Topical bioadhesive formulations
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15 claims: 14 independent, 1 dependent
- 1Zastrzeżenia patentowe 1. Preformulacja obejmująca mieszaninę o małej lepkości zawierajacą:a) co najmniej jeden obojętny diacylolipid i/lub tokoferol, przy czym wymieniony diacylolipid zawiera co najmniej 50% dioleinianu glicerolu;b) co najmniej jeden fosfolipid posiadający grupy polarne - głowy składające się z co najmniej 50% z fosfatydylocholiny;najmniej jednego rozpuszczalnika biozgodnego, organicznego c) 2-30% wag. co zawierającego tlen, obejmującego etanol;ewentualnie obejmująca co najmniej jeden środek bioaktywny rozpuszczony albo zdyspergowany w mieszaninie o małej lepkości, w której preformulacja tworzy lub jest zdolna do tworzenia, co najmniej jedną bioadhezyjną strukturę fazy ciekłokrystalicznej po zetknięciu z płynem wodnym i/lub powierzchnią ciała, oraz stosunek wagowy składników a:b wynosi od 85:15 do 30:70, oraz preformulacje nie zawierają;36% wag. fosfatydylocholiny, 54% wag. dioleinianu glicerolu, 10% wag. etanolu, ewentualnie 500 pg kalcytoniny łososia/g preformulacji;albo 34% wag. fosfatydylocholiny, 51% wag. dioleinianu glicerolu, 5% wag. kwasu oleinowego, 10 % wag. etanolu, ewentualnie 500 pg kalcytoniny łososia/g preformulacji.
- 2Preformulacja według zastrz. 1, znamienna tym, że składnik a) składa się zasadniczo z diacyloglyceroli.
- 3Preformulacja według któregokolwiek z zastrz. 1-2, znamienna tym, że składnik b) oznacza fosfatydylocholinę.
- 4Preformulacja według któregokolwiek z zastrzeżeń 1-3, znamienna tym, że jej lepkości wynosi od 0,1 do 5000 mPas.
- 5Preformulacja według któregokolwiek z zastrz. 1-4, znamienna tym, że posiada strukturę roztworu cząsteczkowego fazy L2 i/lub L3.
- 6Preformulacja według któregokolwiek z zastrz. 1-5, znamienna tym, że zawiera od 35 do 60% wag. składnika a), od 20 do 50% wag. składnika b), i od 10 do 20% wag. składnika c).
- 7Preformulacja według któregokolwiek z zastrz. 1-6, znamienna tym, że składnik c) jest alkoholem.
- 8Preformulacja według któregokolwiek z zastrz. 1-7, znamienna tym, że zawiera dodatkowo do 10% wag. w stosunku do a)+b) naładowanego amfifilu.
- 9Preformulacja według któregokolwiek z zastrz. 1-8, znamienna tym, że wymieniony środek aktywny wybiera się spośród kortykosteroidów, niesteroidowych związków przeciwzapalnych, miejscowych inhibitorów dróg zapalnych, inhibitorów fosfolipazy, przeciwutleniaczy, środków przeciwzakaźnych, cytokin i induktorów/supresorów cytokin.
- 10Preformulacja według któregokolwiek z zastrz. 1-9, znamienna tym, że nadaje się do podawania poprzez płukanie, natryskiwanie, płukanie gardła, w postaci plastra, przez czopek, lub przez lewatywę.
- 11Preformulacja według zastrz. 10 znamienna tym, że zawiera benzydaminę.
- 12Preparat miejscowego działania według któregokolwiek z zastrz. 1-10, do podawania do wnętrza jamy ustnej, znamienny tym, że tworzy bioadhezyjny produkt o kontrolowanym uwalnianiu, w którym wymieniony środek aktywny obejmuje co najmniej jeden związek wybrany spośród:tramadolu, Kodeiny, Nalbufiny, Oksymorfonu, Acetaminofenu, Dihydrokodeiny, Meperydyny, Alfentanilu, ibuprofenu, Hydrokodonu, Lewerorfanolu, Fentanylu benzydaminy, Propoksyfenu, Oksykodonu, Hydromorfonu, i Sefentanilu.
- 13Preformulacja miejscowego działania według któregokolwiek z zastrz. 1-10, do podawania do wnętrza jamy ustnej do leczenia zakażeń okołozębowych i miejscowych, znamienna tym, że środek aktywny stanowi glukonian chlorheksydyny, przy czym preformulacja jest nakładana w postaci produktu płynnego, który tworzy żel powierzchniowy in situ między 1 sek. a 5 min. po nałożeniu.
- 14Preparat miejscowego działania według któregokolwiek z zastrz. 1-10, odpowiedni do podawania ocznego, znamienny tym, że środek aktywny obejmuje co najmniej jeden wybrany spośród diklofenaku, chlorowodorku lewokabastyny, fumaranu ketotifenu, timololu, betaksololu, karteololu, lewobunololu, dorzolamidu, brinzolamidu, epinefryny, klonidyny, atanoprostu, apraklonidyny, trawoprostu, brymonidyny, bimatoprostu, dipiwefryny, pilokarpiny, unoprostonu, chlorowodorku pilokarpiny, deksametazonu, chloramfenikolu i indometacyny.
- 15Preparat miejscowego działania według któregokolwiek z zastrz. 1-10, do podawania dermatologicznego, który tworzy bioadhezyjny produkt o kontrolowanym uwalnianiu, znamienny tym, że środek aktywny wybiera się spośród środków kosmetycznych, zapachów, aromatów, olejków lotnych, środków absorbujących UV oraz mieszanin powyższych. 20311/PE/10 EP 1 848 403 B1 fazę heksagonalną Hii Fig. 2 20311/PE/10 EP 1 848 403 B1 Fig. 3
Independent claims15
372 paragraphs in 4 sections, as filed
[0001] The present invention relates to precursor drug forms (pre-formulations) for forming in situ controlled release lipid compositions. In particular, the invention relates to pre-formulations in the form of mixtures of low-viscosity amphiphilic components (such as molecular solutions) and, optionally, at least one bioactive agent that undergoes at least one phase transition upon contact with aqueous fluids, such as body fluids, forming as a result, the bioadhesive matrix.
[0002] Numerous bioactive agents, including pharmaceuticals, foodstuffs, vitamins, etc., have a "functional range". This means that there is a concentration range in which these agents have a noticeable biological effect. If the concentration in the relevant part of the body (e.g. topical or in the form of serum concentration) is below a certain level, it can not be attributed to any beneficial effect. There is also an upper concentration limit above which no greater benefit is obtained with increasing concentration. In some cases, increasing the concentration above a certain level causes adverse or hazardous effects.
[0003] Certain bioactive agents have a long biological half-life and / or a wide functional range, so they can be administered occasionally while maintaining functional biological concentration for a substantial period of time (e.g. 6 hours to several days). In other cases, the purification factor is large and / or the functional range is narrow, so regular (or even continuous) low doses are required to maintain the biological concentration within this range. This can be particularly difficult when a non-oral route of administration is desired (e.g. parenteral administration). In addition, under certain circumstances, such as implant fitting (e.g., replacement joints or oral implants), the area of desired effect may not be available for repeated administration. In such cases, a single dose must provide the active ingredient at the therapeutic level for the total period during which its activity is necessary.
[0004] Similarly, if the effect of the bioactive agent is locally desirable, it may be difficult or undesirable to administer this agent sufficiently to achieve an effective level throughout the body of the subject. This may be caused by undesirable effects of the measure itself (e.g. as for steroidal anti-inflammatory agents) and because the agent is used to counteract locally the undesirable properties of systemic treatment (such as chemotherapy), although it would weaken the primary treatment in general use.
[0005] However, the main problem with topically applied compositions is the period of their action. These compositions are inherently applied to body surfaces that may be susceptible to rubbing, washing and rinsing with body fluids or applied fluids such as tears, sweat or mucus. A particularly problematic situation when using topical preparations occurs in body cavities, such as the digestive tract. The reason for this is that such cavities are usually coated with a mucosa that is non-adherent and undergoes rapid replacement. In addition, thick, sticky preparations can be difficult to apply effectively in the mouth / throat or anus and are difficult to produce due to the high viscosity that makes it difficult to sterilize by filtration. However, existing compositions typically have either low viscosity and short half-life, or longer half-life at the expense of higher viscosity. In addition, existing topical compositions may often contain the active ingredient only at low concentration due to the poor compatibility between the base composition and the active ingredient. The result is a composition that quickly loses effectiveness as it begins to fade away at the site of action. Therefore, it would be extremely valuable to provide topical formulations that would be bioadherent, even on mucous surfaces, and which could be developed in the form of low viscosity preformulations that would become adherent when contacted with the desired surface. In addition, it would be extremely beneficial if the formulation had protective properties, was non-irritating and exhibited adequate resistance to wear and exposure to the aquatic environment. Publications WO2005 / 046642 and US5807573 disclose certain lipid compositions, which are not, however, bioadhesive compositions.
[0006] The inventors of the present invention have found that by providing a pre-formulation comprising certain amphiphilic components, at least one bioactive agent and a biologically acceptable solvent, especially in a low-viscosity phase, such as a molecular solution, a pre-formulation can be prepared that solves many of the problems encountered in previous formulations. In particular, such a pre-formulation is easy to produce, it can be sterilized by filtration, it has a low viscosity (which allows easy and quick administration) and / or allows the introduction of a high concentration of bioactive agent (this allows the use of a smaller amount of composition and / or ensures efficacy for a long time). The compositions are obtained from non-toxic, biotolerated and biodegradable materials. They are well suited for application to sensitive areas, such as sensitive parts of the body and inflamed areas, and contain lipids, which are part of natural protective surface coatings, e.g., phospholipids. In addition, due to the combination of bioadhesive properties and extremely low water solubility of the main components of the composition, the compositions of the invention used are stable to exposure to the aqueous environment and wear. The composition also provides extended release of a wide spectrum of active ingredients, with a controlled range of their duration of action. The pre-formulation is therefore suitable for the production of depot compositions ensuring continuous administration which is not parenteral (e.g. topical) to body cavities and / or body surfaces or elsewhere, and are formed from lipids that alone can provide natural benefits, in addition to creating very effective carriers and local depots for active agents.
[0007] In a first aspect, the invention therefore relates to a pre-formulation as set out in the appended claims.
[0008] The body fluid will generally be body fluid such as mucus, tears, sweat, saliva, gastrointestinal fluid, extravascular fluid, extracellular fluid, interstitial fluid or plasma, and the preformulation will form a structure in the liquid crystal phase upon contact with the surface of the body, the surface or cavity (e.g. in vivo) due to contact with aqueous body fluid. The pre-formulation of the invention will generally not contain any significant amounts of water prior to administration.
[0009] In a second aspect, the invention also relates to a method of delivering a bioactive cosmetic agent to a human or animal (preferably mammalian) body as set out in the appended claims.
[0010] A method of administration suitable for the above method of the invention will be a method suitable for the condition being treated and the bioactive agent used. A bioadhesive, non-parenteral composition (e.g. topical) in the form of a depot, it can be formed by applying to the surface of the skin, mucous membranes and / or nails, ophthalmological, nasal, oral or internal surfaces, or into cavities such as the nasal, rectal, vaginal or buccal, periodontal pocket or formed cavities after the extraction of a natural or implanted structure or before placing an implant (e.g. joint, stent, cosmetic implant, tooth, tooth filling or other implants).
[0011] Yet another aspect of the present invention is the use of a low viscosity mixture comprising:
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 bioactive agent is dissolved or dispersed in a low viscosity mixture, in the production of a pre-formulation for use with prolonged topical administration of said active agent, wherein said pre-formulation may form at least one liquid crystal phase structure upon contact with the aqueous fluid.
[0012] In a further aspect, the present invention relates to the use of the composition according to the invention in therapy, and in particular to the use of the composition, optionally comprising an active ingredient, in the manufacture of a medicament for the treatment of inflammation and / or irritation, especially on the body surface and / or in the body cavity such as the digestive tract.
[0013] The use of non-lamellar phase structures (such as liquid crystal phases) for the delivery of biologically active agents is now relatively well recognized. Such structures arise when the amphiphilic compound contacts 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 structures formed by amphiphilic compounds in polar and / or nonpolar solvents have a very significant area of polar / nonpolar regions on which other amphiphilic compounds can adsorb and stabilize. The amphiphilic compounds can also be developed to protect active agents, at least to some extent, against agents present in aggressive biological environments, including enzymes, and thereby provide beneficial control over the stability and release of the active agent.
[0014] The phenomenon of the formation of non-lamellar regions in the phase diagrams of an amphiphilic compound / water, amphiphilic compound / oil and amphiphilic compound / oil / water is well known. Such phases include liquid crystalline phases such as cubic P, cubic D, cubic G and hexagonal, which are liquid at the molecular level, but show significant long-range ordering, and the L3 phase, which includes a multi-linked network of two-layer continuous, which are non-lamellar but do not have a long range order of liquid crystal phases. Depending on their curvature of the amphiphilic planes, these phases can be described as normal (average curvature towards the non-polar region) or inverted (average curvature towards the polar region).
[0015] Non-amelar liquid crystalline and L3 phases are thermodynamically stable systems. That is, they are not simply a metastable state that will separate and / or transform into layers, lamellar phases or the like, but are a thermodynamically stable form of the lipid / solvent mixture.
[0016] As used herein, the term "low viscosity mixture" indicates a mixture that can be easily administered to a subject, in particular easily administered by means of a standard syringe and needle kit or by means of a spray sprayer. This can be demonstrated by the example of dispensing a 1 ml disposable syringe through a 22 (or 23) awg needle with manual pressure. In a particularly preferred embodiment, the low viscosity mixture should be a mixture capable of passing through a normal filter sterilizing membrane, such as a syringe filter
0.22 μm. In other preferred embodiments, a similar functional definition of suitable viscosity can be defined as the viscosity of a pre-formulation that provides atomization using a compressor or a pressure atomizing device using conventional spray equipment. A typical range of suitable viscosities could be, for example, from 0.1 to 5000 mPas, preferably from 1 to 1000 mPas, at 20 ° C.
[0017] 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. As exemplified in Figure 2, the addition of only 5% solvent can reduce the viscosity by 100 times, and the addition of 10% can reduce the viscosity by up to 10,000 times. In order to achieve this non-linear synergistic effect, it is important to use a solvent with low viscosity and appropriate polarity when lowering viscosity. Such solvents are described below.
[0018] 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-lamellar phase composed of planes connected to each other which has some phase structure but no ordering of the long range of the liquid crystal phase. Unlike liquid crystal phases, which are generally highly viscous, the L3 phases have a lower viscosity. Of course, mixtures of the L3 phase and a molecular solution and / or L3 phase particles suspended in a bulk molecular solution comprising one or more components are also suitable. The L2 phase is the so-called "reversed micellar" phase or microemulsion. Molecular solutions, L3 phases and mixtures thereof are the most preferred low viscosity mixtures. L2 phases are less preferred except for the swollen L2 phases as described below.
[0019] The present invention relates to a pre-formulation comprising components a, b, c and optionally and preferably 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 combined in a wide range of proportions. In particular, the pre-formulations of the present invention may have been prepared and used having a much greater ratio of phospholipid to neutral diacyl lipid and / or tocopherol 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 be anywhere from 5:95, up to 95: 5. Preferred ratios could generally 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. That is, the weight ratio a: b is below 50:50, e.g. from 48:52 to 2:98, preferably from 40:60 to 10:90 , and more preferably from 35:65 to 20:80.
[0020] The amount of component c in the pre-formulations of the invention will be at least sufficient to obtain a low-viscosity mixture (e.g., molecular solution, see above) of components a, b and c, and will be easily determined for any combination of ingredients, by standard methods. Phase behavior alone can be analyzed by techniques such as visual observation in combination with polarized light microscopy, nuclear magnetic resonance, and cryo-transmission electron microscopy (cryo-TEM) for solutions, L2 or L3 phases or liquid crystal phases. Viscosity can be measured directly by standard methods. As described above, a suitable viscosity is one that allows effective administration via a syringe, and in particular sterilization by filtration and / or pump spraying or pressure spraying. As described in the present invention, this can easily be assessed. The highest amount of component c introduced will depend on the particular application of the pre-formulation, and the generally desired properties will be provided by any amount forming the low viscosity mixture (e.g. molecular solution, see above) and / or a solution with sufficiently low viscosity.
[0021] Since the administration of too much solvent to the subject is usually undesirable, the amount of component c in one embodiment will typically be limited to no more than ten times (e.g., three times) the minimum amount necessary to obtain a low viscosity mixture, preferably no more than five times , and most preferably not more than twice that amount.
[0022] The higher solvent content can also be used for non-parenteral (e.g. topical) applications, especially on the body surface, where the solvent will be released by evaporation instead of absorption by the body. In such cases, up to 100 times the minimum amount of solvent (e.g. up to 95% by weight of the composition, more preferably up to 80% by weight, and most preferably up to 50% by weight), especially if ultimately a very thin non-parenteral depot layer is desired.
[0023] The compositions of the invention formulated as (non-parenteral) aerosol spray compositions (eg, for topical or systemic delivery of an active agent) may also contain a carrier gas. Such compositions may also include a high proportion of the solvent - component c), since most of the solvent will evaporate when the composition is dispensed, especially under the influence of a carrier gas.
[0024] Useful carrier gases are volatile compounds that will mix with the composition of the invention under the pressure of a spray dispenser, without generating high viscosity mixtures. Of course, they should have adequate biocompatibility. Suitable carrier gases can be easily identified by simple tests, and examples thereof include hydrocarbons (especially C1 to C4 hydrocarbons), carbon dioxide and nitrogen. Volatile fluorocarbons such as HFCs 134, 134a, 227ea and / or may also be suitable
152a.
[0025] A general indication is that the mass of component c will usually be about 0.5 to 50% of the total weight of the abc solution. This proportion may be limited to 2 to 30% or 5 to 20% by weight. However, as noted above for sprayable compositions, especially with propellant gas, the amount of c may exceed 50%.
[0026] The formulations of the invention may further contain small amounts of other ingredients, such as polymers, that are soluble in the precursor. Such polymers can act as reinforcement of the swollen liquid crystal phase, causing the film attached to the mucous surface to adhere more strongly. "Reinforcement" according to the same principle can also be obtained by saturating the matrix (paper, polymer mesh or the like) with a precursor. By applying this "patch" to the skin, the preparation itself can act as an adhesive. Unlike conventional adhesives for coating damaged tissue, the preparations according to the invention adhere even to mucous membranes and are not irritating. In many cases, they are simply soothing as described in the present invention, and may contain a suitable active agent.
[0027] Component "a", as already noted, 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 bond may be through an ether, amide, carbon-carbon bond or other bond. Preferred polar head groups are nonionic and include polyols such as glycerol, diglycerol and sugar derived moieties (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.
[0028] In one preferred aspect of the invention, component a is a diacyl lipid that has two non-polar "tail" groups. This is usually more advantageous than the use of monoacyl ("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 independently saturated or unsaturated. Examples of non-polar groups include C6-C32 alkyl and alkenyl groups, which are usually present as esters of long chain carboxylic acids. They are often described in terms of the number of carbon atoms and the number of unsaturations in the carbon chain. Thus, CX: Z is a hydrocarbon chain having X carbon atoms and Z unsaturation. Examples especially include caprooyl (C6: 0), capryloyl (C8: 0), caprylic (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, suitable alcohols. Preferred non-polar chains are palmitic, stearic, oleic and linoleic acids, especially oleic acid.
[0029] 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. As component a, mixtures of any number of diacyl lipids can be used. Most preferably, this component will contain at least a portion of diacylglycerol (DAG), especially glycerol dioleate (GDO). In one preferred embodiment, the component comprises DAG. It can be a single DAG or a mixture
DAG. A very preferred example is DAG containing at least 50%, more preferably at least 80%, and even containing essentially 100% GDO.
[0030] An alternative or very preferred additional class of compounds for use as all or part of component a are tocopherols. The term "tocopherol," as used herein, is used to denote a non-ionic tocopherol lipid, often known as vitamin E, and / or any suitable salts and / or analogues thereof. Suitable analogs will be those that provide phase behavior, no toxicity, and phase change upon contact with aqueous fluids that characterize the compositions of the present invention. Such analogues, usually in the form of a pure compound in water, will not form liquid crystal phase structures. The most preferred of tocopherols 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 amount of "impurity" other than tocopherol, but it will not be enough to change the 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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[0031] In a further preferred embodiment, component a) consists in particular of tocopherol, an embodiment of the invention, essentially of tocopherols as shown above.
[0032] 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 from 2:98 to 98: 2 by weight tocopherol: GDO, e.g. from 10:90 to 90:10 tocopherol: GDO, in particular from 20:80 to 80:20 these compounds. Mixtures of tocopherol with other DAGs are also suitable.
[0033] 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 is essentially a 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.
[0034] Preferred polar head phospholipid groups include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol. Phosphatidylcholine (PC) is most preferred. In a preferred embodiment, component b) thus contains at least 50% PC, preferably at least 70% PC, and most preferably at least 80% PC. Component b) may consist essentially of PC.
[0035] The phospholipid portion, even more preferably than any diacylolipid portion, may be from a natural source. Suitable 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.
[0036] Since the pre-formulations of the invention are to be administered to a subject for the controlled release of an active agent, it is preferred that components a and b are biocompatible. It is therefore preferable to use, for example, diacyl lipids and phospholipids instead of monoacyl (lyso) compounds. A special exception is the tocopherol described above. Although it has only one alkyl chain, it is not a "lyso" lipid in terms of definition. The nature of tocopherol, as a well-tolerated basic vitamin, obviously makes it very suitable in terms of biological compatibility.
[0037] The nature of the compositions of the invention, as suitable for the healing and healing of irritation and inflammation on the body surface, creates a significant need for tolerated lipids. In particular, the lipid composition will be present in high concentration when in contact with tissue that may be damaged or inflamed. As a result, a high level of compatibility, for example of the diacyl lipids of the present invention, is very important compared to the less tolerated components such as monoacyl lipids.
[0038] In addition, it is also preferred that 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 in the subject. This is not only more convenient for the subject, but may increase the residence time of the composition in the form of a depot, because at the site of administration, less activity of the immune system is stimulated and there is less tendency for the subject to damage this area. In some cases, however, it may be beneficial to have a non-naturally occurring lipid in components a and / or b. This may be, for example, an "ether lipid" in which the head and tail groups are linked by an ether bond instead of an ester linkage. Such non-naturally occurring lipids may be used, for example, to alter the rate of degradation of the composition in the form of a depot due to their greater or less solubility or sensitivity to degradation mechanisms present at the site of release of the active agent. Although any proportions are included within the scope of the present invention, generally at least 50% of each of components a and b will be naturally occurring lipids. They will preferably constitute at least 75% and may constitute substantially up to 100%.
[0039] Two particularly preferred combinations of components a and b are GDO with PC and tocopherol with PC, especially in the range of 30-90% by weight GDO / tocopherol, 10-60% by weight PC and 1-30% solvent (especially ethanol, NMP and / or isopropanol). The most preferred combinations are 30-90% (e.g. 40-55) GDO from 20 to 50% (e.g. 25 to 45%) of PC. They are especially suitable in combination with ethanol, especially in an amount of 5 to 25% (e.g., 7 to 19%).
[0040] In addition to the amphiphilic components a and b, the pre-formulations of the invention may also contain relatively small amounts of additional amphiphilic components. In one embodiment of the invention, the pre-formulation comprises up to 10% (based on the total weight of components a and b) of a charged amphiphilic compound, particularly an anionic amphiphilic compound such as 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 acid or 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 provide a particularly advantageous sustained release composition. In part, this may be due to better protection of the peptide against degradation enzymes present in vivo.
[0041] The "c" component of the pre-formulations of the invention is an oxygen-containing organic solvent. Since the pre-formulation is to generate the depot / bioadhesive 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 outside the pre-formulation. in aqueous fluid. Therefore, solvents having at least moderate water solubility are preferred.
[0042] In a unique case, the composition of the invention takes the form of aerosol spray compositions. Then component c may include a carrier gas having low water solubility. Any mixing ratio can be considered, from substantially pure carrier gas to mainly oxygen-containing organic solvents. When dispensing the formulation, the carrier gas will evaporate to a large extent. When c is mainly a carrier gas, a sudden increase in viscosity can be seen after spraying the formulation. This is due to the rapid evaporation of the carrier gas and this can be an advantage due to the more effective initial staying at the application site and thus avoids the potential disadvantage that the formulation has a low viscosity during "curing" (water uptake and phase transformation into the liquid crystal phase) highly viscous).
[0043] 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 16%, e.g. up to 10% or even lower, can result in a large reduction in viscosity, e.g. by a row size or more. As described in the present invention, the addition of a 10% solvent may result in a viscosity reduction of two, three or even four orders of magnitude compared to the non-solvent composition, even if the composition is a solvent-free or L2 phase solution or containing an unsuitable solvent such as water (special case considered below) or glycerol.
[0044] 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 suitable alcohols include ethanol, isopropanol and glycerol formal.
Monohydric alcohols are more preferred than diols and polyols. When diols or polyols are used, preferably in combination with at least an equal amount of a monohydric alcohol or other preferred solvent. Examples of ketones include acetone, n-methylpyrrolidone (NMP), 2-pyrrolidone and propylene carbonate. Suitable ethers include diethyl ether, glycofurol, diethylene glycol monoethyl ether, dimethylisobarbide and polyethylene glycols. Suitable esters include ethyl acetate and isopropyl acetate, and a suitable sulfide solvent is dimethyl sulfide. Suitable amides and sulfoxides include dimethylacetamide (DMA) and dimethyl sulfoxide (DMSO). Less preferred solvents include dimethylisosorbide, tetrahydrofurfuryl alcohol, diglyme and ethyl lactate. The most preferred solvent is ethanol, and in particular comprises at least 80% ethanol, preferably at least 90% ethanol.
[0045] Since the pre-formulations are to be administered to a living subject, 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 a subject. Such solvents will most often 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 because they tend to have lower biocompatibility. When a halogenated solvent, such as dichloromethane or chloroform, is required, this proportion will usually be minimized. Apparently, the range of suitable solvents will be greater in formulations for use on healthy external surfaces than on internal, sensitive and / or damaged surfaces, where only the most biologically compatible will usually be acceptable. Furthermore, in the case of aerosol spray compositions , halogenated hydrocarbons may also be considered as the carrier gas, since they will largely evaporate during dispensing.
[0046] 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 suitable 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 observations of the inventors of the present invention is that the low viscosity oxygen-containing solvents described herein exhibit very favorable and unexpected intermolecular interactions with the lipid parts of the composition, thereby providing a non-linear reduction of viscosity when adding a small volume of solvent.
[0047] The viscosity of the "low viscosity" solvent (single solvent or mixture) component c should typically be no more than 18 mPas at 20 ° C. Preferably it is not more than 15 mPas, more preferably not more than 10 mPas, and most preferably not more than 7 mPas at 20 ° C.
[0048] The solvent component c will generally be at least partially released upon formation of the depot / bioadhesive composition upon contact with the surface (e.g. body surface or implant surface) 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. Oxygen-containing solvents with a relatively low number of carbon atoms (e.g. up to 10 carbon atoms, preferably up to 8 carbon atoms) are also preferred in this regard. Of course, with more oxygen atoms, 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 with a ratio outside one of these preferred ranges is used, preferably the amount should not be greater than 75%, preferably not 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 the pre-formulation to control the rate of formation of the liquid crystal depot phase.
[0049] A further advantage of the present pre-formulations is that a larger amount of a bioactive agent can be introduced into the system. In particular, large quantities of active agent can be dissolved or suspended in the pre-formulations by proper selection of ac (especially c) components. In general, the lipid components in the absence of water are relatively poorly soluble, but in the presence of water they form too viscous phases for easy administration. A larger amount of the biologically active agent can be introduced by using the appropriate solvents as component c and this amount 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. Appropriate solvent selection will be possible through routine experimentation carried out in accordance with the guidelines set forth in the present invention. In particular, the present inventors have found that the combination of a low molecular weight alcohol solvent (such as ethanol or isopropanol) with the lipid components of the present invention surprisingly effectively dissolves many drugs and other active molecules.
[0050] The pre-formulations of the present invention usually do not contain significant amounts of water. Since it is generally not possible to remove trace amounts of water from the lipid composition, it should be assumed that there is only a residual amount of water that cannot be easily removed. Such an 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 trace amount of water as just described.
[0051] In some cases, the composition may contain a trace amount of water (or polar solvent with similar properties) such that it forms the L2 (inverse micellar) phase with a rather low viscosity. It can also help to dissolve some active ingredients in the formulation, especially those that are only soluble in water.
[0052] However, there is one embodiment of the present invention in which a larger proportion of water can be tolerated. This happens when water is present as part of the solvent component in combination with the additional component c mixable with water (a single solvent or mixture). In this embodiment, the water content may be up to 10% by weight, provided that the content of component c is also at least 3% by weight, preferably at least 5%, and more preferably at least 7% by weight, component c is miscible with water and that the viscosity of the obtained pre-formulation remains low and therefore no liquid crystalline phase is formed. Generally, the weight amount of component c) will be greater than the weight of water contained in the pre-formulation. The most suitable solvents for use with water in this aspect of the invention include ethanol, isopropyl alcohol, NMP, acetone and ethyl acetate.
[0053] The pre-formulations of the present invention contain one or more biologically active agents (also described in the present invention as "active agents"). The active agents can be any compounds having the desired biological or physiological effect, such as protein, drug, antigen, foodstuff, cosmetic, fragrance, aroma, diagnostic agent, pharmaceutical, vitamin or dietetic agent and will be developed at a level sufficient for ensuring in vivo concentration at the functional level (including local concentrations for topical compositions).
[0054] Therapeutic agents that can be delivered by the present invention include drugs that act on cells and receptors, peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, cardiovascular system, smooth muscles, circulatory system, endocrine system and endocrine, 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. The present invention may also provide therapeutic agents designed for local stimulating or inhibiting action on enzymes or proteins. The action of the delivered therapeutic agent may also be associated with a direct effect on the synthesis of DNA and / or RNA, such as on transcription, translation or post-translational modifications. These effects can be both stimulating and inhibitory.
[0055] 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 nonsteroidal anti-inflammatory drugs and corticosteroids, cardiovascular drugs such as antihypertensives and hypotensive agents ( especially topical agents), analgesics, prostaglandins and derivatives. Diagnostic agents include radionuclide labeled compounds and contrast agents, including contrast enhancers in X-ray, ultrasonic and NMR (especially for use on the internal surface of the body cavity). Nutrients include vitamins, coenzymes, dietary supplements, etc., which can be used, e.g., for local rescue action against the effects of a systemic drug, such as folate rescue with the effects of a folate analog such as methotrexate.
[0056] Particularly suitable active agents include those that normally have a short residence time due to rapid degradation or excretion, and those that have poor oral bioavailability, especially if their effect can be provided by topical treatment, thereby bypassing systemic absorption. . These are active agents based on peptides, proteins and nucleic acids, hormones and other agents that occur naturally in their native or modified forms. By administering such depot agents to a composition formed from the pre-formulations of the present invention, the agents are delivered in an amount that is maintained for a period of time despite high removal rates from the body. This provides obvious benefits in terms of patient stability and submission to repeated dosing each day for such a period. In one preferred embodiment, the active agent therefore has a biological half-life (on entering the bloodstream) of less than 1 day, preferably less than 12 hours, and more preferably less than 6 hours. In some cases it can only be
1-3 hours or less. Suitable agents are also those which have poor oral bioavailability relative to that achieved by injection, where the bioavailability of the active agent is also or alternatively below 0.1%, especially below 0.05% in oral preparations. Similarly, some agents will be inappropriate or undesirable for systemic administration, but they can be administered topically, especially to external surfaces.
[0057] Active agents based on peptides and proteins are very suitable for surface incorporation in the form of a depot composition according to the invention. Such agents can be introduced for their local action or can be applied to the surface for systemic effect. Suitable topically or systemically 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, atrial natriuretic peptides, bioadhesive peptides, bradykinins and related peptides, calcitonins and related peptides, protein fragments of cell surface receptors, 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, fibronectin fragments and related peptides, gastrointestinal peptides, gastrointestinal peptides, agonists and antagonists that release gonadotropin (peptides), releasing growth hormone, 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, neurotransmitter peptides, opiate peptides, oxytocins, vasopressins and related peptides, its peptides and hormones protein and related peptides, somatostatin and related peptides, substance P and related, transforming growth factors (TGF) and related peptides, tumor necrosis factor, toxin and toxoid toxin fragments, 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), interleukins, leptins, leukemia inhibiting factors, stem cell factors, transforming growth factors and tumor necrosis factors.
[0058] A further significant advantage of the depot compositions of the present invention is that the active agents are released gradually over a long period of time, without the need for repeated dosing. The compositions are therefore very suitable for children or people whose lifestyles are at odds with reliable or repeated dosing regimens. As well as being suitable for an active "lifestyle" where the inconvenience of repeated dosing could outweigh the benefit of using the active agent.
[0059] Cationic peptides are particularly suitable for use if part of the preformulation 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.
[0060] In one preferred aspect of the present invention, the composition according to the invention is such that the I2 phase or mixed phase comprising the I2 phase is formed on contact with aqueous fluids and a polar active agent is included in the composition. Particularly suitable polar active agents include peptide and protein active agents, oligonucleotides and small water-soluble active agents, including those mentioned above. Particularly interesting in this aspect are the octreotide peptide and other somatostatin-related peptides, alpha and beta interferons, glucagon-like peptides 1 and 2 and their receptor agonists, luprorelin and other GnRH agonists, abarelix and other GnRH antagonists, interferon alpha and beta, zolendronate and iband and other bisphosphonates, as well as the polar active agent chlorhexidine (e.g., chlorhexidine digluconate or chlorhexidine dihydrochloride). Consider excluding her. Most of the agents mentioned as particularly interesting are suitable for parenteral administration, except for chlorhexidine!
[0061] The amount of bioactive agent to be combined 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 to provide sustained release. Usually, the dose developed for a particular agent will be approximately equivalent to a normal single daily dose multiplied by as many times as much as the duration of action of the preparation. Of course, this amount should be adjusted to take into account any harmful side effects of the high initial dose, and therefore this will generally be the maximum dose used. The exact amount appropriate in each case will be easily determined by appropriate experimentation.
[0062] The formulations of the present invention may form non-parenteral depots where the active agent is released slowly on the body surface. It is particularly important that the compositions formed from the pre-formulations are bioadhesive, since this allows local release of the active agent over an extended period of time. That is, the compositions should coat the surface to which they are applied and / or formed, and should remain, even when the surface is subjected to air or liquid flow and / or friction. It is particularly preferred that the liquid crystal depot compositions prepared are resistant to washing with water. For example, a small volume (e.g. 100 μΐ) of the depot precursor can be applied to the body surface and subjected to a flow of five hundred times as much water per minute for 5 minutes. After this operation, the composition may be biodegradable if less than 50% of the biologically active agent is lost. Preferably this level of loss will be met when water with a volume 1000 times, and more preferably 10,000 times the volume of the composition will flow for a minute, five or preferably 10 minutes.
[0063] Another advantageous property of the compositions of the invention is that the film formed following administration need not only act as a depot system. This film may also have the advantage of reducing water evaporation from damaged areas or affected areas (where the barrier properties of the skin are reduced). As such, the compositions may possess additional beneficial properties and exhibit additional and / or synergistic benefits in combination with active agents, for example in the prophylaxis of inflammation or in allergic dermatitis, and for the care and restoration of sensitive or tense skin.
[0064] 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 with which they are in contact, some additional water may also be absorbed from the surrounding air. In particular, when a thin layer with a large surface is formed, the affinity of the composition for water may be sufficient to form a liquid crystalline phase structure by contact with water from air. The "aqueous fluid" referred to herein means, at least in part, air containing some moisture in this embodiment.
[0065] Non-parenteral depot compositions will usually be prepared by applying the pre-formulation topically to the body surface (outer surface or into a natural or artificially created body cavity) and / or to the surface of the implant. This administration can be done by direct application of liquids, such as spraying, dipping, washing, applying with 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), application with a plaster and other similar methods. Spraying with an aerosol or atomizer is a very effective method and of course requires that the viscosity of the pre-formulation is as low as possible, so it is a method well suited to the composition of the invention. Non-parenteral depots can, however, be used for the administration of systemic agents, e.g. mucosal or transdermal. [0066] If the formulation is administered with a patch, this may depend on the "adhesive" function of the composition. This "adhesive property" may be beneficial for tissue in contact with the formulation because the compositions can be soothing and moisturizing as indicated herein. This is in contrast to previously known patches, in which the adhesive is usually inert in the best case.
[0067] Conditions particularly suitable for causal or symptomatic treatment of the topical bioadhesive depot compositions of the present invention include skin diseases (such as soreness from any cause including cracking, scratching and skin diseases 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), and in particular inflammation and / or irritation on any surface of the body. Two particularly suitable conditions that can be treated using the compositions of the invention are oral mucositis and inflammatory bowel disease (e.g., Crohn's disease or ulcerative enteritis). Bioadhesive formulations for topical administration may also be used for systemic administration of active agents (e.g., treatment), particularly by dermal, oral, transdermal or rectal adsorption. A preferred example is the treatment of motion sickness, as well as the administration of nicotine (e.g. in smoking cessation agents). If the context allows, the term "topical application" referred to herein includes systemic agents administered parenterally to a specific area of the body.
[0068] Periodontal infections are particularly suitable for treatment with the compositions of the present invention. In particular, known compositions for treating periodontal infections are difficult to apply or are generally ineffective. The most commonly used periodontal depot composition involves the introduction of collagen "flap" into the periodontal space from which the anti-infectious agent is released. This petal is difficult to insert and does not adjust 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 in the form of low viscosity preformulations, can be easily and quickly injected into the periodontal space and will continue to flow, taking the exact shape of this space and filling it. The compositions then quickly absorb water to form a strong gel that is resistant to water in the mouth. The only known prior approach to such injectable periodontal treatment was a relatively high viscosity dispersion that was difficult to apply and which was subject to undesirable phase separation. All these drawbacks have been resolved in the compositions of the present invention as described herein. Very suitable active agents for periodontal administration are antibacterial agents, antibiotics, anti-inflammatory local analgesics, especially benzydamine, tramadol and especially chlorhexidine. [0069] Non-parenteral depot compositions are also particularly preferred in combination with non-pharmaceutical active agents such as cosmetic active agents, aromas, fragrance oils etc. Such non-pharmaceutical depots will retain important aspects of bioadhesion and sustained release, providing prolonged cosmetic effects, and can be easily applied by spraying or rubbing. In addition, this applies to agents that have both cosmetic and medical (especially prophylactic) advantages, such as sunscreen agents. Because topical depot compositions provide strong water resistant barriers in which large amounts of active agents can dissolve, and especially they are useful for sunscreen filters and blockers in combination with UV absorbers and / or light scattering agents (UV, e.g. UVa) , UVb and / or UVc), especially when a high level of protection is desired. The compositions are also highly biocompatible and can have a moisturizing and soothing effect on the skin during solar exposure. Compositions of the invention containing soothing agents, such as aloe vera extract, are also very suitable for soothing and moisturizing, after exposure to sunlight or for skin that is dry, inflamed or damaged, for example as a result of irritation, burns or abrasions.
[0070] Active agents, particularly adapted for non-parenteral (e.g. topical) depot administration, which includes oral, buccal, nasal, ocular, cutaneous, rectal and 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 - adult acne or certain vaginal infections), antiviral agents including acyclovir, anti-infective agents such as bibrocatol, ciprofloxacin, levofloxacin, topical analgesics such as benzydamine, lidocaine, prilocaine, xuplacaine , fentanyl, hydromorphone, methadone, oxycodone, codeine, aspirin, acetaminophen, NSAID, such as ibuprofen, flurbiprofen, naproxen, ketoprofen, fenoprofen, diclofenac, etodalac, diflunisal, oxaproxin, piroxicam, indometansin, sulindac, tolmetin, salicylic acids such as salicylamide and diflunisal, Cox1 or Cox2 inhibitors such as celecoxib, rofecoxib or valdecoxib, corticosteroids, anti-chloquinol, 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 colony-stimulating factor painkillers, sufentanil, morphine, granulocytes and macrophages), immunosuppressants (cyclosporin, sirolimus, tacrolimus), nicotine and antiviral agents ( e.g. acyclovir), vitamin D3 and its derivatives. [0071] Other particularly suitable active agents include: acetaminophen, ibuprofen, propoxyphene, codeine, dihydrocodeine, hydrocodone, oxycodone, nalbuphine, meperidine, leverorphanol, hydromorphone, oxymorphone, alfentanil, fentanyl and sefentanil.
[0072] The inventors have found that some specific active agents form very effective depots of the compositions of the present invention, which include the following:
[0073] For local 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 a prolonged effect on the oral mucosa, in particular damaged, allergic, infected mucosa, e.g. in patients suffering from oral mucositis (caused e.g. by chemotherapy and radiation). In particular for the treatment of stomatitis.
ii. tramadol (a painkiller). Provides a composition with prolonged systemic analgesic effect.
iii. chlorhexidine gluconate (antibacterial agent) for the treatment of periodontal and local infections. Particularly useful for long-term operation in the periodontal pocket. The compositions provide depots releasing chlorhexidine for more than 1 hour, preferably more than 6 hours, most preferably more than 24 hours when administered as a fluid that forms a bioadhesive gel in situ.
The observed gel formation time on the surface is between a second and 5 minutes.
[0074] The depots i and iii formed are depots with a high content of active agent and a high degree of washing resistance. Preformulations in the form of a fluid administered as an aerosol or a liquid rinse in case i and ii and a gel forming fluid in case iii, wherein the fluid is administered into the periodontal pocket, e.g. by injection.
[0075] For non-parenteral (e.g. local or systemic) bioadhesive controlled release products for nasal administration:
i. fentanyl (an analgesic) provides the elimination of pain sensations with a rapid onset and long duration of action when given as a nasal or oral spray.
ii. diazepam (anxiolytic) provides a non-parenteral depot for the nose or mouth, with systemic effects, fast onset and long duration of action. Served as a spray.
[0076] For local bioadhesive ophthalmic controlled-release products: i. Diclofenac (NSAID) with a long duration of action. Administered as in situ phase forming fluid.
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).
[0077] Depots from i to vii prepared as a liquid spray or more preferably drops for direct application to the eye surface provide in situ depot formation with high resistance to tear washing and abrasion by eye blinking / rubbing. The composition according to the invention shows excellent suitability for ocular use. Safety tests on the rabbit model show no irritation and no blurring.
[0078] Other active agents suitable for ophthalmic compositions include antihistamines, mast cell stabilizers, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids (e.g. for the treatment of allergic conjunctivitis), anti-glaucoma agents including suppressive / suppressive 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).
[0079] For non-parenteral (e.g. local or systemic) controlled release bioadhesive products for dermatological administration:
i. acyclovir (antiviral agent). The composition generates a bioadhesive long-lasting film forming product. It can be used as an aerosol spray or dispensed with a pump, or as a liquid.
ii. testosterone undecanoate (hormone deficiency). A bioadhesive film-forming composition with long-lasting effects. It can be used as an aerosol spray or dispensed with a pump, or as a liquid.
[0080] Particularly suitable applications of dermatological preparations 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 work, etc.). Bioadhesive depots formed from the compositions of the invention provide the user with effective and lasting protection. Compositions with anti-infectious agents may also be used in situations where the sterility of the user's skin is important to the health of others, such as in the case of nurses or physicians visiting many patients in a hospital, where cross-infection should be avoided. Prior coating with the composition of the present invention may serve to create resistance to the accumulation of the infectious agent in one place, and thus to prevent its transfer to other places.
[0081] In the treatment methods of the present invention, as well as in the corresponding use in therapy and in the production of a drug, the active ingredient is not always necessary.
In particular, lipids, especially phospholipids, such as PC, have a relationship as being extremely beneficial in nature with the treatment of certain diseases (including those described below). Without going into theory, it is believed that the corresponding lipids, such as those in the formulations of the present invention, naturally occur in a protective layer on and around many body structures, such as the linings of many body cavities and joint contact surfaces. These layers can serve as protection against adhesion and attack of various chemical and biological agents (such as on the surfaces of the stomach and gastrointestinal lining), they can act as glidants (especially in joints but especially also on liners and membranes surrounding many internal structures, such as heart and lungs) and can additionally contribute to cell wall repair, by allowing lipid exchange and diluting undesirable agents that are membrane-bound and film-soluble. The lipid nature of the composition also creates a harmless substrate for unwanted inflammatory lipase enzymes, including phospholipases, such as phospholipase A2 (PLA2).
[0082] In an alternative embodiment of the treatment methods and corresponding uses of the present invention, suitable active agents can be introduced, both as the only beneficial agent and in the form of complementary action of the respective lipid components. Such active agents will usually be tailored to treat inflammation and / or irritation, such as steroidal and nonsteroidal anti-inflammatory drugs and local immunomodulators. Examples of such agents are well known and repeatedly mentioned elsewhere in the present invention. These include cis-urate acid, corticosteroids such as prednisone, methylprednisolone and hydrocortisone, and non-steroidal anti-inflammatory compounds, derivatives such as benzydamine, paracetamol, ibuprofen, salicylic acid derivatives, including acetylsalicylate and 5-aminosalicylates. Local inflammatory pathway inhibitors, including antigen recognition suppressors, methotrexate, azathioprine or 6-mercaptopurine, and phospholipase inhibitors such as PLA2 inhibitors are also suitable.
[0083] The pre-formulations of the present invention provide non-lamellar liquid crystal depots compositions upon contact with aqueous fluids, especially when in contact with body surfaces. The term "non-lamellar" as used herein means a normal or reversed liquid crystalline phase (such as a cubic 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 a "normal" or "inverted" (preferably inverted) hexagonal phase, and the "cubic" phase means any cubic liquid crystalline phase, unless otherwise stated. By means of 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 obtained in a wider range of relative component concentrations than previous lipid depot systems, without the risk of phase separation or obtaining high viscosity injectable solutions. In particular, the present invention relates to the use of phospholipid concentrations above 50% based on the total content of amphiphilic compounds. This allows access to the phases observed only at high phospholipid concentrations, especially the hexagonal liquid crystalline phases.
[0084] For many lipid combinations, only certain non-lamellar phases exist or exist in any stable state. An unexpected feature of the present invention is that the disclosed compositions often exhibit non-lamellar phases which are not present in many other combinations of ingredients. Thus, in one particularly preferred embodiment, the present invention provides compositions having a combination of components for which an I2 and / or L2 phase region exists, after dilution with an aqueous solvent. The presence or absence of such areas can be easily checked for any combination by simply diluting the composition with an aqueous solvent and testing the resulting phase structures by the methods described in the present invention. [0085] In a very preferred embodiment, the compositions of the invention may form an I2 phase or a mixed phase comprising an I2 phase upon contact with water. Phase I2 is an inverted cubic liquid crystal phase having discontinuous water regions. This phase is particularly advantageous for the controlled release of active agents, and especially in combination with polar active agents, such as water-soluble active agents, because discontinuous polar domains prevent rapid diffusion of active agents. Depot precursors in the L2 phase are more effective in combination with the formation of the I2 phase depot. This is because the L2 phase is a so-called "reversed micellar" phase having a continuous hydrophobic region surrounding separate polar cores. Thus L2 has similar advantages with hydrophilic active agents.
[0086] 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. Without going into theory, it is believed that this transient formation of the surface phase, especially the liquid crystal surface phase, serves to significantly reduce the "ejection / delay" profile of the present compositions by directly limiting the rate of exchange between the composition and the environment. Transient phases may include (generally in order from the outside to the center of the depot): HII or La, I<sub>2</sub>, L<sub>2</sub> and liquid (solution). Very preferably the composition according to the invention can form at least two, and more preferably at least three of these phases simultaneously in transient stages, after contact with water, at physiological temperatures. In particular, very preferably one of the phases formed, at least transiently, is the I2 phase.
[0087] It is important to appreciate that the pre-formulations of the present invention have low viscosity. As a result, these pre-formulations must not be in the state of any large volume liquid crystal phase, since all liquid crystal phases have a viscosity significantly higher than that of being able to be administered by a syringe or spray dispenser. The pre-formulations of the present invention will therefore not be in a liquid crystal state, such as a solution, L2 or L3 phase, and especially a solution or L2 phase.
The L2 phase used herein is preferably the "swollen" L2 phase containing more than 10% by weight of the solvent (component c) having a viscosity-reducing effect. This is in contrast to the "concentrated" or "non-swelling" L2 phase, containing no solvent 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 that are mentioned in the present invention .
[0088] In one embodiment, a small amount (e.g., less than 5% by weight) of reinforcing polymer can be added to the pre-formulation.
[0089] Upon administration, the pre-formulations of the present invention undergo a change in phase structure, from the low-viscosity mixture to the high-viscosity (tissue-adherent) depot composition. Generally, it will be a transformation from a molecular mixture of swollen L2 and / or L3 phase to one or more liquid (high viscosity) liquid phases, such as normal or inverted hexagonal or cubic liquid crystal phases or mixtures thereof. As outlined above, further phase changes may also occur after administration. Of course, full 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 preparation 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 remainder of the composition may change to a liquid crystalline phase more slowly by diffusion and / or as the surface area disperses.
[0090] In one preferred embodiment, the invention relates to the pre-formulation described in the present invention, at least a portion of which upon contact with an aqueous fluid forms a hexagonal liquid crystalline phase. The hexagonal phase thus formed may gradually disperse to release the active agent or may in turn transform into a cubic liquid crystal phase which in turn gradually disperses. The hexagonal phase is believed to provide faster release of the active agent, in particular the hydrophilic active agent, than the cubic phase structure, especially the I2 and L2 phases. Thus, when the hexagonal phase forms before the cubic phase, this will initially release the active agent rapidly bringing the concentration to an effective level, followed by a gradual release of the "maintenance dose" as the cubic phase breaks down. In this way the release profile can be controlled.
Without going into theory, it is believed that upon contact (e.g., 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 environment body (e.g., humid air close to the body or in vivo environment), such that at least part of the formulation produces a non-lamellar structure, especially the liquid crystal phase. In most cases, these non-lamellar structures are very sticky and do not dissolve or disperse easily in vivo and are bioadhesive, and thus do not rinse or wash off easily. In addition, because the non-lamellar structure contains large polar, non-polar and border regions, it very effectively dissolves and stabilizes many types of active agents and protects them against degradation mechanisms. As the depot composition prepared from the pre-formulation gradually breaks down over hours, days or even weeks or months (depending on the nature and location of application) the active agent is gradually released and / or diffuses out of the composition. Because the environment inside the depot composition is relatively protected, the pre-formulations of the invention are very suitable for active agents with a relatively low biological half life (see above).
[0092] 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 strong adhesion of the composition to biological structures, "barrier" coatings created by spraying or applying liquids can be formed from the present compositions to reduce contact with potential infectious or irritating factors or to reduce surface body contamination. The strength of the composition and resistance to washing provide beneficial features to such barriers that can be conveniently applied as a liquid or by spraying. Without delving into theory, it is believed that the stability and wear resistance of topical compositions used is due to the individual phase transitions of the compositions upon contact with aqueous fluid / moisture, and their adhesion, along with the low water solubility of diacyl lipid components.
[0093] The preparations, compositions and methods of the invention relating to the treatment of inflammation or irritation are particularly suitable for overcoming inflammation and / or irritation in the body cavity. Administration in the body cavity is therefore very suitable in this respect and will be carried out by a method suitable for the cavity being treated. For example, mouth rinses may be suitable for treating the mouth or cheeks, while other parts of the digestive tract may be appropriately treated with oral preparations, including dispersions, and dry pre-preparations and rectal preparations such as enemas or suppositories. Rinses and pessaries are similarly suitable for vaginal delivery.
[0094] The compositions of the present invention are very suitable for the treatment of inflammation in the body cavity, due to the highly bioadhesive nature of the non-lamellar phase and the long-term effects achieved. The natural soothing nature and high biocompatibility of ingredients is also important and can play a passive or active role in the treatment of inflammation.
[0095] The methods of treatment and corresponding uses of the present invention are therefore best used in inflammatory diseases and inflammations caused, for example, by injury, abrasion or a reaction to aggressive therapy, such as radiation and / or chemotherapy. Inflammatory diseases affecting at least one body cavity are particularly suitable. Gastrointestinal diseases are very suitable for treatment with the compositions of the present invention, especially inflammatory bowel disease, including disease
Crohn's and ulcerative colitis and stomatitis such as stomatitis. Similarly, using the properties of the preparations, you can also apply the application in the body cavity during surgery. They can therefore be applied directly, for example by spraying or brushing, to alleviate inflammation resulting from or visualized during the surgical procedure, as well as to reduce the tendency of surgical manipulated tissue to "stick" and / or create adhesions / bridges in undesirable places. [0096] The invention therefore particularly provides a method of treating an inflammatory disease (e.g. Crohn's disease, ulcerative colitis and stomatitis), the method comprising administering the pre-formulation of the present invention with or without the active ingredient or comprising at least one anti-inflammatory or anti-infective active agent such as an agent selected from corticosteroids such as prednisone , methylprednisolone and hydrocortisone, and derivatives of nonsteroidal anti-inflammatory compounds such as benzydamine, paracetamol, Ibuprofen and salicylic acid derivatives, including acetylsalicylate and 5-aminosalicylates. Topical inflammatory inhibitors, including antigen recognition suppressors methotrexate, azathioprine or 6-mercaptopurine, and phospholipase inhibitors such as PLA2 inhibitors are also suitable. Other suitable active agents include glutamine, antioxidants such as ascorbate, beta-carotene, vitamin E, oxypentifylline, azelastine hydrochloride, allopurinol, chlorhexadine, povidone iodine, nystatin, clotrimazole, polymyxin E, tobramycin, amphotericin B factor (G-CSF), granulocyte macrophage stimulating factor (GM-CSF), cytokines and cytokine inducing agents / suppressors.
[0097] A particularly preferred method and corresponding use is a method of treating oral mucositis in a human or animal (especially when needed) with a composition of the present invention (especially including preferred combinations of components a), b) and c)) comprising at least one topical analgesic or anti-inflammatory agent, especially benzydamine or a derivative thereof. Optionally, they may be combined with one or more of the active agents listed above for the treatment of inflammation, and / or with a local pain reliever such as lignocaine, cocaine, difendramine or particularly HCl diclone.
[0098] The invention will now be explained in more detail in the following non-limiting embodiments and based on the drawings in which;
Figure 1 shows the cumulative release of methylene blue (MB) from a depot formulation containing a PC / GDO / EtOH mixture (45/45/10% by weight) when it is injected into excess water;
Fig. 2 shows the non-linear decrease in viscosity of the pre-formulation with the addition of N-methylpyrrolidinone (NMP) and EtOH;
Fig. 3 shows the in vitro release into excess of the aqueous phase of chlorhexidine from a depot formulation containing a PC / GDO / EtOH mixture (36/54/10% by weight) 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 [0099] To illustrate that after equilibrating the depot precursor with excess water various liquid crystal phases can be obtained, injection preparations have been prepared containing different amounts of phosphatidylcholine ("PC" - Epicuron 200) and glycerol dioleate (GDO) with EtOH as solvent.
[0100] The 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.
[0101] Each formulation was injected into the vial and equilibrated with excess water. Phase behavior was assessed visually and between crossed polarizers at 25 ° C. The results of the results are presented in Table 1.
TABLE 1
<td colspan="2">PC preparation</td><td rowspan="2">GDO (wt.%)</td><td rowspan="2">EtOH (wt.%)</td><td rowspan="2">Phase H2O</td>
<td></td><td>(Wt.%)</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>I2</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>Hn / La</td>
<td>L2</td><td colspan="2">= reverse micellar phase</td><td></td><td></td>
<td>I2</td><td>= liquid crystal phase</td><td>cubic</td><td>inverted</td><td></td>
<td>HII</td><td colspan="3">= reversed hexagonal liquid crystal phase</td><td></td>
<td><sup>L</sup>and</td><td>= lamellar phase</td><td></td><td></td><td></td>
Example 2
In vitro release of a water-soluble substance [0102] A water-soluble dye, methylene blue (MB), was dispersed in formulation C (see example 1) to a concentration of 11 mg / g formulation. After injecting 0.5 g of the preparation into 100 ml of water, a rigid inverted hexagonal HII phase was formed. 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.
[0103] The MB release profile (see Fig. 1) from the hexagonal phase indicates that this (and similar) formulation is the expected depot system. In addition, the formulation appears to give a small 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) when adding the solvent (EtOH, PG and NMP) [0104] 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 hour) 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 several days before measuring the viscosity at a shear rate of 0.1 s<sup>-1</sup>using a Physica UDS 200 rheometer at 25 ° C.
[0105] This example clearly illustrates the need for solvent to be present with some depot precursors in order to obtain an injectable formulation (see Fig. 2). The viscosity of the solvent-free PC / GDO mixture increases as the amount of PC increases. Systems with a low PC / GDO ratio (more GDO) are injectable at a lower solvent concentration.
Example 4
Composition and in vitro phase study [0106] The compositions described in Table 2 were prepared in accordance with the method described in Example 1. The active substance (peptide), salmon calcitonin (sCT) was added to each preparation to obtain a concentration of 500 μg sCT / g preparation . The formulations were designed as homogeneous suspensions for parenteral administration (mixing is necessary shortly before use because the drug is not completely soluble in the PC / GDO / EtOH system).
[0107] In this example, a phase study was conducted with excess rat serum at 37 ° C to simulate the situation in vivo. Table 2 shows that the same phases are formed as in water (compare with Table 1).
TABLE 2
<td>Preparation</td><td>PC (Wt.%)</td><td>GDO (Wt.%)</td><td>OA (Wt.%)</td><td>EtOH (Wt.%)</td><td>Phase serum rat</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>I2</td>
<td>G</td><td> 34</td><td> 51</td><td> 5</td><td> 10</td><td>I2</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>Hii / L "</td>
<td>OA = acid</td><td>oleic</td><td></td><td></td><td></td><td></td>
Example 5
Sterilization by filtration of reduced viscosity formulations [0108] Reducing the viscosity using various solvents is sometimes necessary to prepare an injectable formulation and to allow administration of the system with a simple syringe (see example 3). Another important activity of the viscosity reducing solvent is that the formulations can be sterilized by filtration.
[0109] Formulations E to I in Example 4 were tested in a sterile filtration test using a 0.22 μm filter (before addition of active substance). Formulations E to H were successfully filtered, but formulation I could not be filtered because its viscosity was too high. Therefore, there was a necessary procedure for aseptic preparation
Production example 6
Preparation of depot precursor compositions with various solvents.
[0110] Certain solvents may be advantageous depending on the formulation composition and the nature and concentration of the active substance.
[0111] Depot precursor preparations (PC / GDO / solvent (36/54/10)) were prepared by the method described in Example 1, using various solvents: NMP, PG, PEG400, glycerol / EtOH (90/10). All precursor depot compositions were homogeneous single-phase solutions with a viscosity that allowed injection with a syringe (23G - i.e. needle 23; 0.6 mm x 30 mm). After injecting the precursor formulations 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 an inverted cubic 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, slightly sticky material. 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 7: Preparation of depot compositions containing benzydamine.
[0112] Benzydamine is a non-steroidal anti-inflammatory drug and is widely used as a topical drug for inflammation.
[0113] 1 g of a depot formulation containing 1.5 mg of benzydamine was obtained 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 25 ° C for at least two weeks. Balancing the precursor formulation with excess water gave a highly viscous monolithic liquid crystal phase (structure I2).
Example 8: Resistance of a preparation to changes in excipient quality. [0114] Depot precursor preparations were prepared using several different GDO species (supplied by Danisco, DK), Table 3, according to the method of Example 1. The final depot precursors contained 36 wt. PC, 54 wt. GDO, and 10 wt. EtOH. The appearance of the depot precursors did not undergo the quality changes used, and after contact with excess water, a monolith was formed showing the behavior of the cubic reversed micellar phase (structure I2).
<td>Table 3 Quality</td><td colspan="3">. Tested types of GDO quality. Monoglyceride Diglyceride GDO (% wt) (% wt)</td><td>triglyceride (Wt.%)</td>
<td>AND</td><td></td><td> 10,9</td><td> 87,5</td><td> 1,6</td>
<td>B</td><td></td><td> 4,8</td><td> 93,6</td><td> 1,6</td>
<td>C</td><td></td><td> 1,0</td><td> 97,3</td><td> 1,7</td>
<td>D</td><td></td><td> 10,1</td><td> 80,8</td><td> 10,1</td>
<td>E</td><td></td><td> 2,9</td><td> 88,9</td><td> 8,2</td>
<td>F</td><td></td><td> 0,9</td><td> 89,0</td><td> 10,1</td>
Example 9: Preparation of a depot composition containing saturated PC (Epikuron 200SH).
[0115] Depot precursor preparations 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 preparations are shown in Table 4. All precursor preparations were homogeneous monophasic samples in room temperature, becoming more viscous as the amount of Epikuron 200SH increases. 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 cloudy, presumably indicating the separation of Epikuron 200SH and other components upon contact with water and the formation of phase I2.
Table 4. Depot composition containing saturated PC
<td></td><td>Saturated PC,</td>
<td>Preparation</td><td>Epikuron PC</td>
<td></td><td>200SH (% wt.)</td>
<td>G1</td><td> 3,9</td>
<td>G2</td><td> 7,0</td>
<td>G3</td><td> 14,3</td>
<td colspan="2"></td><td>EtOH</td>
<td>(Wt.%)</td><td>GDO (wt.%)</td><td>(% Wt.</td>
<td> 34,6</td><td> 51,9</td><td> 9,6</td>
<td> 33,5</td><td> 50,2</td><td> 9,3</td>
<td> 30,8</td><td> 46,3</td><td> 8,6</td>
Example 10: Bioadhesive spray for depot precursor formulation.
[0116] A spray bottle has been found to be a convenient way to apply the formulation locally, e.g., to the skin or oral mucosa.
[0117] The depot precursor formulation obtained 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 was formed with mechanical properties suitable for the solid.
Example 11: Resistance of the local film.
[0118] After applying the depot precursor formulation to the skin, as described in Example 22, (36 wt% PC, 54 wt% GDO and 10 wt% EtOH), the applied formulation was rinsed with water (10 L / min) for 10 minutes . The preparation exhibited excellent bioadhesive and flushing resistance properties, and the loss of preparation was imperceptible.
Example 12: Formation of a cubic phase with solid properties after exposure to the depot precursor formulation.
[0119] After exposure of the depot precursor formulation 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, a solid cubic phase was formed. The formation of the cubic phase structure shows that after application, the local layer acquires the properties of a non-lamellar depot without the need for direct contact with an excess of aqueous fluid.
Example 13: Preparation for the treatment of periodontitis or implant area inflammation.
[0120] For the treatment of periodontitis or peri-implant inflammation, an antibacterial preparation is injected into the periodontal pocket and prolonged exposure is usually expected.
[0121] The rat periodontal pocket is injected with a syringe of 100 μL of the preparation prepared in Example 1, with the addition of the chlorhexidine antibiotic (PC / GDO / EtOH / chlorhexidine (35/53/10/2)). It is observed that the injected composition transforms from a low viscosity formulation, which initially spreads filling the voids into a solid mass by the uptake of fluids from the gums. In this way an antimicrobial depot is delivered.
[0122] Chlorhexidine levels in GCF in periodontal pockets remain clinically effective (MIC 125 μg / ml) for more than 1 week. The depot system is completely broken down by enzymes within 7 to 10 days and there is no need to remove it.
Example 14: Another antibacterial preparation for the treatment of periodontitis or peri-implantitis.
[0123] Another antibacterial preparation was prepared, prepared as described in Example 1 and containing Gardol (N-methyl-N- (1oxododecyl) glycine sodium) detergent (PC / GDO / EtOH / Gardol (34/51/10/5 )). This preparation is injected into the periodontal pocket of a rat.
[0124] Gardol levels are observed to remain clinically effective in GCF in periodontal pockets for extended periods of time (several days). The depot system is completely broken down by enzymes within 7 to 10 days and there is no need to remove it.
Example 15: Adhesion of the preparation to high energy surfaces.
[0125] For the treatment of implant area inflammation, it is important not only to adhere to biological surfaces, but also to high energy surfaces, such as a gold or titanium implant. It is also important that the preparation adheres to ceramic and plastic surfaces.
[0126] The formulation (PC / GDO / EtOH (36/54/10)) as prepared in Example 1 was applied to various surfaces in the oral cavity. The composition showed excellent adhesion to 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 at the application site for at least 6 hours.
Example 16: Bioadhesive formulation for prolonged release of sodium fluoride for use on teeth.
[0127] Fluoride-containing compounds are often needed to prevent caries attack, so a bioadhesive precursor formulation with depot properties was prepared as indicated in Example 1 from a mixture of
PC / GDO / EtOH / sodium fluoride (35/53/10/2). The preparation was a dispersion of sodium fluoride because it was insoluble in the precursor. A liquid preparation was applied to the teeth with a brush. By saliva uptake, the product solidified and formed a depot providing sustained release of sodium fluoride over a prolonged period (several hours).
Example 17: An oral depot aerosol composition. [0128] The mechanical properties of the system were selected by reducing the PC / GDO ratio to obtain an oral depot system suitable for the oral cavity.
[0129] A mixture containing PC / GDO / EtOH (27/63/10) was prepared according to example 1. To visualize the formulation after application, a drop of patent blue was added. About 300 μΐ of the preparation was sprayed into the mouth from the spray bottle. Shortly after application, the formulation increased viscosity / solidified due to phase change by uptake of aqueous fluid (saliva) and loss of solvent (EtOH). The preparation had excellent bioadhesion to hard surfaces, such as the palate and gums. There, the film remained for several hours despite salivation and mechanical abrasion with the tongue. The period of staying on soft surfaces of mucous membranes was much shorter (minutes).
300 μΐ oral preparation
Example 18: Liquid oral depot composition.
[0130] In order for the formulation to be suitable for pipetting, the solidification / viscosity of the formulation must be delayed relative to the spraying of the formulation. This allows, after application, to conveniently spread the preparation with the tongue on a thin layer in the mouth.
[0131] To the preparation prepared as in Example 1, propylene glycol (PG) and EtOH were added, to obtain the final composition PC / GDO / EtOH / PG (24/56/10/10) it was conveniently pipetted and spread with a tongue over a thin film in the mouth. After about 20 seconds, the viscosity of the preparation began to increase because it was phase changed by uptake of aqueous fluid (saliva) and loss of solvent (EtOH and PG). After about one minute, solidification / viscosity appeared to be complete. The preparation had excellent bioadhesion to hard surfaces, such as the 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 19 - Bioadhesive nail depot [0132] The mixture of example 29 was sprayed onto the nail bed and areas between the toes of the legs. The product solidifies / increases viscosity slowly by the uptake of aqueous fluids (e.g. sweat). Solidification can be accelerated by adding water after applying the spray. The preparation had excellent bioadhesive properties and had a shelf life of several hours.
Example 20: Maximum content of benzydamine as a biologically active agent in precursor preparations.
[0133] Formulations as shown in Table 5 were prepared using the method of Example 1. An excess amount of benzydamine (50 mg) was added to 0.5 g of the formulations. The vials were placed on a shaker for three days at 15 ° C, after which the solutions were filtered through a filter (0.45 pm) to get rid of crystals of undissolved benzydamine. The concentration of benzydamine in each formulation was determined by reversed-phase gradient HPLC and UV detection at 306 nm, and the results are shown in Table 5.
Table 5
<td>Composition GDO / PC (Lipoid S100) / EtOH</td><td>Benzydamine concentration in preparation</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 21: Compositions containing PC and tocopherol [0134] Depot precursor preparations were prepared with several different PC / α-tocopherol compositions using the method of Example 1 (first PC was dissolved in the appropriate amount of EtOH, then α-tocopherol was added to obtain clear, homogeneous solutions).
[0135] Each formulation was injected into the vial and equilibrated with excess water. Phase behavior was assessed visually and between crossed polarizers at 25 ° C. The results are shown in Table 6.
Table 6
<td>α-tocopherol</td><td>PC</td><td>Ethanol</td><td>Phase in excess H<sub>2</sub>ABOUT</td>
<td>2.25g</td><td>2.25g</td><td>0.5g</td><td>hii</td>
<td>2.7 g</td><td>1, 8g</td><td>0.5g</td><td>Hii / I2</td>
<td>3, 15g</td><td>1,35g</td><td>0.5g</td><td>l2</td>
<td>3, 6g</td><td>0, 9g</td><td>0.5g</td><td>I2 / L2</td>
Example 22: In vitro release of a water-soluble fluorescein disodium salt [0136] A water-soluble dye, fluorescein disodium salt (Fluo), was dissolved in a formulation containing
PC / a-tocopherol / ethanol (27/63/10% by weight) up to a concentration of 5 mg Fluo / g of preparation. After injecting 0.1 g of the formulation into 2 ml of phosphate buffered saline (PBS), an inverted micellar phase (I2) was formed. 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. [0137] The release of Fluo from the PC ^ -tocopherol formulation (see Table 7) indicates that this formulation (and the like) are the expected depot systems. In addition, it is worth noting the lack of burst effect, and the release indicates that the substance can be released for several weeks to months, because after 3 days only about 0.4% Fluo is released.
Table 7
<td rowspan="2">Preparation</td><td colspan="2">% release (37 ° C)</td>
<td>24 h</td><td>72 hours</td>
<td>PC / alpha-tocopherol / EtOH: 27/63/10% by weight</td><td> <0,1*</td><td> 0,43</td>
<td>* Release below boundary</td><td colspan="2">absorbance test</td>
Example 23: Formulation with an analgesic / anti-inflammatory agent of benzydamine [0138] Formulations as in Example 1 were prepared by mixing benzydamine with a mixture of GDO, PC, ethanol and optionally PG / AP in the following proportions.
<td>Preparation</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 soy phosphatidylcholine LIPOID S100, GDO means glyceryl dioleate, PG means propylene glycol and AP means ascorbyl palmitate.
[0139] All formulations are low viscosity liquids that form liquid crystal phase compositions when exposed to aqueous conditions.
Example 24: Nasal formulation with fentanyl [0140] Formulations as in Example 1 were prepared by mixing a fentanyl narcotic analgesic with a mixture of GDO, PC, ethanol and optionally PG in the following proportions.
<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 means ethanol, PC means soy phosphatidylcholine LiPOiD S100, GDO means glycerol dioleate and PG means propylene glycol.
[0141] All formulations are liquids of low viscosity suitable for administration as a nasal spray, which on contact with aqueous conditions form liquid crystal phase compositions.
Example 25: Preparation for nasa with diazepam [0142] Formulations were prepared, as in the previous examples, by mixing a benzodiazepine anxiolytic diazepam with a mixture of GDO, PC, ethanol and optionally PG in the following proportions.
<td>Preparation</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 means ethanol, PC means soy phosphatidylcholine LiPOiD S100, GDO means glycerol dioleate and PG means propylene glycol.
[0143] All formulations are low viscosity liquids suitable for administration as a nasal spray which, when contacted with aqueous conditions, form liquid crystal phase compositions.
Example 26: Anti-acne preparations with clindamycin [0144] 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 (weight).
<td>Preparation</td><td>Clindamycin HCl</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> 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>
[0145] Obtained preformulations are liquids of low viscosity, which, when applied, become resistant to water, sweat, etc. The formulations are applied topically to the skin in the form of a gel or by spraying and are bioadhesive, with good film-forming properties.
Example 27: Further examples of viscosity in PC / GDO mixtures with addition of cosolvent [0146] 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 (By weight)</td><td>EtOH / % by weight</td><td>Glycerol/ % by weight</td><td>H2O / % by weight</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*10<sup>6</sup></td>
<td> 20</td><td> 40/60</td><td> -</td><td> -</td><td> 3</td><td> 2,5*10<sup>8</sup></td>
<td> 21</td><td> 40/60</td><td> -</td><td> -</td><td> 5</td><td> 4*10<sup>7</sup></td>
[0148] This example illustrates the need for a solvent with the ability to reduce 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 28: Sunscreen formulations [0149] Formulations as in Example 1 were prepared by mixing each several UV absorbing / dispersing agents with a mixture of GDO, PC, and ethanol in the following proportions (by weight)
<td>Preparation</td><td>PC</td><td>GDO</td><td>EtOH</td><td>Tioveil CM</td><td>Spectraveil FINN</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>
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.
[0150] The precursor preparations have a low viscosity when preparing the formulation and are easily sprayable with a pump. Upon contact with body surfaces, an elastic UV protection layer is created.
Example 29: Depot compositions with chlorhexidine for the periodontium. [0151] Formulations as in Example 1 were prepared by mixing the anti-infective agent chlorhexidine digluconate with a mixture of GDO, PC and ethanol in the following proportions (by weight)
Table. Depot formulation with chlorhedexin digluconate
<td>Preparation</td><td>digluconate chlorhedeksyny</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>
[0152] Chlorhexidine depot pre-formulations have low viscosity and are easily administered to the periodontal pocket. Compared with products such as Periochip®, the compositions provide better distribution and distribution of the active substance throughout the periodontal pocket.
[0153] 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.
[0154] The release of chlorhexidine digluconate from 250 mg of preparation A (see above) in 0.9% aqueous NaCl solution (500 ml) was studied. The USP release measurement formulation was held in a cylindrical metal cup that was placed in a Teflon handle at the bottom of a standard USP bath. Contact area between the preparation and the surrounding brine solution<sub>2</sub> was 2.4 cm and the solution was mixed with a spatula at 100 rpm.
[0155] The release curve shown in Figure 3 shows the sustained and substantially uniform release of chlorhexidine from the formulation over a 24 hour period.
Example 30: Local action preparation with NSAID [0156] Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID). It belongs to the group of phenylacetic acid and is used in inflammation of various etiologies, degenerative joint diseases and many other pain-related diseases.
[0157] A topical formulation containing diclofenac sodium was prepared by previously preparing a placebo formulation.
Composition of the placebo preparation [0158
<td>excipient</td><td>Shortcut</td><td>Concentration (%)</td>
<td>phosphatidylcholine (from soybeans)</td><td>SPC</td><td> 45,0</td>
<td>Glycerol dioleate</td><td>GDO</td><td> 45, 0</td>
<td>Ethanol 99.5%</td><td>EtOH</td><td> 10, 0</td>
[0159] Diclofenac sodium 5% was dissolved in the placebo formulation. The oily liquid obtained was slightly yellowish, transparent and had a low viscosity.
Example 31. Liquid crystal phase formation [0160] One drop of the diclofenac sodium formulation of Example 30 was added via pipette to 3 mL of aqueous sodium chloride solution. A uniform liquid crystalline phase formed.
Example 32. Creating a rigid layer in situ [0161] One drop of the diclofenac sodium formulation of Example 30 was applied to the skin of a healthy volunteer arm and spread on a thin film covering an area of about 2-4 cm<sup>2</sup>. Immediately after application, the liquid preparation transformed into a much stiffer layer by capturing small amounts of water from the skin and / or air.
Example 33. Improving the spray pattern by reducing the viscosity [0162] A placebo formulation with the composition given in the table in Example 30 was filled into a standard spray pump bottle. After preparing the pump with the preparation, the preparation could be applied to the skin with a sub-optimal, standard spray.
[0163] In addition, by diluting the EtOH formulation, the viscosity of the formulation decreased, and at an EtOH concentration corresponding to about 25%, the formulation was suitable for application to the skin in the form of a mist. As a result of spraying on the arm skin
<td>healthy</td><td>volunteer</td><td>established</td><td>stiff</td><td>film</td><td colspan="2">after evaporation</td>
<td>EtOH and</td><td>uptake</td><td>small</td><td>amounts</td><td>water from</td><td>skin</td><td>and / or</td>
<td colspan="2">from the air.</td><td></td><td></td><td></td><td></td><td></td>
<td>Example</td><td colspan="2">34. Correction</td><td>design</td><td>spray</td><td>by</td><td>use</td>
compressors [0164] A placebo formulation with the composition given in the table in Example 30 was filled into a standard compressor with a spray pump. A good mist / aerosol and reference spray were obtained from this device. As a result of spraying the skin of the arm of a healthy volunteer, a rigid film formed after evaporation of EtOH and uptake of small amounts of water from the skin and / or air.
Example 35. Use of a pressure device [0165] A placebo formulation with the composition given in the table in Example 30 was filled with a pressure spray device, driven either with either a hydrocarbon carrier gas or HFC-134a as carrier gas, respectively. It turned out that both carrier gases form homogeneous, low viscosity mixtures with the preparation. As a result of spraying the skin of the arm of a healthy volunteer, a rigid film formed after evaporation of EtOH and uptake of small amounts of water from the skin and / or air.
Example 36. Aerosol formulation with very low EtOH concentration [0166] A formulation was prepared having the composition given in the following table by evaporating EtOH from the placebo formulation having the composition given in the table in Example 30 using a rotary evaporator (vacuum, 40 ° C). The resulting preparation was highly viscous, but after mixing with the carrier gas (hydrocarbon carrier gas or HFC-134a) and filling the spray bottle, the preparation was suitable for spraying the skin of the arm of a healthy volunteer where a rigid film was formed after evaporation of EtOH and uptake of small amounts of water from the skin and / or from the air.
Composition of a placebo preparation [0167]
<td>excipient</td><td>Shortcut</td><td>Concentration (%)</td>
<td>Phosphatidylcholine (from soybeans)</td><td>SPC</td><td> 49, 0</td>
<td>Glycerol dioleate</td><td>GDO</td><td> 49, 0</td>
<td>Ethanol 99.5%</td><td>EtOH</td><td> 2,0</td>
Example 37. Selecting different surfaces as targets by changing the formulation composition [0168] By changing the PC / GDO ratio in the formulation, the duration of the formulation can be adjusted at different locations in the mouth. The formulation PC / GDO / EtOH (36/54/10) particularly preferably adheres to hard surfaces such as teeth, whereas the formulation PC / GDO / EtOH (27/63/10) was more suitable for the upper palate.
Example 38. Formation of a liquid crystal phase from precursors using mixtures of different solvents [0169] To improve the solubility of the active substance in the precursors, it may be useful to change the solvent in the formulation. In the precursor formulations (see table), a variety of different solvent mixtures were used and their ability to form a liquid crystal phase when contacted with excess aqueous solution was traced. One drop of each preparation was added by pipette to 3 ml of aqueous sodium chloride solution. Regardless of the solvent (mixture) used, a uniform liquid crystalline phase was formed.
Composition of preparations [0170]
<td>excipients</td><td>Composition (% by weight)</td>
<td>PC / GDO / EtOH</td><td> 45/45/10</td>
<td>PC / GDO / EtOH / NMP</td><td> 45/45/5/5</td>
<td>PC / GDO / EtOH / propylene carbonate</td><td> 45/45/5/5</td>
<td>PC / GDO / EtOH / dimethyl isosorbide</td><td> 45/45/5/5</td>
<td>PC / GDO / EtOH / dimethylacetamide</td><td> 45/45/5/5</td>
<td>PC / GDO / EtOH / ethyl acetate</td><td> 45/45/5/5</td>
Example 39 - topical formulation with testosterone enanthate [0171] A topical formulation containing 2% testosterone enanthate was prepared by mixing the ingredients in the following table. Shortly after applying the liquid preparation to the skin, it transformed into a much stiffer layer by the uptake of small amounts of water from the skin and / or air.
Composition of a topical preparation with testosterone enanthate [0172]
<td>Ingredient</td><td>Quantity (g)</td><td>Composition (% by weight)</td>
<td>Testosterone Enanthate</td><td> 0, 060</td><td> 2,00</td>
<td>Soy phosphatidylcholine</td><td> 1,323</td><td> 44, 10</td>
<td>Glycerol dioleate</td><td> 1,323</td><td> 44, 10</td>
<td>Ethanol</td><td> 0,294</td><td> 9, 80</td>
Description of the figures:
[0173]
Fig. 1. Cumulative release of MB from the reverse hexagonal HII phase depot.
Fig. 2. Depot viscosity decrease after addition of solvents. PC / GDO (6/4) is a precursor to the reversed hexagonal HII phase, and PC / GDO (3/7) is a precursor to the inverted cubic phase I2.
Figure 3: Release of chlorhexidine from formulation A, see example 33.
20311 / EP / 10
EP 1 848 403 B1
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| ES2400034T3 | Spain | T3 | |
| PL1888031T3 | Poland | T3 | |
| JP5198261B2 | Japan | B2 | |
| PL2206495T3 | Poland | T3 | |
| US2013190341A1 | United States of America | A1 |
Numbers
- Application
- 5818337
Titles2
- English
- TOPICAL BIOADHESIVE FORMULATIONS
- Polish
- Preparaty bioadhezyjne o działaniu miejscowym
Classification
- CPC, 18
- A61K9/0014
- A61K9/0043
- A61K9/006
- A61K9/0063
- A61K9/12
- A61K9/1274
- A61K9/7015
- A61K45/06
- A61P1/02
- A61P1/04
- A61P13/08
- A61P15/00
- A61P15/08
- A61P17/00
- A61P25/28
- A61P27/02
- A61P35/00
- A61P5/28
- IPC, 3
- A61K9 10
- A61K9 06
- A61K9 12