure I₂).

Example 41: Alendronate [0158] Bisphosphonates are structural analogues of pyrophosphates and have bone-specific pharmacological activity due to the strong affinity of bisphosphonates for hydroxyapatite, the major inorganic bone component. These compounds are used to treat postmenopausal osteoporosis, tumor hypercalcaemia and metastatic bone disease (MBD).

[0159] The non-aqueous formulation precursor was made by dissolving PC (360 mg) and GDO (540 mg) in EtOH (100 mg). Alendronate (12 mg) was dissolved in water (80 mg) and then this solution was added to the non-aqueous formulation precursor to obtain a low viscosity depot formulation precursor. Injection of the depot precursor into excess water (23 G syringe; 0.6 mm x 30 mm) gave a monolithic liquid crystal phase (structure I₂).

Example 42: Olanzapine [0160] Olanzapine is a low molecular weight drug used to treat patients suffering from schizophrenia.

[0161] A depot formulation precursor was prepared by mixing in turn 50 mg olanzapine, 360 mg PC and 100 mg EtOH. 540 mg GDO was added to the mixture to obtain the final precursor of depot formulation.

[0162] Injection of the formulation precursor into excess water (23 G syringe; 0.6 mm x 30 mm) gave a monolithic liquid crystal phase (structure I₂).

Example 43: Anti-acne formulations with clindamycin [0163] Formulations were prepared as in the previous examples by mixing the semi-synthetic antibiotic clindamycin (as the free base or salt) with a mixture of GDO, PC, ethanol and PG in the following proportions (by weight).

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<td>formulation</td><td>clindamycin^.HCI</td><td>PC</td><td>GDO</td><td>EtOH</td><td>PG</td>

<td> 1</td><td> 1</td><td> 30</td><td> 54</td><td> 10</td><td> 5</td>

<td> 2</td><td> 2</td><td> 29</td><td> 54</td><td> 10</td><td> 5</td>

<td> 3</td><td> 1</td><td> 34</td><td> 50</td><td> 10</td><td> 5</td>

<td> 4</td><td> 2</td><td> 33</td><td> 50</td><td> 10</td><td> 5</td>

<td>formulation</td><td>Clindamycin, base</td><td>PC</td><td>GDO</td><td>EtOH</td><td>PG</td>

<td> 5</td><td> 1</td><td> 30</td><td> 54</td><td> 10</td><td> 5</td>

<td> 6</td><td> 2</td><td> 29</td><td> 54</td><td> 10</td><td> 5</td>

<td> 7</td><td> 1</td><td> 33</td><td> 54</td><td> 2</td><td> 10</td>

<td> 8</td><td> 2</td><td> 32</td><td> 54</td><td> 2</td><td> 10</td>

[0164] The pre-formulations obtained are low-viscosity liquids, which, when applied, become resistant to water, sweat, etc. The formulations are applied topically to the skin as a gel or by spraying and are bioadhesive, with good film-forming properties.

Example 44: Further examples of viscosity in PC / GDO mixtures with addition of a cosolvent [0165] Mixtures of PC / GDO and cosolvent were prepared according to the methods of Example 1 and Example 3 in the proportions indicated in the table below.

Samples were allowed to equilibrate for several days before viscosity measurements were carried out using a Physica UDS 200 rheometer at 25 ° C.

<td>A sample</td><td>PC / GDO (w / w)</td><td>EtOH / wt.%</td><td>Glycerol / wt.</td><td>H2O / wt.</td><td>Viscosity / mPas</td>

<td> 1</td><td> 50/50</td><td> 3</td><td> -</td><td> -</td><td> 1900</td>

<td> 2</td><td> 50/50</td><td> 5</td><td> -</td><td> -</td><td> 780</td>

<td> 3</td><td> 50/50</td><td> 7</td><td> -</td><td> -</td><td> 430</td>

<td> 4</td><td> 50/50</td><td> 8</td><td> -</td><td> -</td><td> 300</td>

<td> 5</td><td> 50/50</td><td> 10</td><td> -</td><td> -</td><td> 210</td>

<td> 6</td><td> 50/50</td><td> 15</td><td> -</td><td> -</td><td> 100</td>

<td> 7</td><td> 45/55</td><td> 3</td><td> -</td><td> -</td><td> 1350</td>

<td> 8</td><td> 45/55</td><td> 5</td><td> -</td><td> -</td><td> 540</td>

<td> 9</td><td> 45/55</td><td> 7</td><td> -</td><td> -</td><td> 320</td>

<td> 10</td><td> 45/55</td><td> 8</td><td> -</td><td> -</td><td> 250</td>

<td> 11</td><td> 45/55</td><td> 10</td><td> -</td><td> -</td><td> 150</td>

<td> 12</td><td> 45/55</td><td> 15</td><td> -</td><td> -</td><td> 85</td>

<td> 13</td><td> 40/60</td><td> 3</td><td> -</td><td> -</td><td> 740</td>

<td> 14</td><td> 40/60</td><td> 5</td><td> -</td><td> -</td><td> 400</td>

<td> 15</td><td> 40/60</td><td> 7</td><td> -</td><td> -</td><td> 240</td>

<td> 16</td><td> 40/60</td><td> 8</td><td> -</td><td> -</td><td> 200</td>

<td> 17</td><td> 40/60</td><td> 10</td><td> -</td><td> -</td><td> 130</td>

<td> 18</td><td> 40/60</td><td> 15</td><td> -</td><td> -</td><td> 57</td>

<td> 19</td><td> 40/60</td><td> -</td><td> 10</td><td> -</td><td> 8*10⁶</td>

<td> 20</td><td> 40/60</td><td> -</td><td> -</td><td> 3</td><td> 2,5*10⁸</td>

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<td> 21</td><td> 40/60</td><td> -</td><td> -</td><td> 5</td><td> 4*10⁷</td>

[0166] This example illustrates the need for a solvent that reduces viscosity to produce an injectable formulation. Mixtures containing glycerol (sample 19) or water (samples 20 and 21) are too viscous to be injectable at solvent concentrations equivalent to samples containing EtOH (compare with samples 13, 14 and 17).

Example 45: Octreotide formulation compositions [0167] Formulations were prepared as in Example 1 by mixing the active octreotide peptide with a mixture of GDO (with one of several levels of purity) or tocopherol, PC, ethanol and optionally dioleoyl PG in the following proportions (by weight)

<td>formulation</td><td>OCT</td><td>EtOH</td><td>PC</td><td>GDO1</td><td>GDO2</td><td>GDO3</td><td>TP</td><td>DOPG</td>

<td>E</td><td> 2</td><td> 10</td><td> 35,2</td><td> -</td><td> -</td><td> 52,8</td><td> -</td><td> -</td>

<td>F</td><td> 2</td><td> 10</td><td> 35,2</td><td> 52,8</td><td> -</td><td> -</td><td> -</td><td> -</td>

<td>G</td><td> 2</td><td> 10</td><td> 35,2</td><td> -</td><td> 52,8</td><td> -</td><td> -</td><td> -</td>

<td>H</td><td> 2</td><td> 10</td><td> 26,4</td><td> -</td><td> -</td><td> -</td><td> 61,6</td><td> -</td>

<td>AND</td><td> 1</td><td> 10</td><td> 35,6</td><td> 53,4</td><td> -</td><td> -</td><td> -</td><td> -</td>

<td>J</td><td> 2</td><td> 5</td><td> 37,2</td><td> -</td><td> -</td><td> 55,8</td><td> -</td><td> -</td>

<td>K</td><td> 3</td><td> 5</td><td> 36,8</td><td> -</td><td> -</td><td> 55,2</td><td> -</td><td> -</td>

<td>L</td><td> 6</td><td> 5</td><td> 35,6</td><td> -</td><td> -</td><td> 53,5</td><td> -</td><td> -</td>

<td>M</td><td> 3</td><td> 5</td><td> 35,8</td><td> -</td><td> -</td><td> 55,2</td><td> -</td><td> 1</td>

<td>N</td><td> 3</td><td> 5</td><td> 33,8</td><td> -</td><td> -</td><td> 55,2</td><td> -</td><td> 3</td>

<td> 0</td><td> 3</td><td> 5</td><td> 30,8</td><td> -</td><td> -</td><td> 55,2</td><td> -</td><td> 6</td>

<td>P</td><td> 3</td><td> 5</td><td> 46</td><td> -</td><td> -</td><td> 46</td><td> -</td><td> -</td>

<td>Q</td><td> 3</td><td> 10</td><td> 43,5</td><td> -</td><td> -</td><td> 43,5</td><td> -</td><td> -</td>

<td>R</td><td> 6</td><td> 10</td><td> 42</td><td> -</td><td> -</td><td> 42</td><td> -</td><td> -</td>

<td>S</td><td> 3</td><td> 7</td><td> 45</td><td> -</td><td> -</td><td> 45</td><td> -</td><td> -</td>

<td>T</td><td> 6</td><td> 7</td><td> 43,5</td><td> -</td><td> -</td><td> 43,5</td><td> -</td><td> -</td>

where OCT means octreotide, EtOH means ethanol, PC means soybean phosphatidylcholine LIPOID S100, GDO means glyceryl dioleate, TP means α-tocopherol, DOPG means dioleoyl phosphatidylglycerol

GDO quality (according to AC)

<td></td><td>monoglycerides</td><td>diglycerides</td><td>triglycerides</td>

<td>GDO1</td><td> 10,9%</td><td> 87,5%</td><td> 1,4%</td>

<td>GDO2</td><td> 4,2%</td><td> 92,1%</td><td> 3,5%</td>

<td>GDO3</td><td> 0,5%</td><td> 95,3%</td><td> 4,0%</td>

[0168] Formulation P (composition - see above) was given to the rat by subcutaneous injection at a level of 1 ml formulation per kg body weight, which corresponds to 30 mg / kg octreotide.

[0169] Plasma octreotide levels were monitored after administration for 5 days to determine the burst profile. It was observed that the highest plasma concentration was less than three times higher than the average plasma concentration for the first 5 days.

[0170] The test results are shown in Figure 6

EP 1 768 650 B1

Example 46: Sunscreen formulations [0171] Formulations were prepared as in Example 1 by mixing each of several UV absorbing / dispersing agents with a mixture of GDO, PC, and ethanol in the following proportions (by weight)

<td>formulation</td><td>PC</td><td>GDO</td><td>EtOH</td><td>Tioveil CM</td><td>Spectraveil FIN</td><td>Solaveil CT-100</td><td>Tioveil 50 MOTG</td>

<td> 1</td><td> 38</td><td> 42</td><td> 5</td><td> -</td><td> -</td><td> -</td><td> 15</td>

<td> 2</td><td> 38</td><td> 42</td><td> 5</td><td> -</td><td> -</td><td> 15</td><td> -</td>

<td> 3</td><td> 37</td><td> 38</td><td> 5</td><td> 15</td><td> 5</td><td> -</td><td> -</td>

[0172] Where TIOVEIL CM (Uniqema) contains cyclomethicone (and) titanium dioxide (and) dimethicone copolyol (and) aluminum stearate (and) alumina, SPECTRAVEIL_FIN (Uniqema) contains zinc oxide (and) C12-15 alkyl benzoate (and) polyhydroxystearic acid, SOLAVEIL CT-100 (Uniqema) contains C12-15 alkyl benzoate (and) titanium dioxide (and) polyhydroxystearic acid (and) aluminum stearate (and) alumina, and TIOVEIL 50 MOTG (Uniqema) contains titanium dioxide (and) caprylic / capric triglyceride (and) mineral oil (and) polyhydroxystearic acid (and) aluminum stearate (and) alumina.

[0173] The obtained formulation precursors have low formulation viscosity and can be easily applied with a pump spray. Upon contact with body surfaces, an elastic UV protection layer is created.

Example 47: Periodontal chlorhexidine depot compositions.

[0174] Formulations were prepared as in Example 1 by mixing the anti-infectious agent chlorhexidine digluconate with a mixture of GDO, PC, and ethanol in the following proportions (by weight)

Table. Chlorhexidine digluconate formulation compositions.

<td>formulation</td><td>Chlorhexidine digluconate</td><td>PC</td><td>GDO</td><td>EtOH</td>

<td>AND</td><td> 5</td><td> 34</td><td> 51</td><td> 10</td>

<td>B</td><td> 5</td><td> 36</td><td> 54</td><td> 5</td>

<td>C</td><td> 7</td><td> 33</td><td> 50</td><td> 10</td>

<td>D</td><td> 10</td><td> 32</td><td> 48</td><td> 10</td>

<td>E</td><td> 15</td><td> 30</td><td> 45</td><td> 10</td>

[0175] Chlorhexidine depot pre-formulations have low viscosity and are easily administered into the periodontal pocket. Compared with products such as Periochip®, the compositions provide better distribution and distribution of the active substance throughout the periodontal pocket.

[0176] The depot made after application provides protection against re-infection of the pouch. Depot also has excellent bioadhesive properties and sticks to the surface of mucous membranes, teeth and bones.

[0177] The release of chlorhexidine digluconate from 250 mg formulation A (see above) in 0.9% aqueous NaCl solution (500 ml) was studied. The USP release measurement formulation was kept in a cylindrical metal cup that was placed in a Teflon handle at the bottom of a normal bath. Contact field between₂ formulation and the surrounding brine solution was 2.4 cm², the solution was mixed with a spatula at a speed of 100 rpm.

[0178] The release curve shown in Figure 7 shows the sustained and substantially uniform release of chlorhexidine from the formulation over a 24 hour period.

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