Delivery pharmaceutical compositions including permeation enhancers

Abstract

To provide a pharmaceutical composition that enables the delivery of drugs or pharmaceuticals using films transdermally or transmucosally, where the drugs or pharmaceuticals can permeate or otherwise cross a biological membrane in an effective and efficient manner.SOLUTION: A pharmaceutical composition comprises: a polymeric matrix; a pharmaceutically active component including a peptide in the polymeric matrix; and a permeation enhancer including a surfactant.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] (Priority Claim) This application claims priority to U.S. Provisional Patent Application No. 62 / 563,534, filed September 26, 2017. and is incorporated by reference in its entirety.

[0002] (Technical field) The present invention relates to a pharmaceutical composition. [Background technology]

[0003] (Technical field) The present invention relates to a pharmaceutical composition.

[0004] (background) The active ingredient, such as a drug or medicine, is delivered to the patient in a planned manner. Transdermal or transmucosal delivery of a drug or medicament is effective and efficient. The modality may require penetrating or otherwise crossing a biological membrane. Summary of the Invention

[0005] (overview) Generally, the pharmaceutical composition comprises a polymer matrix, a peptide in the polymer matrix, and a permeation enhancer comprising a surfactant.

[0006] In another embodiment, the active pharmaceutical ingredient can be octreotide.

[0007] In one embodiment, the surfactant is a cationic surfactant, the structure of which is , which is [ka] (In the formula: A is either nitrogen or phosphorus; C is a scissionable bond; B is a group connecting A to C and is an alkylene, alkenylene, cycloalkylene, or aralkylene groups, and derivatives thereof optionally containing one or more heteroatoms. can be done; R 1 , R 2 , and R 3 each independently represents hydrogen, optionally having one or more heteroatoms; From the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, and aralkyl groups; Selected; R 4 is an alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkyl group, optionally having one or more heteroatoms. is selected from the group consisting of aryl, arylalkyl, and aralkyl groups; D- is A + (Anionic counterion to

[0008] In one embodiment, R 1 , R 2 , and R 3 Each of the is independently, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Ara It may be an alkyl group or a derivative thereof optionally having one or more heteroatoms. .

[0009] In some embodiments, B is C 1-20 Alkylene, C 2-20 Alkenylene, C 2-20 Alkina N, C 3-20 Cycloalkylene, C 4-20 Aralkylene group, or one or more heteroatoms optionally It may be a derivative thereof having the above structure.

[0010] In one embodiment, R 4 is C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-30 Cycloalkyl, C 4-30 Aralkyl groups, or those optionally containing one or more heteroatoms The derivatives may be:

[0011] In certain embodiments, C is converted to acetylated ... C can be a degradable group, for example, but not limited to, carbonate. amide bond, ester bond, acetal bond, hemiacetal bond, ortho-ester bond Ternyl bonds, carbamides, sulfonates, phosphonates, thioesters, ureas, isocyanates ester bond, hydrozone, disulfide bond, and combinations thereof. It is possible.

[0012] In some embodiments, D- is a chloride ion, a bromide ion, an iodide ion, an sulfate ion, or a phosphate ion. The cation may be an ion, a sulfonate ion, a carbonate ion, or a hydroxide ion.

[0013] In one embodiment, the surfactant has multiple amino groups as substituents, e.g., The amino acid sequence may include one, three, four or more amino groups.

[0014] In one embodiment, the surfactant comprises dodecyltrimethylammonium bromide. It is possible to do so.

[0015] The cationic surfactant is hexadecyltrimethylammonium bromide (HDTMAB or CTAB).

[0016] The cationic surfactant can include benzalkonium chloride (BAC).

[0017] In certain embodiments, the permeation enhancer, such as a cationic surfactant, Or, it can be combined with an anionic surfactant.

[0018] In another embodiment, the cationic surfactant may be combined with a chelating agent. In yet another embodiment, the surfactant is in combination with a cyclodextrin. It is possible to combine them.

[0019] In another embodiment, the surfactant may be combined with a fatty acid.

[0020] In certain embodiments, the permeation enhancer may be biodegradable.

[0021] In another embodiment, the permeation enhancer is a glycine betaine derivative. can be done.

[0022] In some instances, the octreotide is delivered from the pharmaceutical composition film.

[0023] For example, the octreotide is delivered from a pharmaceutical film having an occlusive layer and an active layer. The octreotide and permeation enhancer can be used to enhance the activity of the pharmaceutical composition film. It may be embedded in a layer.

[0024] In one embodiment, the permeation activity of (dodecyltrimethylammonium bromide) DDTMAB is concentration dependent as shown in an ex vivo permeation model. The permeation enhancer can be 1% by weight DDTMAB, 0. It may also be 5% by weight or 0.1% by weight DDTMAB.

[0025] In one embodiment, the permeation enhancer is 10% by weight glycine betaine ester (C12 The permeation enhancer may be 5% by weight glycine betaine, 0.5% by weight glycine betaine, It can also be lysine betaine, or 0.15% by weight glycine betaine ester.

[0026] In one embodiment, the polymer matrix comprises polyethylene oxide. can be done.

[0027] In one embodiment, the polymer matrix comprises a polymer selected from the following group: hydroxypropyl methacrylate; cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, Hydroxypropyl cellulose, and carboxymethyl cellulose and carboxymethyl The cellulosic polymer may be selected from sodium cellulose.

[0028] In one embodiment, the polymer matrix is ​​hydroxypropylmethylcellulose. The device may include a base.

[0029] In one embodiment, the polymer matrix is ​​made of polyethylene oxide and hydrochloride. It may contain xypropyl methylcellulose.

[0030] In one embodiment, the polymer matrix is ​​made of polyethylene oxide and polyvinyl chloride. It may contain diphenylpyrrolidone.

[0031] In one embodiment, the polymer matrix is ​​made of polyethylene oxide and polysilicon. It may contain chlorides.

[0032] In one embodiment, the polymer matrix is ​​polyethylene oxide, hydroxy The binder may include dimethyl cellulose, and polysaccharides.

[0033] In one embodiment, the polymer matrix is ​​polyethylene oxide, hydroxy It may include dimethyl methylcellulose, polysaccharides, and polyvinylpyrrolidone.

[0034] In one embodiment, the polymer matrix is ​​selected from the group consisting of pullulan, polyvinyl chloride, and the like. Pyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, Xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, polyaca Acrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, zeolite Latin, ethylene oxide-propylene oxide copolymer, collagen, albumin, The polymer is selected from polyamino acids, polyphosphazenes, polysaccharides, chitin, chitosan, and derivatives thereof. The polymer may include at least one polymer selected from the group consisting of fluoropolymers, ...

[0035] The polymer matrix may include a dendritic polymer. The material may include a hyperbranched polymer.

[0036] The method of making the pharmaceutical composition includes adding a permeation enhancer comprising a surfactant to octreotide. and mixing the pharma- ceutical active ingredient containing octreotide with a pharmaceutical active ingredient containing octreotide. This can include embedding in a film.

[0037] Generally, a pharmaceutical composition can be dispensed from a device. The device contains a quantity of the pharmaceutical composition. a housing for holding an object, the pharmaceutical composition comprising a polymer matrix, the polymer matrix A pharmaceutical active ingredient including octreotide in a cyclodextrin, and a permeation enhancer including a surfactant and an opening for dispensing a predetermined amount of the pharmaceutical composition. This can be done.

[0038] In certain embodiments, the pharmaceutical composition may include a stabilizer.

[0039] In yet another embodiment, the pharmaceutical composition comprises a hydrophilic saccharide bond linked to the hydrophilic saccharide. Suitable non-toxic, non-ionic alkyl glycosides having hydrophobic alkyl groups are selected from the group consisting of: (a) agglomeration (b) charge modifiers; (c) pH regulators; (d) degradative enzyme inhibitors; (e) mucolytic or mucus-clearing agents; (f) ciliostatic agents; (g) the following: (i) detergents; (ii) bile salts; (ii) phosphates (iii) an alcohol; (iv) an enamine; (v (vi) nitric oxide donating compounds; (vii) long chain amphiphilic molecules; (vii) small molecule hydrophobic penetration enhancers; (vi (ii) sodium or salicylic acid derivatives; (ix) glycerol esters of acetoacetic acid; (x) cyclo (xi) a dextrin or β-cyclodextrin derivative; (xi) a medium chain fatty acid; (xii) a chelating agent; (xi (ii) an amino acid or a salt thereof; (xiv) an N-acetylamino acid or a salt thereof; (xv) a compound that binds to a selected membrane component; (ix) inhibitors of fatty acid synthesis; (x) inhibitors of cholesterol synthesis; and (xi) (h) a membrane permeation enhancer selected from any combination of the membrane permeation enhancers described in (i) to (x); (i) vasodilators; (j) selective transport enhancers; and (k) stabilizers for transport. a delivery vehicle, carrier, mucoadhesive, support, or complex-forming species, The compound is effectively combined, associated, contained, encapsulated, or bound to enhance The stabilizing delivery vehicle, carrier, mucosal composition and method of the present invention provide stabilization of compounds for improved mucosal delivery. In combination with a mucosal delivery-enhancing agent selected from a membrane-adherent material, a support, or a complex-forming species. wherein a formulation of the compound containing a mucosal delivery enhancer reduces the amount of the compound in the plasma of a subject. This provides increased bioavailability of the

[0040] In one embodiment, the pharmaceutical composition comprises a polymer matrix; and causing increased blood flow or allowing tissue flushing. The composition may contain an interactive substance that alters the transmucosal uptake of the medicament active ingredient.

[0041] In one embodiment, the pharmaceutical composition comprises a polymer matrix; and a pharmaceutical active ingredient having a positive or negative heat of solution and altering (increasing or decreasing) transmucosal uptake. The present invention may include an interactive substance used as an aid in the

[0042] In another embodiment, the pharmaceutical composition comprises a polymer matrix, and an interacting agent, the composition comprising at least one of said pharmaceutical active ingredients having a common border. The composition is contained in a multilayer film having at least one surface.

[0043] Generally, the method of treating a medical condition includes providing a polymer matrix, and a permeation enhancer comprising a surfactant. The method can include administering a pharmaceutical composition comprising: It can block the release of growth hormone from the body. This is because growth hormone-producing tumors ( thyroid-stimulating hormone-secreting pituitary tumors (e.g., thyroid thyrotropinoma, diarrhea and flushing associated with carcinoid syndrome episodes of diarrhea in people with vasoactive intestinal peptide-secreting tumors (VIPomas) It can be used to treat acute bleeding from esophageal varices in cirrhosis of the liver. Other aspects, embodiments, and features are described in the following description, drawings, and the accompanying drawings. These and other objects, features and advantages of the present invention will become apparent from the following detailed description and claims. [Brief description of the drawings]

[0044] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] With reference to FIG. 1, Franz diffusion cell 100 includes donor compound 101, donor chamber 102, membrane 103, sampling port 104, receptor chamber 105, stir bar 106, and heater / circulator 107. [Diagram 2] 2, the pharmaceutical composition is a film 100 that includes a polymer matrix 200, with the pharma- ceutical active 300 dispersed in the polymer matrix. The film can include a permeation enhancer 400, which can be a surfactant. [Diagram 3] Referring to FIG. 3, this graph shows the effect of octreotide concentration on permeation using DDTMAB. [Figure 4] With reference to FIG. 4, this graph shows octreotide permeation according to Fick's first law of diffusion. [Diagram 5]Referring to FIG. 5, this graph shows the structure-activity relationship of aliphatic trimethylammonium bromide surfactants. [Figure 6] With reference to FIG. 6, this graph shows the effect of microneedles on octreotide permeation using porcine buccal tissue. [Figure 7] With reference to FIG. 7, this graph shows results from a pre-clinical study in which octreotide solution was applied to the buccal and sublingual spaces following microneedle application. [Figure 8] With reference to FIG. 8, this image shows a pharmaceutical composition bilayer film containing octreotide as the active pharmaceutical ingredient. [Figure 9] With reference to Figure 9A, the graph shows the concentration-dependent permeation activity of dodecyltrimethylammonium bromide. With reference to Figure 9B, the graph shows the effect of a permeation enhancer (DDTMAB) on the ex vivo permeation of octreotide from bilayer films. [Figure 10] With reference to FIG. 10, this graph shows octreotide plasma concentrations following sublingual or subcutaneous administration. [Figure 11] With reference to Figure 11A, the graph shows the concentration-dependent permeabilization activity of glycine betaine esters. With reference to Figure 11B, the graph shows the effect of alkyl chains on the permeabilization activity of glycine betaine esters. [Figure 12] Referring to FIG. 12, this graph shows a comparison of the permeabilization activity of glycine betaine ester C12 with DDTMAB. [Figure 13] Referring to FIG. 13, this graph shows the effect of cetyl pyridium chloride tetrahexylammonium bromide on octreotide permeation in an ex vivo permeation model. [Figure 14] Referring to FIG. 14, this graph shows the effect of tetrahexylammonium bromide on octreotide permeation in an ex vivo permeation model. [Figure 15]With reference to FIG. 15, this graph shows the effect of benzalkonium chloride concentration on octreotide permeation in an ex vivo permeation model with benzalkonium chloride as the permeation enhancer. [Figure 16] With reference to FIG. 16, this graph shows the octreotide plasma concentration (ng / ml) versus time profile following sublingual or intravenous (IV) administration to male minipigs. [Figure 17] With reference to FIG. 17, this graph shows arm #1 of the human study with 10 mg octreotide / 25 mg BAC. [Figure 18] With reference to Figures 18A-C, these graphs show the results of degradation studies of GBE-C12 in gastric fluid, intestinal fluid, and tissue extracts, respectively. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] (Detailed Description) Mucosal surfaces, such as the oral mucosa, are highly vascularized and permeable, allowing the passage of blood through the digestive system. Increased bioavailability because it does not require first-pass metabolism. Mucosal surfaces are an important hub for drug delivery to the body due to the fact that they provide a rapid onset of action and a high level of potency. In particular, the buccal and sublingual tissues are convenient routes for the administration of This is the area that allows diffusion of drugs from the oral mucosa so that they have direct access to the systemic circulation. These tissues provide advantageous sites for drug delivery because they allow It provides increased convenience and therefore enhances patient compliance. For active pharmaceutical ingredients, permeation enhancers help overcome mucosal barriers and improve permeability. Permeation enhancers can aid in the permeability of the barrier layer in favor of drug absorption. Permeability enhancers promote the transport of molecules across epithelia. The files and their speeds may vary depending on, but are not limited to, film size, drug loading, enhancer Various parameters such as type / loading, polymer matrix release rate and mucosal residence time can be controlled and regulated by

[0046] Pharmaceutical compositions are designed to deliver a pharmacologic active ingredient in a planned and tailored manner. However, the in vivo dissolution of the medicament active ingredient, particularly in the mouth of a subject, The solution and permeability can vary considerably. Certain classes of permeation enhancers enhance the In particular, the in vivo uptake and bioavailability of the filtrate can be improved. When delivered to the mouth via a mucosa, the penetration enhancer acts to facilitate the passage of the drug through the mucosa and into the bloodstream of the subject. The permeability of the active ingredient can be improved. The permeation enhancer can enhance the absorption of the medicament active ingredient. The rate and amount can be adjusted to 10%, 20%, 30%, 40%, 50%, 60%, 70%, depending on the other ingredients in the composition. %, 80%, 90%, 100%, 150%, 200% or more improvement.

[0047] In some embodiments, the pharmaceutical composition comprises a hydrophobic saccharide linked by a bond to a hydrophilic saccharide. Suitable non-toxic, non-ionic alkyl glycosides having hydrophilic alkyl groups are selected from the group consisting of: (a) anti-aggregation agents; (b) charge modifiers; (c) pH regulators; (d) degradative enzyme inhibitors; (e) mucolytic or mucus-clearing agents; (f) (g) agents that inhibit ciliary motility; (i) detergents; (ii) bile salts; (ii) phospholipid additives, mixed micelles, (iii) an alcohol; (iv) an enamine; (v) an NO donor compound; (vi) a long (vii) a small molecule hydrophobic permeation enhancer; (viii) sodium or salicylic acid (ix) glycerol ester of acetoacetic acid; (x) cyclodextrin or β-cyclodextrin derivatives (xi) a kistrin derivative; (xii) a chelating agent; (xiii) an amino acid or a salt thereof; (xiv) (xv) an enzyme capable of degrading selected membrane components; (ix) a fatty acid (x) an inhibitor of cholesterol synthesis; and (xi) a membrane permeation promoter according to any one of (i) to (x). (h) a membrane permeability enhancer selected from any combination of the following: (i) vasodilators; (j) selective transport enhancers; and (k) stabilizing delivery vehicles, carriers, mucoadhesives. a reactive material, support, or complex-forming species with which the compound is effectively combined; and / or by attachment to, association with, inclusion within, encapsulation or binding to, a compound for enhanced transmucosal delivery. The stabilizing delivery vehicle, carrier, mucoadhesive, support, or in combination with a mucosal delivery enhancing agent selected from a complex-forming species, Formulations of the compound with enhancers provide increased bioavailability of the compound in the plasma of a subject. do.

[0048] "Alkyl" means a straight or branched, acyclic or cyclic, unsaturated alkyl group having 1 to 24 carbon atoms. It means a saturated aliphatic hydrocarbon. Representative saturated linear alkyl groups are methyl, ethyl, n- Propyl, n-butyl, n-pentyl, n-hexyl, etc.; saturated branched alkyl Examples include isopropyl, sec-butyl, isobutyl, tert-butyl, and isopentyl. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, unsaturated cyclic alkyl includes cyclopentenyl and and cyclohexenyl. Charged lipids containing unsaturated alkyl chains have been shown to increase membrane It has been found to be particularly useful in forming fluid lipid-nucleic acid particles. See U.S. Patent Publication No. 2013 / 0338210, which is incorporated herein by reference. .

[0049] (Permeation Enhancer) Penetrance enhancers are described in J. Nicolazzo et al., J. of Controlled Disease, 105 (2005) 1-15, which is incorporated herein by reference. There are many reasons why the nasal cavity is an attractive site for the delivery of therapeutic agents to the systemic circulation. Avoiding first-pass metabolism in the liver and intestine due to direct drainage of blood into the venous system The first-pass effect is the poor bioavailability of some compounds when administered orally. In addition, the mucous membrane lining the oral cavity is easily accessible, which may be the main reason for this. This means that the dosage form can be applied to the area where it is needed and easily removed in case of emergency. However, like the skin, the buccal mucosa acts as a barrier to the absorption of xenobiotics. This can impede the penetration of the compound beyond this tissue. In addition, the identification of safe and effective permeation enhancers is an important step in the quest to improve oral mucosal drug delivery. It is a big goal.

[0050] Chemical permeation enhancers are substances that control the permeation rate of co-administered drugs across biological membranes. Extensive studies have demonstrated how permeation enhancers alter intestinal and transdermal permeability. The current focus is on gaining a better understanding of how buccal penetration enhancement can be achieved. Little is known about the mechanism.

[0051] The buccal mucosa outlines the inner lining of the cheeks and the area between the gums and the upper and lower lips. This is 100cm 2 The surface of the buccal mucosa is covered by a wavy basement membrane (approximately 1-2A thick). It is separated from the underlying connective tissue (lamina propria and submucosa) by a continuous layer of extracellular material (m It is composed of stratified squamous epithelium. This stratified squamous epithelium is divided into a basal region and a superficial region where cells are shed. It consists of differentiated layers of cells that change in size, shape, and content as they move. It contains approximately 40-50 cell layers, giving rise to a buccal mucosa 500-600 μm thick.

[0052] The permeability of the buccal mucosa is greater than that of the skin, but less than that of the intestine. The differences are the result of structural differences between the tissues. The absence of lamellae results in greater permeability to foreign compounds compared to the keratinized epithelium of the skin. On the other hand, the increased thickness and lack of tight junctions may make the buccal mucosa less permeable than intestinal tissue. Brings about becoming.

[0053] The primary barrier properties of the buccal mucosa are attributed to the upper one-third to one-quarter of the buccal epithelium. showed that the permeability barrier of the non-keratinized oral mucosa beyond the surface epithelium is formed from membrane-coated granules. It is known that this is due to contents extruded into the intercellular spaces of epithelial cells.

[0054] The intercellular lipids of the non-keratinized areas of the oral cavity are more abundant than those of the epidermis, palate, and gingiva. It is more polar in nature, and differences in the chemical properties of this lipid are observed between these tissues. This contributes to the difference in permeability that occurs between the keratinized layer, which creates a more effective barrier. Not only is there a greater degree of intercellular lipid packing in the stratum corneum of the modified epithelium, but the barrier It is clear that the chemistry of the lipids present within the cells is also a factor.

[0055] The presence of hydrophilic and lipophilic regions in the oral mucosa has allowed researchers to determine the transport of two types of fluid through the buccal mucosa. The existence of drug transport pathways - paracellular (between cells) and transcellular (across the cells) - has been postulated.

[0056] Drug delivery across the buccal mucosa is limited by the barrier properties of the epithelium and the area available for absorption. Therefore, various enhancement strategies are required to deliver therapeutically relevant amounts of drugs to the systemic circulation. Various methods, including the use of chemical penetration enhancers, prodrugs, and physical methods, have been proposed. Methods can be utilized to overcome the barrier properties of the buccal mucosa.

[0057] Chemical permeation enhancers, or absorption promoters, enhance the membrane permeation or absorption of co-administered drugs. is a substance added to pharmaceutical preparations to increase the rate of absorption. The chemical penetration enhancers can be applied to the skin, nose, and / or skin without causing toxicity. There has been a great deal of research investigating the effects on mucosa and the delivery of compounds across the intestine. Recently, more attention has been paid to the effect of these substances on the permeability of the buccal mucosa. Permeability across the lateral mucosa is considered to be a passive diffusion process, so the steady-state flux The donor chamber concentration (CD) increases with increasing donor chamber concentration (Jss) according to Fick's first law of diffusion. It should increase.

[0058] Surfactants and bile salts have been shown to inhibit the release of various compounds both in vitro and in vivo. The data from these studies have shown that it enhances permeability across the buccal mucosa. The authors found that the increased permeability was due to the action of surfactants on the intercellular lipids of the mucosa. Surfactants typically act by disrupting the intercellular lipid and protein domains. Surfactants function by disrupting the ions in the blood. They can be cationic, nonionic, or anionic. Examples of cationic surfactants include DDTMA, CTAB, and BAC. Examples of anionic surfactants include sodium glycodeoxycholate (GDC). and sodium deoxycholate (DOC). Examples of non-ionic surfactants are Poloxamer F127, Azone / Dimethylcyclodextrin (DMCD), Peseol, Love These include RAZOLU, and TDM.

[0059] Fatty acids have been shown to enhance the penetration of some drugs through the skin, , which has been shown by DSC and FTIR to be associated with increased fluidity of intercellular lipids. An example of a fatty acid is oleic acid.

[0060] Cyclodextrins also play a role in enhancing permeation by inclusion of complexes and extraction of membrane compounds. Examples of cyclodextrins include dimethyl-cyclodextrin and β-cyclodextrin is an example.

[0061] Chelating agents are also used to enhance permeation by interfering with Ca2+ calcium ions. Examples of chelating agents include EDTA and EGTA.

[0062] In addition, pretreatment with ethanol reduced the uptake of tritiated water and albumin across the ventral tongue mucosa. It has been shown to enhance the permeability of caffeine across the buccal mucosa in pigs. In addition, Azone® has been shown to have an enhancing effect on the permeability of compounds through the oral mucosa. In addition, chitosan, a biocompatible and biodegradable polymer, has been shown to be effective in the intestines and It has been shown to enhance drug delivery across a variety of tissues, including the nasal mucosa.

[0063] Oral transmucosal drug delivery (OTDD) is the delivery of pharmaceutical active substances to the oral mucosa to achieve a systemic effect. The permeation pathway and prediction model of OTDD are described in, for example, M. Sattar's "Oral Administration Oral transmucosal drug delivery - current status and future prospects nt status and future prospects)”, Int'l. Journal of Pharmaceutics, 47(2014) 49 8-506, which is incorporated herein by reference. Compared with the dermal and nasal delivery routes, Despite limited characterization of their permeation pathways within the oral cavity, recent studies have demonstrated that ionized molecules penetrate the buccal epithelium. Researchers' growing understanding of how the human body permeates the oral cavity, as well as new assays to study the oral cavity The advent of technology and the ongoing development of in silico models to predict buccal and sublingual penetration This is encouraging.

[0064] To deliver a broader class of drugs across the buccal mucosa, it is necessary to reduce the barrier capacity of this tissue. A reversible method for reversing the buccal mucosa should be utilized. This requirement is based on the limitation of the buccal mucosa permeability. This has prompted research into penetration enhancers that safely modify the buccal permeation pathway. agents, fatty acids and their derivatives, chelating agents, cyclodextrin and chitosan. This can be improved by using various classes of transmucosal and transdermal penetration enhancers. Chemical agents used to enhance drug permeation include bile salts. This can be done.

[0065] An in vitro study on the enhancing effect of bile salts on the buccal permeation of compounds was carried out by Sevda Sene In the article "Drug permeation enhancement by the buccal route: Possibilities and limitations" via buccal route: possibilities and limitations), Journal of Controlled Releases e 72 (2001) 133-144, which is incorporated herein by reference. The article also includes information on dihydroxybile salts, sodium glycodeoxycholate, and guanidine diphosphate (GDC) and sodium taurodeoxycholate (TDC) and tri-hydroxy bile salts, Sodium glycocholate (GC) and sodium taurocholate (TC) at a concentration of 100 mM Recent studies on the effects of buccal epithelial permeability have also been performed to assess permeability in relation to histological effects. The changes in the fluorescein isothiocyanate (FITC), morphine sulfate, and Each was used as a model compound.

[0066] Chitosan has also been shown to inhibit the activity of small polar molecules and peptides / peptides in animal models and human volunteers. It has been shown to enhance the absorption of protein drugs through the nasal mucosa. Other studies have shown that it is effective against the intestinal mucosa. and show an enhancing effect on the permeation of compounds across cultured Caco-2 cells.

[0067] The permeation enhancer can be a plant extract. The plant extract can be obtained by distillation of the plant material. In some circumstances, the essential oil may be an essential oil extracted by a method such as the use of a sedative or a composition containing an essential oil. In this regard, plant extracts are synthetic analogs (i.e., organic compounds) of compounds extracted from plant material. The plant extract may contain phenylpropanoids. , for example, phenylalanine, eugenol, eugenol acetate, cinnamic acid, cinnamic acid ester cinnamic acid, cinnamaldehyde, hydrocinnamic acid, chavicol, or safrole, or combinations thereof The plant extract may include extracts of the clove plant, such as the leaves, stems, Or it can be an essential oil extract of the flower buds. The clove plant is Syzygium aromaticum The plant extract is Syzygium aromaticum. It contains 60-95% eugenol, e.g. The extract contains 80-95% eugenol. The extract also contains 5-15% ethyl acetate. The extract may also contain caryophyllene. The extract may also contain up to 2.1% α-humulene. Other volatile compounds present in lower concentrations are β-pinene, limonene, and farnesol. , benzaldehyde, 2-heptanone and ethyl hexanoate.

[0068] Additional permeation enhancers may be added to improve the absorption of the drug. Hansar is a natural or synthetic bile salt, such as sodium fusidate; glycocholate or deoxycholic acid; fatty acids and derivatives, e.g. sodium laurate, oleic acid, oleic acid oleyl alcohol, monoolein, and palmitoyl carnitine; chelating agents, e.g. For example, disodium EDTA, disodium EGTA, sodium citrate and sodium lauryl sulfate. sodium, azone, sodium cholate, sodium 5-methoxysalicylate, sorbitan la Urate, Glyceryl Monolaurate, Octoxynonyl-9, Laureth-9, Polysorbate glycerides, such as caprylocaproyl polyoxylglyceride; Examples include Labrasol.

[0069] Some natural products of plant origin have been shown to have vasodilatory properties. There are several mechanisms or ways in which products of this drug can cause vasodilation. For further details, see McNeill JR and Jurgens, T. See, for example, .M., Can. J. Physiol. Pharmacol. 84:803-821 (2006). The vasorelaxant effect of eugenol has been reported in several animal studies. Lahlou, S. et al., J. Cardiovasc. Pharm. acol. 43:250-57 (2004); Damiani, CEN et al., Vascular Pharmacol. 40:59-66 (2 003), Nishijima, H. et al., Japanese J. Pharmacol. 79:327-334 (1998), and Hume et al. See WR, J. Dent Res. 62(9):1013-15 (1983). Calcium Channels Blockade is the primary cause of vasorelaxation induced by plant essential oils, or their main component, eugenol. It has been suggested that. See reference Fundamental & Clin. Pharmacol. 21: 497-506 (2007).

[0070] The fatty acids can be used as inactive ingredients in drug preparations or drug vehicles. Fatty acids are also used in formulations due to certain of their functional effects and their biocompatible properties. Fatty acids, both free and part of complex lipids, are the main It is an essential component of all membranes and gene regulators, providing metabolic fuel (storing and transporting energy). For reviews, see Rustan AC and Drevon, CA, which are incorporated herein by reference. .'s article, "Encyclopedia of Life Sciences, Fatty Acids: Structures and Properties" Perties, Encyclopedia of Life Sciences (2005). There are two families of essential fatty acids: omega-3 and omega-6 polyunsaturated fatty acids (PUFAs). If the first double bond is found between the third and fourth carbon atoms from the ω carbon, then These are called omega-3 fatty acids. The first double bond is between the sixth and seventh carbon atoms. When these fatty acids are combined, they are referred to as omega-6 fatty acids. PUFAs can be further divided into omega-6 fatty acids by the addition of carbon atoms and unsaturation. Linoleic acid, an omega-6 fatty acid, is metabolized in the body by glycation (removal of hydrogen). Linolenic acid, dihomo-γ-linolenic acid, arachidonic acid, adrenic acid, tetracosatetraene It is metabolized to omega-3 fatty acids, tetracosapentaenoic acid, and docosapentaenoic acid. α-Linolenic acid is a component of octadecatetraenoic acid, eicosatetraenoic acid, and eicosapentaenoic acid. EPA, docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and is metabolized to docosahexaenoic acid (DHA).

[0071] Fatty acids such as palmitic acid, oleic acid, linoleic acid, and eicosapentaenoic acid Na + K + -Inhibits relaxation and activation of porcine coronary artery smooth muscle cells through a mechanism involving activation of the APTase pump. and hyperpolarization, and as the degree of cis-unsaturation increased, fatty acids showed higher potency. It has been reported that the . See, S. Iello et al., Hypertension 31:615-20 (1998). The pulmonary vascular response to arachidonic acid, a metabolite of linoleic acid, varied according to dose, animal species, and Depending on the mode of administration of rachidonic acid and the tone of the pulmonary circulation, it may have vasoconstrictive or vasodilatory properties. For example, arachidonic acid can be either cyclooxygenase-dependent or -independent. It has been reported that these drugs cause chronic pulmonary vasodilation. Incorporated reference Feddersen, CO et al., J. Appl. Physiol. 68(5):1799-808 (1999) 0); and Spannhake, EW et al., J. Appl. Physiol. 44:397-495 (1978) and Wicks See, TC et al., Circ. Res. 38:167-71 (1976).

[0072] Many studies have shown that EPA and DHA, when administered in orally available forms, can improve vascular function. Several studies have reported effects of EPA-DHA or EPA alone on forearm microenvironment. In the circulation, it inhibits the vasoconstrictor action of norepinephrine or inhibits the vasodilator action of acetylcholine. Chin, et al., J. Immunol. 1999, 144:1311-1323, each of which is incorporated herein by reference. , JPF et al., Hypertension 21:22-8 (1993), and Tagawa, H. et al., J Cardiov See, e.g., J. Pharmacol 33:633-40 (1999). Another study showed that both EPA and DHA increased the total It tends to increase the compliance of the arterial system of the body and decrease pulse pressure and total vascular resistance. It has been found that Nestel, P. et al., Am. See J. Clin. Nutr. 76:326-30 (2002). On the other hand, studies have shown that EPA, rather than DHA enhances vasodilatory mechanisms in the forearm microcirculation of overweight men with hyperlipidemia; and Mori, et al., J. Med. Soc., 1999, 144:1311-1315, which is incorporated herein by reference, found that the vasopressin-induced contractile response was attenuated by the vasopressin-induced contractile response. See TA et al., Circulation 102:1264-69 (2000). We discovered that DHA has a vasodilatory effect on rhythmic contractions of isolated human coronary arteries in mice. Wu, K.-T. et al., Chinese J. Physiol. 5, incorporated herein by reference. 0(4):164-70 (2007).

[0073] Adrenergic receptors (or adrenoceptors) are receptors that bind catecholamines, especially norepinephrine. G protein, the target of nephrine (noradrenaline) and epinephrine (adrenaline) Epinephrine (adrenaline) is a class of α- and β-adrenergic receptors. The α receptors react with both epithelial and vascular endothelial cells, causing vasoconstriction and vasodilation, respectively. Although less sensitive to nephrin, peripheral α1 receptors are more sensitive than β-adrenoreceptors When activated, they mediate β-adrenoreceptor-mediated vascular As a result, high levels of circulating epinephrine cause vasoconstriction. At relatively low levels of circulating epinephrine, β-adrenoreceptor stimulation dominates, resulting in α1-adrenoreceptors stimulate smooth muscle contraction, resulting in vascular dilation and subsequent reduction in peripheral vascular resistance. vasoconstriction in the skin, mucous membranes, and abdominal viscera, and constriction of the gastrointestinal (GI) tract and bladder It is known that α1-adrenergic receptors are involved in muscle contraction. q Protein-Coupled Receptor Upon activation, it is a member of the heterotrimeric G protein, G q is phospho It activates lipase C (PLC). Its mechanism of action involves interaction with calcium channels. , which alters intracellular calcium content. Smith RS et al., Journal of Neurophysiology 102(2): 1103-14 (200 9) Many cells have these receptors.

[0074] The α1-adrenergic receptor may be the primary receptor for fatty acids. For example, Saw palmetto extract (SPE), which is widely used to treat benign prostatic hyperplasia (BPH), inhibits α1-adrenergic receptors. Phosphamine-, muscarinergic, and 1,4-dihydropyridine (1,4-DHP) calcium channel blockers It has been reported that these compounds bind to receptors that are antagonistic to the agonist agonist receptors. Abe M. et al., Biol. Pharm. Bull. 32(4) 646-650 (2009), and Suz See Uki M. et al., Acta Pharmacologica Sinica 30:271-81 (2009). SPE is Various acids, including lauric acid, oleic acid, myristic acid, palmitic acid, and linoleic acid Lauric and oleic acids are alpha 1-adrenergic and muscarinic. It binds noncompetitively to phospho- and 1,4-DHP calcium channel antagonist receptors. It is possible.

[0075] In one embodiment, the permeability enhancer is an adrenergic receptor blocker. This adrenoceptor blocker is a terpene (e.g., derived from the unit of isoprene). volatile unsaturated hydrocarbons found in plant essential oils, or C10-C22 alcohols or acids In one embodiment, the adrenoceptor blocker is farnesol. linoleic acid, arachidonic acid, docosahexanoic acid, eicosapentaenoic acid, and / or docosahexanoic acid The acid may be carboxylic acid, phosphoric acid, sulfuric acid, hydroxamine, or cosapentanoic acid. The derivative may be an ester or an amide. For example, the adrenergic receptor blocker may be a fatty acid or a fatty alcohol. There can be.

[0076] The C10-C20 alcohol or acid optionally has at least one double bond, at least one triple bond, A straight C10-C22 hydrocarbon chain containing a double bond or at least one double bond and one triple bond The hydrocarbon chain may optionally be an alcohol or acid having a C 1-4 Alkyl, C 2- 4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, hydroxyl, halo, amino, nitro , Cyano, C. 3-5 Cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered Heteroaryl of C 1-4 Alkylcarbonyloxy, C 1-4 Alkyloxycarbonyl, C1 -4 and optionally further substituted by -O-, -N (R a )-, -N(R a )-C(O)-O-, -OC(O)-N(R a )-, -N(R a )-C(O)-N(R b )- or -OC(O)-O- in between It's stuck. R a and R b Each of the is independently hydrogen, alkyl, alkenyl, alkynyl , alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.

[0077] The compositions described herein can include a charged lipid or a mixture of charged lipids. As used herein, the term "charged lipid" refers to a lipid having one or two fatty acyl or fatty aryl groups. The term "quaternary amine" is intended to include lipids having an alkyl chain and a quaternary amino head group. It carries a permanent positive charge. The head group is made up of primary, secondary, or cyclic alkyl groups that can be protonated at physiological pH. or tertiary amines. The presence of a quaternary amine may , the pKa of this ionizable group is determined by the absence of a quaternary amine (e.g., a tertiary amine is not a tertiary amine) (wherein the pKa of the group is replaced by In some embodiments, the charged lipids are referred to as "amino lipids." The composition comprises a lipid having a quaternary amine, and a lipid having a quaternary amine and a quaternary It is possible to include lipids that do not have amines but have protonatable amine groups. The amine-containing lipids can be in the form of a salt and can be prepared from the corresponding lipids containing a tertiary amine. The tertiary amine can be, for example, an alkyl group with a suitable alkyl halide. Alternatively, alkyl-substituted lipids can be converted to quaternary amines by polymerization. The groups are different (e.g., N-ethyl-N-methylamino-, N-propyl-N-ethylamino-, etc.). Examples include those with alternative fatty acid groups and alternative quaternary groups, including R1 and For embodiments in which R2 are both long chain alkyl or acyl groups, they are the same. Generally, lipids with less saturated acyl chains (e.g., The electrolytic lipids are preferably selected so that the complexes are sized to be less than about 0.3 microns for purposes of filter sterilization. Unsaturated fatty acids with carbon chain lengths in the range of C10 to C20 are more easily sized when Other scaffolds are also available that utilize the amino groups ( For example, it can be used to separate the amino groups of charged lipids and the fatty acid or fatty alkyl moieties. It is possible.

[0078] Fatty acids with higher degrees of unsaturation are good candidates for enhancing drug permeation. Fatty acids showed higher enhancement than saturated fatty acids, and the enhancement increased with the number of double bonds. A. Mittal et al., "Status of Fatty Acids as Skin Penetration Enhancers: A Review" ``Atty Acids as Skin Penetration Enhancers - A Review)'', Current Drug Delivery, 2 009, 6, pp. 274-279. The position of the double bond also influences the enhancement of the activity of the fatty acid. The difference in the physicochemical properties of fatty acids due to the difference in the position of the double bond is believed to be a skin penetration enhancer. The location of the double bond most likely determines the potency of these compounds. As the double bond shifts to the even position, the skin distribution increases. The fatty acids with double bonds at several positions are more likely to cause perturbations in the structure of both the stratum corneum and the dermis. It has also been reported that cis-unsaturation in the chain increases activity. There is a tendency for

[0079] The adrenergic receptor interactor can be a terpene. Terpenes in essential oils The antihypertensive activity of has been reported. See, for example, IA et al., Z. Naturforsch. 65c:652-66 (2010). In the present invention, the penetration enhancer can be a sesquiterpene. The sesquiterpene is It consists of three isoprene units and has the empirical formula C 15 H 24 It is a class of terpenes having the formula: Like monoterpenes, sesquiterpenes may be acyclic or have many unique structures. Biochemical modifications such as oxidation or rearrangement may result in the formation of related rings. Produces sesquiterpenoids.

[0080] Adrenergic receptor interactors can be unsaturated fatty acids, such as linoleic acid. Cut.

[0081] In certain embodiments, the penetration enhancer can be farnesol. Farnesol is a 15-carbon organic compound that is an acyclic sesquiterpene alcohol. This is the naturally occurring dephosphorylated form of farnesyl pyrophosphate. Under standard conditions, It is a colorless liquid. It is hydrophobic and therefore insoluble in water, but is compatible with oils. Farnesol is a stimulant of citronella, neroli, cyclamen, and moonflower. It can be extracted from the oils of plants such as cereals, dairy products, and dairy products. This is due to the fact that mevalonic acid is produced in vertebrates. It is an intermediate step in the biosynthesis of cholesterol in the blood. It has a delicate floral or weak citrus-like aroma. It has a sweet odor and is used by performers. Selectively kills acute myeloid leukemia blasts and leukemia cell lines in preference to primary hematopoietic cells. It has been reported that the above-mentioned method can be used to treat pulmonary circulation disorders. See FEBS Lett 467 (2-3): 291-5 (2000). The tube working characteristics have been reported. Roullet, J. See, .-B. et al., J. Clin. Invest., 1996, 97:2384-2390. and N-acetyl-S-trans,trans-farnesyl-L-cysteine ​​(AFC), farnesyl Both synthetic mimics of the carboxyl terminus of the substituted proteins were expressed in rat aortic rings. Inhibited vasoconstriction.

[0082] In some embodiments, the interacting agent can be an aporphine alkaloid. For example, the interactor can be dicentrin.

[0083] In general, the interactive agent may also be a vasodilator or a therapeutic vasodilator. A vasodilator is a drug that opens or widens blood vessels. Vasodilators are commonly used to treat hypertension, heart failure, and angina pectoris, but is also used to treat other conditions including glaucoma. Some vasodilators (arteriodilators) that act primarily on resistance vessels can be used to Used for hypertension, heart failure, and angina; however, reflex cardiac stimulation may be involved. Arterial dilators are not suitable for angina pectoris. Venodilators are very effective for angina pectoris and sometimes Vasodilators are used in the treatment of heart failure, but not as primary therapy for hypertension. It is a mixed (or balanced) vasodilator in that it dilates both the blood vessels and veins. It can therefore be widely applied in hypertension, heart failure, and angina pectoris. Tonicity agents, due to their mechanism of action, in some cases enhance their therapeutic utility. Another important feature that may be of use is the ability to For example, some calcium channel blockers not only dilate blood vessels, but also impair the mechanical and electrical function of the heart, thereby reducing their antihypertensive properties. It can enhance the blood pressure effect and provide additional therapeutic benefits such as blocking arrhythmias. It can be granted.

[0084] Vasodilators are classified based on their site of action (arterial vs. venous) or by mechanism of action. They can be classified into three types: mainly drugs that dilate resistance blood vessels (arteriodilators; e.g., hydralazine, There are also drugs that affect venous capacitance (venodilators; e.g., nitroglycerin) and drugs that affect venous volume (venous dilators; e.g., nitroglycerin). Many vasodilators, such as phentolamine, are mixed arterial and venous dilatators. (mixed dilators; e.g., α-adrenergic receptor antagonists, angiotensin receptor antagonists, (Answer)

[0085] However, it is more common to classify vasodilators based on their primary mechanism of action. The diagram on the right depicts the important mechanistic classes of vasodilators. Other classes that produce ductal dilation include: α-adrenergic receptor antagonists (α-blockers); Angiotensin-converting enzyme (ACE) inhibitors; Angiotensin receptor blockers (ARBs); β2-adrenergic receptor blockers Calcium channel blockers (CCBs); centrally acting Sympatholytics; direct acting vasodilators; endothelin receptor antagonists; ganglion blocking agents Drugs; nitrodilators; phosphodiesterase inhibitors; potassium channel openers; renin inhibitors Included.

[0086] Generally, the active or inactive ingredient or material produces increased blood flow or tissue flushing. Substances that allow for changes or differences (increases or decreases) in the transmucosal uptake of the API. or compounds that have a positive or negative heat of solution and that alter (increase or decrease) transmucosal uptake. The term may be a substance or compound used as an adjuvant to reduce the

[0087] The pharmaceutical composition may be a spray, gum, gel, cream, tablet, liquid, or film. The composition may have textures, such as microneedles or microprojections on the surface. Recently, the use of micron-scale needles in increasing skin permeability has been Contains large molecules, and has been shown to significantly increase transdermal delivery, especially for macromolecules Most drug delivery studies have focused on in vitro transdermal delivery for a wide range of molecules and nanoparticles. The emphasis is on solid microneedles, which have been shown to increase permeability. The study will explore the effects of oligonucleotide delivery, insulin-induced blood glucose reduction, and protein synthesis. These studies have demonstrated the induction of immune responses from both genetic and DNA vaccines. Regarding the needle array, the needle array is designed to puncture the skin and enhance transport by diffusion or iontophoresis. or as a drug carrier to release drugs into the skin from a microneedle surface coating. Hollow microneedles have also been developed and used to microinject insulin into diabetic rats. To address the practical application of microneedles, it has been shown that the crushing strength of the microneedle is important for skin insertion. The ratio of force to force (i.e., margin of safety) for needles with small tip radii and large wall thicknesses is Microneedles inserted into the skin of human subjects were reported as painless. Taken together, these results suggest that microneedles may be useful for therapeutic applications for a wide range of potential applications. These results suggest that this could be a promising technology for delivering compounds to the skin. Using microneedles, they have been made in a wide range of sizes, shapes and materials. , a polymeric microscopic needle that delivers encapsulated drugs in a minimally invasive manner. However, other suitable materials can be used.

[0088] The applicant believes that microneedles may be useful in the delivery of drugs through the oral mucosa, particularly with the claimed compositions. The researchers found that microneedles can be used to deliver microscopic particles into the oral mucosa to enhance the The solid membrane creates pores of different sizes, which can enhance the delivery of drugs across the mucosa. The present invention provides a method for producing microneedles that are solid, hollow, or dissolvable, using a variety of materials including metals, polymers, glasses, and ceramics. The microfabrication process may be made of any suitable material, including but not limited to: , photolithography, silicon etching, laser cutting, metal electroplating, metal electroplating The microneedles can be used to prepare tissue, and can include grinding and shaping. The drug-loaded material described in this application may be a solid that is removed prior to application of the film. The loaded polymer film can be used as the matrix material for the microneedle itself. These films can have microneedles or microprojections fabricated on their surfaces. These form microchannels in the mucosa through which drugs can permeate. It will dissolve after

[0089] The term "film" refers to a film of any shape, including rectangular, square, or any other desired shape. The films can be of any desired thickness and size. In a preferred embodiment, the film is administered to a user, e.g. The thickness and size of the filter may be such that the filter can be placed in the oral cavity of a patient. The film may have a relatively thin thickness of about 0.0025 mm to about 0.250 mm, or the film may have a relatively thin thickness of about 0.0025 mm to about 0.250 mm. Some films may have a slightly thicker thickness of about 0.250 mm to about 1.0 mm. The thickness may also be relatively large, i.e., greater than about 1.0 mm, or The film may be relatively thin, i.e., less than about 0.0025 mm. or the film may be multi-layered, including laminated or multi-cast films. It can be a layer.

[0090] Oral dissolving films are divided into three main classes: fast dissolving, intermediate dissolving and slow dissolving. Instantly dissolving films can be classified into two types: instantaneous dissolving films, which dissolve in the mouth for about 1 to 30 seconds, and instantaneous dissolving films, which dissolve in the mouth for about 3 Moderately soluble films dissolve in the mouth in about 1 to about 30 minutes. The slowly dissolving film can dissolve in the mouth in more than 30 minutes. As a general trend, the instant dissolving films are made of low molecular weight hydrophilic polymers (e.g., those with a molecular weight of about 1,000 -9,000, or polymers having a molecular weight of up to 200,000 In contrast, slowly dissolving films are generally made of high molecular weight polymers (e.g., The moderately soluble films are a mixture of fast dissolving films and slow dissolving films. They tend to fall between sex films.

[0091] It may be preferred to use a film that is a moderately soluble film. The dissolvable film is capable of dissolving fairly quickly, but also has a good level of mucoadhesion. Moderately soluble films are also flexible, rapidly wettable, and typically Such moderately soluble films are non-irritating to the user. It is desirable to provide a dissolution rate of about 1 minute to about 20 minutes, while preventing the oral cavity of the user from becoming congested. acceptable mucoadhesion such that the film is not easily removed once placed on the This provides a level of solubility that can ensure delivery of the pharmaceutical active ingredient to the user. do.

[0092] The pharmaceutical composition film can be produced with an occlusive layer and an active layer in a suitable formulation. In one example, applicants have produced a film having a occlusion layer and an active layer. The sealing layer may be, for example, a suitable cellulosic polymer, cellulose, a thickener, a polyol compound, or the like. a liquid vehicle (e.g., perseol), a taste additive or taste masking agent, and / or The active layer may contain, for example, an active pharmaceutical ingredient (in this case, octyldodecyl) octides), water-soluble ingredients or resins (e.g., Sentry Polyox, etc.), flavor additives or flavor masks sugar or sugar substitutes, and permeation enhancers (in this case, activator).

[0093] (Active pharmaceutical ingredient) The pharmaceutical composition may contain one or more pharmacologic active ingredients. The active pharmaceutical ingredient may be one or a combination of active pharmaceutical ingredients. Medicines, steroidal anti-inflammatory drugs, antihistamines, local anesthetics, bactericides, disinfectants, vasoconstrictors , hemostatic agents, chemotherapy agents, antibiotics, keratolytic agents, cauterizing agents, antiviral agents, antirheumatic agents, Antihypertensives, bronchodilators, anticholinergics, anxiolytics, antiemetic compounds, hormones, peptidase The pharmaceutical active ingredient can be a compound, a drug, a peptide, a protein, or a vaccine. A pharma- ceutically acceptable salt, prodrug, derivative, drug conjugate, or analog of the drug. The term "prodrug" refers to a compound that is metabolized in the body to produce a biologically active drug. refers to a biologically inactive compound that can

[0094] (Octreotide) In certain instances, the pharmacologic active ingredient can be a peptide, such as a cyclic peptide. The pharmaceutical active ingredient can mimic natural hormones. It pharmacologically mimics somatostatin, but does not inhibit the growth hormone glucagon or insulin. Octreotide, an octapeptide, is a more potent inhibitor than the natural hormone. Octreotide is effective in treating growth hormone-producing tumors (acromegaly and gigantism), thyroid Diarrhea associated with pituitary tumors secreting stimulating hormones (thyrotropinomas) and carcinoid syndrome and flushing episodes, and in humans with vasoactive intestinal peptide-secreting tumors (VIPomas) Octreotide is often used to treat diarrhea in patients with bronchitis, as it is administered intravenously through the portal vein. Management of acute bleeding from esophageal varices in cirrhosis based on reducing blood pressure It is given as an infusion to treat chronic conditions, but current evidence suggests that this effect is only temporary. It has been suggested that octreotide is effective in treating pulmonary arterial disease and does not improve survival time. In the scanning procedure, indium-111 labeling (Octreoscan) was used to study neuroendocrine and somatic It can be used to non-invasively image other tumors that express tostatin receptors. More recently, it has been radiolabeled with carbon-11 or gallium-68 and used for positron emission tomography (PET). ), which provides higher resolution and sensitivity. Otides can be labeled with various radionuclides, such as yttrium-90 or lutetium-177. This allows the development of peptide receptor radionuclides for the treatment of unresectable neuroendocrine tumors. Octreotide also inhibits the production of excess growth hormone (GH) and allows for progesterone reuptake therapy (PRRT). Octreotide is a somatostatin analogue that can be used to treat acromegaly. and inhibits the release of GH from the pituitary gland through a process normally involved in negative feedback. To inhibit.

[0095] (Franz diffusion cell) Franz diffusion cells were used in formulation development to identify the most active permeation enhancers. This is an apparatus used for ex vivo tissue permeation assays. The device consists of two chambers separated by a membrane of, for example, animal or human skin. The test product is applied to the membrane through the upper chamber. The lower chamber is Samples were then taken at regular intervals for analysis to determine the amount of activity permeating the membrane at that time point. This includes fluids that are

[0096] With reference to FIG. 1, a Franz diffusion cell 100 includes a donor compound 101, a donor chamber 102, a membrane 10 3, sampling port 104, receptor chamber 105, stirrer 106, and heater / thermal It has 107 curators.

[0097] With reference to FIG. 2, the pharmaceutical composition is a film 100 comprising a polymer matrix 200, The pharmaceutical active ingredient 300 is dispersed in the polymer matrix. The permeation enhancer 400 may be a surface active agent such as a surfactant. The surfactant may be a nonionic or anionic surfactant, or a cationic, nonionic surfactant. The surfactant may also be a combination of ionic and / or anionic surfactants. EXAMPLES

[0098] Example 1 - Performance ranking of octreotide enhancers Certain permeation enhancers are typically used in conjunction with the elution of a pharmaceutical active ingredient and / or the permeation enhancer. With respect to penetration enhancers, Applicants believe that certain enhancers may induce lysis. The compatibility with octreotide is relatively improved in terms of the permeability, and They found that these compounds did not induce precipitation of enhancers. Ionic surfactants (e.g., DDTMAB, CTAB, and BAC), higher concentrations of certain anions ionic surfactants (GDC, DOC), certain nonionic surfactants (e.g., poloxamer F127, Azone / DMCD, Labrasol, TDM), certain chelating agents (e.g., EDTA), certain cyclohexyl and cyclodextrins (e.g., dimethyl-cyclodextrin). The relative compatibility and relative permeation ranking with treotide is shown. (Table 1) [Table 1] *Octreotide 10% w / w is soluble after vigorous stirring

[0099] As shown in Table 1, the cationic surfactant surprisingly had a rank score of 3 ( High permeability) demonstrated both strong compatibility and permeability enhancement of octreotide. The use of one or a combination of hydrophilic surfactants may improve the compatibility of octreotide with the subject. Alternatively, any of the cationic surfactants may be used. or a rank 2 or rank 1 enhancer that also exhibits octreotide compatibility (e.g., G DC, Azone, EDTA, and dimethylcyclodextrin) This provides a pharmaceutical composition that provides enhanced delivery of octreotide to a subject. It can be provided.

[0100] Example 2 Applicant also discloses the following penetration enhancers and enhancers, as shown in Table 2 below: Concentrations of 100 mg / kg / day were tested and the average flux obtained from the ex vivo permeation model was compared. (Table 2) [Table 2] TIFF2024156672000005.tif220170TIFF2024156672000006.tif248170(Description) [Table 3]

[0101] As can be seen from the above, glycine betaine alkyl ester and dodecyl trimethyl ester Ammonium bromide surprisingly provided enhanced average flux. Cyltrimethylammonium bromide, azone, and benzalkonium chloride (BAC) are also , giving the enhanced average flux results. Exemplary structures of these enhancers are shown below: [ka] .

[0102] (Example 3 DDTMAB permeation activity) With reference to FIG. 3, Applicants have shown that the octanoic acid concentration of 5% by weight DDTMAB increases the permeation The effect of treotide concentration was examined. The graph shows the flux (μg / cm) as a function of time. m 2 * indicates minutes. Square data points indicate 3 mg octreotide with DDTMAB enhancer. The diamond data points represent the 1.5 mg octreotide with DDTMAB enhancer. The cross-hatched data points indicate the results for the 0.6 mg Octolase with DDTMAB enhancer. The triangle data points indicate the 0.3 mg octyltin derivative with the DDTMAB enhancer. Indicates punch line.

[0103] As shown in the graph, 5% DDTMAB showed the following results: over 50 minutes, over 60 minutes, over 70 minutes, over 80 minutes, over 90 minutes, and about 50 to 100 minutes, including about 100 minutes, more than 0.1 flux, more than 0.2 flux, and 0.3 flux Including greater than 0.4 flux, and about 0.5 flux, approaching 0.5 flux. For octreotide, the maximum flux was about 2 to 2.5 in about 175 minutes. For this, a maximum flux of 1.5 was obtained at about 175 min. Lower concentrations were 0.25 flux. It took about 125 min for the DDTMAB concentration to approach . shows that permeation is dependent on octreotide concentration.

[0104] With reference to FIG. 4, octreotide permeation follows Fick's first law of diffusion. The drug concentration in the treatment compartment is constant and that in the receiver compartment is zero. If , the data points show a linear relationship between flux and drug concentration. A flux of 0.500ug / cm2*min was achieved at an octreotide concentration of approximately 5mg / ml. Flash of 2.0 to 2.5 ug / cm2* or more, including more than 1, 2.2, 2.3, 2.4, and about 2.5 ug / cm2*. The following are included in the 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, and about 20 mg / ml: However, this was achieved with octreotide concentrations between 15 and 20 mg / ml.

[0105] Example 4 With reference to FIG. 5, Applicant has discovered that aliphatic trimethylammonium bromide surfactants (e.g., The structure-activity relationship of the compounds (n=5, 7, 9, 11, 15) was examined. The graph shows the The data show that the permeation activity is dependent on the alkyl chain length, with an optimal length. As the graph shows, the hexyl, octyl, and decyl derivatives was not active at 1 wt.%. Decyltrimethylammonium bromide (CMC ~ 1.7 wt.%) %) was active at 5 wt. %. At 1 wt. %, compounds containing C12 and C16 chains were the most active. It was.

[0106] The data below also indicate that the quaternary amine site is important for activity. (Table 4) [Table 4]

[0107] Example 5 With reference to FIG. 6, Applicant has performed a CT scan of fresh porcine buccal tissue for octreotide permeation. The effect of microneedles was tested. In this test, the applicant used 0.75 mm microneedles and a thickness of approximately 1 μm. 100 tissue samples were punched 3 times before exposure to 3 mg octreotide. Graph shows time course in minutes. The triangular data points represent the average amount of octreotide permeated through the microneedle and 0 Data using % EDTA are shown. Diamond data points represent microneedles and 2% EDTA. The square data points are where no microneedle was used. Data are from the same experiment using 2% EDTA. More than 20ug, 25ug, or more than 1000, 1100, 1200, or more than 1250, including about 1000 to 1250 minutes Permeation of 20-30ug was achieved, including greater than ug, and about 30ug, less than 30ug, less than 35ug, and less than 20ug. This indicates that

[0108] Between 30 and 40ug, including over 30ug, over 35ug, and about 40ug, less than 40ug, less than 35ug, and less than 30ug Permeation is greater than 1250 minutes, greater than 1300 minutes, greater than 1350 minutes, greater than 1400 minutes, greater than 1450 minutes, and about 1500 minutes, inclusive. This was achieved in 1250-1500 minutes.

[0109] Applicants also found that application of microneedles to buccal tissue did not cause octreotide degradation. As shown in the table below, microneedles were applied to the buccal tissue. The mice were incubated with octreotide solution (2 ml, 1 mg / ml) at 37°C for 4 hours. (Table 5) [Table 5]

[0110] Example 6 With respect to FIG. 7, the graph shows the results for 500 μl PBS buffer and 5% by weight dodecyltrimethylammonium chloride. A test solution of 12 mg octreotide in niobium bromide was used after a 2-hour exposure period. The results of a POC test on nibig are shown. The solution was removed by scraping off the mucin with a spatula. The area was then treated with microneedles (750um on the buccal side, 500um under the tongue) and placed Methocel (40% in water) was used as adhesive to attach the holder containing the solution onto the tissue. The test substance was easily monitored in case of any drug loss during the experimental set-up. It was colored so that it could be knitted.

[0111] The circular data points represent the buccal space. The square data points represent the sublingual space. The presence of octreotide in the blood was observed in all of the animals.

[0112] Below is a summary of the average data values ​​reflected in Figure 7: We show that DDTMAB is an effective permeation enhancer of octreotide in It also shows that absorption is more efficient through the sublingual mucosa compared to the buccal mucosa. [Table 6]

[0113] Example 8 The pharmaceutical composition film can be produced with an occlusive layer and an active layer in a suitable formulation. In some instances, the occlusive layer may be a suitable amount of cellulose, such as Metalose 90-S. H 4000, thickeners, such as cellulose ethers, such as Methocel E15, polyol compounds may contain additives such as glycerin, perseool, color additives, and / or flavor additives (FD&C). With reference to FIG. 8, this figure shows an image of an exemplary pharmaceutical composition film. In an embodiment, the film provides an adequate amount of pharmaceutical agent in the buccal and / or sublingual space. It has an aspect ratio suitable for dispensing ingredients. For example, the aspect ratio is greater than 1:1.9. , over 1:1.8, over 1:1.7, over 1:1.6, over 1:1.5, over 1:1.4, over 1:1.3, over 1:1.2, over 1:1.1, about 1:1 , less than 1:1.2, less than 1:1.3, less than 1:1.4, less than 1:1.5, less than 1:1.6, less than 1:1.7, less than 1:1.8, and about 1:1 to 1:2, including less than 1:1.9. In one example, the film is 22 mm wide, 25.6 mm long, The strips were manufactured with a length of 1 mm and a backing layer width of 3 mm. (Occluded layer) [Table 7] (active layer) [Table 8]

[0114] Example 9 With reference to FIG. 9A, this graph shows the concentration of DDTMAB with 3 mg octreotide in PBS (pH 7.4). The triangle data points show concentration-dependent activity in the presence of 5% DDTMAB as a permeation enhancer. The data points marked with diamonds show the amount of permeation using 1% DDTMAB as a permeation enhancer. The amount of transmission is shown using the formula:

[0115] With 5% DDTMAB, the amount of octreotide permeated after 6 hours was >510ug, >520ug, and >530ug. The steady state flux was 3.24±1.24ug / (cm 2 * minutes Furthermore, with 5% DDTMAB, the permeation amount was in the range of 100-200 μg between 100 and 150 minutes. Ta.

[0116] With reference to FIG. 9B, this graph shows the results over time for 3 mg octreotide in a bilayer film. The mean amount of octreotide permeated is shown. The triangular data points indicate the mean amount of octreotide permeated by the DDTMAB enhancer. The diamond data points show data without enhancer. The data show that with the DDTMAB enhancer, the amount of octreotide permeated over time was increased by 15 The steady-state flash was greater than 170ug, including greater than 100ug ± 122ug, greater than 160ug, and greater than 170ug. The viscosity is 1.0±0.45ug / (cm 2 *min). In contrast, without enhancer, the amount of permeation was The data were quite low, less than 25ug, including less than 20ug and less than 15ug. Using the sensor, the amount of permeation began to increase significantly, which was greater than 25ug, greater than 50ug, and , over 75ug, over 100ug, over 150ug, over 200ug, about 200ug, less than 200ug, less than 150ug, less than 100ug Includes less than 75ug, less than 50ug, and less than 25ug, as well as over 25ug and up to 150-200ug. The therapeutic window is >100 min, >110 min, >120 min, >130 min, >150 min, >200 min, >250 min. , over 300 minutes, about 350 minutes, less than 350 minutes, less than 300 minutes, less than 250 minutes, less than 200 minutes, less than 150 minutes, and 1 It may range from 100 to 350 minutes, including less than 30 minutes, less than 120 minutes, and less than 110 minutes.

[0117] Example 10 With reference to FIG. 10, this graph shows the results of using a sublingual film with and without microneedles. Results from an in vivo study are shown. Octreotide plasma concentrations were measured following sublingual or intravenous administration to male minipigs. The circular data points represent the concentration of 100 μg octreotide administered subcutaneously in ng / ml. The square data points represent the 15 mg octanoate administered in the pharmaceutical composition film. Triangular data points represent 15 mg octreotide administered by microneedle. The data show that in the pharmaceutical composition film, the octreotide concentration (ng / ml) was greater than 10ng / ml, 15 >ng / ml, >20ng / ml, >25ng / ml, >30ng / ml, >35ng / ml, >40ng / ml, >45ng / ml, 50ng / >55ng / ml, <55ng / ml, <50ng / ml, <45ng / ml, <40ng / ml, <35ng / ml , less than 30 ng / ml, less than 25 ng / ml, less than 20 ng / ml, less than 15 ng / ml, and less than 10 ng / ml, These concentrations were in the range of ~55ng / ml over 5, 10, 15, and 20 minutes. , over 25 minutes, over 30 minutes, over 35 minutes, over 40 minutes, over 45 minutes, over 50 minutes, over 60 minutes, over 70 minutes, over 80 minutes, over 90 minutes , and over 100 minutes, less than 200 minutes, less than 150 minutes, less than 100 minutes, less than 90 minutes, less than 80 minutes, less than 70 minutes, 60 Approximately 50 to 100 minutes, including less than 50 minutes, less than 45 minutes, less than 40 minutes, less than 35 minutes, and less than 30 minutes It was done. [Table 9]

[0118] The above data demonstrate that significant absorption of octreotide from solutions and films occurred in vivo. In this particular test, the effect of the microneedle (500 um) pretreatment was I couldn't.

[0119] Example 11 The applicant has found that a biodegradable cationic surfactant has a stronger affinity for the mucous membrane than a non-degradable one. They concluded that these lipids would be less irritating if subjected to acid / base hydrolysis or enzymatic manipulation. Some lipids have a cationic group and a long alkyl chain. The present applicant has designed and prepared a polymerizable compound by placing a degradable linker between the polymerizable compound and the polymerizable compound. It was reasoned that the dissolution products would be more biocompatible if they were naturally occurring. For example, the decomposition products from glycine betaine alkyl esters include glycine betaine and long chain Glycine betaine is a naturally occurring organic osmolyte in cells. It should be biocompatible and non-toxic. It should have no adverse effects and occur naturally. The fatty alcohols are converted to , will be converted to naturally occurring fatty acids. [ka] Glycine betaine (2-(nodecyloxy))-N,N,N-trimethyl-2-oxoethane Structure of 1-amino-1-aminium carbonate

[0120] Applicants performed an ex vivo screen for permeation enhancers for octreotide delivery. The tissue thickness was 300um, 3mg of octreotide was used, and the duration was up to 6 hours. Svibo bovine tissue was used.

[0121] With reference to FIG. 11A, the results of a test of the concentration-dependent permeability activity of glycine betaine ester-C12 are shown. The graph shows the effect of glycine betaine as a permeation enhancer for octreotide. Average flux (μg / cm) as a function of time using Stell (GBE) 2 * indicates minutes.

[0122] The square data points represent 5 wt.% GBE. The triangle data points represent 1 wt.% GBE. The cross-hatched data points reflect 0.5 wt. % glycine betaine. The permeation activity depends on the concentration of GBE C12.

[0123] As the graph shows, the average flux obtained was less than 100 min for GBE 5% and 100 min for GB Approximately 1 (μg / cm) in approximately 200 min for E 1% and approximately 270 min for GBE 0.5% 2 * minutes) 1 to 3.5 (μg / cm 2 *The average flux of >50 min, >75 min, >100 min, >150 min, >200 min More than 250 minutes, more than 300 minutes, more than 350 minutes, and about 400 minutes, less than 400 minutes, less than 350 minutes, less than 300 minutes, 2 50-400, including less than 50 minutes, less than 200 minutes, less than 150 minutes, less than 100 minutes, less than 75 minutes, and less than 50 minutes This was accomplished in minutes.

[0124] With reference to FIG. 11B, the permeation activity for glycine betaine esters with the effect of alkyl chains. The maximum activity was observed for GBE with C12 alkyl chains compared to GBE with C16 alkyl chains. The presence of unsaturation in the alkyl chain had no effect on activity. It was found that 5 wt% GBE-docecyl is shown as a square data point. , which include more than 250 minutes, more than 260 minutes, more than 270 minutes, less than 280 minutes, and less than 290 minutes and less than 300 minutes. 3-3.5 (μg / cm 2 *The flux of GBE-Hexadecyl 5-fold is reached in minutes. The percentage by volume includes over 250 minutes, over 260 minutes, over 270 minutes, under 280 minutes, and under 290 minutes and under 300 minutes. It was shown to reach a flux of 3-3.5 in 250-300 minutes. GBE-Oleyl 5 The weight percent includes over 250 minutes, over 260 minutes, over 270 minutes, less than 280 minutes, and less than 290 minutes and less than 300 minutes. It was shown that the flux reached 3 to 3.5 within 250 to 300 minutes.

[0125] Example 12 With reference to FIG. 12, this graph shows a comparison of the permeation activity of GBE C12 and DDTMAB (1 wt %). For both, over 220 minutes, over 230 minutes, over 240 minutes, over 250 minutes, over 260 minutes, over 270 minutes, under 300 minutes, 290 minutes Between 200 and 300 minutes, including under 280 minutes, under 270 minutes, and under 260 minutes, there was an average flash of about 4 (μg / cm 2 As shown in this graph, the biodegradable permeation enhancer , with an efficiency comparable to that of DDTMAB.

[0126] (Example 13) With reference to FIG. 13, this graph shows the effect of cetylpyridinium chloride as a permeation enhancer. (CPC) results are presented as average flux (μg / cm) as a function of time (min). 2 *The CPC is expressed in minutes. It is a thionic surfactant, in which the quaternary nitrogen is part of a ring structure. As shown: The diamond data points represent CPC at 5 wt.%. The square data points represent CPC at 1 wt.%. The triangular data points represent CPC at 0.5 wt.%. The cross-hatched data points represent CPC at 0.5 wt.%. The data point represents 0.1 wt % CPC.

[0127] Example 14 With reference to FIG. 14, this graph shows the effect of multiple quaternary nitrogen-linked amines as permeation enhancers. Tetrahexylammonium bromide, a cationic surfactant with a long alkyl chain The diamond data points show the results for tetrahexylammonium bromide. The 5% by weight of tetrahexylammonium bromide shows approximately 0.05% in the range of 50 to 300 minutes. The square data points indicate the flux of tetrahexylammonium. 1% by weight of tetrahexylammonium bromide is 250 to 300 Achieve a flux of approximately 0.2 over the course of a minute.

[0128] Example 15 With reference to FIG. 15, this graph shows the effect of benzalkonium chloride (BAC) as a permeation enhancer. The diamond data points represent 5 wt.% BAC. The square data points represent 5 wt.% BAC. The dots represent 1 wt% BAC. The triangular data points represent 0.1 wt% BAC. Lined-cross-hatched data points indicate 0.01% BAC. The cross-hatched data points represent 0.05 wt% BAC. The results show that the permeation activity increased with concentration. This indicates that the drug is dependent on the 1.8μg / cm 2 *Average flux of 10 min achieved using 5 wt% BAC It was done.

[0129] As shown by this data, the 5 wt% BAC was greater than 150, greater than 160, greater than 170, greater than 180, and greater than 200. Over 20, Over 240, Over 250, Over 260, Over 260, Over 270, Over 280, Less than 300, Less than 290, Less than 280, Less than 270 Between 150 and 300 minutes, including less than 260 minutes, an average flux of 1.5 to 2 was achieved.

[0130] 1% BAC is over 50, over 60, over 70, over 80, over 90, less than 100, less than 90, less than 80, less than 70, and A flux of approximately 1 was achieved between 50 and 100 min, including less than 60 min.

[0131] 0.01% is over 300, over 310, over 320, over 330, over 340, over 350, less than 350, less than 340, and less than 330 A flux of approximately 1 was achieved between 300 and 350 min, including below 320 and below 310 min.

[0132] 0.01% BAC is over 300, over 310, over 320, over 330, over 340, over 350, less than 350, less than 340, and 330 A flux of approximately 0.25 was achieved between 300 and 350 minutes, including <300, <320, and <310 minutes. .

[0133] 0.05% BAC is over 300, over 310, over 320, over 330, over 340, over 350, less than 350, less than 340, and 330 A flux of approximately 0.25 was achieved between 300 and 350 minutes, including <320, <310 minutes. .

[0134] Example 16 With reference to FIG. 16, this graph shows the effect of octocog alfa on the efficacy and safety of octocog alfa after sublingual or intravenous (IV) administration to male minipigs. 4 shows the profile of treotide plasma concentration (ng / ml) versus time. [Table 10]

[0135] Circle data points represent 100 μg Sandostatin (iv) (n=1). Square data points represent Int(8-1-1) is an 11 mg film (sublingual, one film strip as a permeation enhancer) This bilayer film contains an average of 32 mg of benzalkonium chloride per tablet (n=4). It has a slower dissolving backing layer to increase the residence time of the drug in the Data point (3-1-1) is for an 11.5 mg monolayer film (sublingual, with phytosalicylic acid as a permeation enhancer) Each strip contained an average of 35 mg of dodecyltrimethylammonium bromide (n=4). For 3-1-1, active wetting was done with a coat gap of 5 mils (0.127 mm). The solid triangle data points (9-1-1 ) contains 16.1 mg bilayer film (sublingual, per film strip as a permeation enhancer) The average concentration of dodecyltrimethylammonium bromide is 25 mg, n=4. The film size was 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, and 110 or more. , over 120, over 130, over 140, less than 150, less than 140, less than 130, less than 120, less than 110, less than 100, 90 About 50 to 150 minutes, including less than 80, less than 70, and less than 60 minutes, and about 10 to 30 mg / ml of octreotide concentration was achieved.

[0136] 11.5mg film: over 50, over 60, over 70, over 80, over 90, over 100, over 110, over 120, over 130, over 14 Over 0, under 150, under 140, under 130, under 120, under 110, under 100, under 90, under 80, under 70 Octreotide concentrations of approximately 10 to 18 were achieved in approximately 50 to 150 minutes, including less than 60 minutes.

[0137] 11mg film: over 50, over 60, over 70, over 80, over 90, over 100, over 110, over 120, over 130, over 140 Over, under 150, over 160, over 170, over 180, over 190, over 200, under 190, under 180, under 170, under 160 Full, Less than 150, Less than 140, Less than 130, Less than 120, Less than 110, Less than 100, Less than 90, Less than 80, Less than 70 , achieving octreotide concentrations of approximately 10-18 in 50-200 minutes, including less than 60 minutes.

[0138] Both benzalkonium chloride and dodecyltrimethylammonium bromide had an average Octreotide is a highly efficient permeation enhancer with a bioavailability of approximately 8-10%. I realized something.

[0139] (Example 17) In one example, the inventors have used high intensity focused ultrasound (H The HIFU was used with a variety of settings, including intensity, duty cycle, pulse repetition frequency, and exposure time. Depending on ultrasound parameters such as time, mechanical, cavitational or thermal effects can be produced in the tissue. In this experiment, HIFU was applied to the buccal tissue for 30 seconds (180 watts detection, de The permeation of octreotide through tissue was already observed in The ex vivo permeation model described (using full thickness tissue including the submucosal connective tissue) The tissue was monitored for 2 hours. Approximately 60 μg of octreotide was found to have permeated the tissue. However, in the absence of HIFU application, no octreotide penetration was observed.

[0140] The target for matching to the 0.5 mg reference listed drug (RLD) in humans is 15 mg Octreo. The human trials were conducted in two arms: 10 mg / 25 mg BAC and 15 mg / 40 mg BAC. With respect to FIG. 17, this graph shows the results of a human study (10 mg octreotide / 25 mg BAC ) arm #1. The best profile with the highest bioavailability was seen at 3.1% bioavailability. The lowest is 0.3% bioavailability and the lowest is average / mean n) curve showed a 1.3% bioavailability. Unexpectedly, the results showed improved bioavailability. The two higher profiles were indicative of permeation. The four lowest values ​​show an increase in stimulation, demonstrating that the enhancer works well. The profile shows only relatively minor irritation (reddening). Transmucosal delivery was demonstrated by the rapid onset of its availability in plasma.

[0141] (Summary of statistics on transmucosal absorption) Applicants have demonstrated the first demonstrated transmucosal absorption of peptides. The associated plasma concentrations showed a mean Cmax of 4600.55 pg / mL and a mean Tmax of 2.33 hours. This was a validation of the permeation enhancer mechanism. The level of stimulation correlated with the best PK profile. Regarding the tables below, the statistical summary and initial implications are as follows: ons) is shown. [Table 11]

[0142] In comparison, Sandostatin (oral tablet) 0.1 mg subcutaneous injection had a Cmax of ~4100 pg / mL; AUC of 1370 0 pg / mL, and BA >1% (maximum profile >3%) (data from Chiasma Overview (Cited from , September 2018). Surprisingly, this data supports the applicants' findings that This shows that delivery via the oral tablet exhibits similar Cmax and improved AUC compared to the oral tablet.

[0143] (Decomposition test) 18A-18C, Applicant has demonstrated that GBE-C12 Decomposition tests were conducted on The biologically relevant media tested were plasma (human BioIVT, K2-EDTA), esterase solution , simulated gastric fluid (pepsin / low pH), simulated intestinal fluid (pancreatin), and tissue homogenates (1 g each) The conditions were: 1) 6mL PBS solution → homogenizer (FastPrep) → centrifugation → supernatant. Below, GBE-C 12 The ester is hydrolyzed at 37°C to give glycine betaine + dodecanol. As shown in the graphs of Figures 18A to 18C, this study revealed new permeation enzymes. Enhancer GBE-C 12 However, it was found to be highly bioavailable as quantified by glycine betaine analysis. As expected for an ester group, this was shown to be degradable in acidic environments. This result suggests that the use of acid-sensitive linkers such as acetals is Show that it is possible. [ka]

[0144] (Active pharmaceutical ingredient) In some embodiments, more than one pharma- ceutical active may be included in the film. The active pharmaceutical ingredient is an ACE inhibitor, an antianginal, an antiarrhythmic, an antiasthmatic, an anticholesterol Hypotensive drugs, analgesics, anesthetics, anticonvulsants, antidepressants, diabetes medications, antidiarrheal preparations , detoxifiers, antihistamines, antihypertensives, anti-inflammatory drugs, anti-lipid drugs, antimanic drugs, anti-nausea drugs , anti-stroke drugs, anti-thyroid preparations, anti-tumor drugs, anti-viral drugs, acne drugs, alkaloids , amino acid preparations, antitussives, anti-urinary tract stones, anti-virals, anabolic preparations, systemic and and non-systemic infectious diseases, anti-neoplastics, anti-Parkinson's, anti-rheumatic, appetite Promoting drugs, blood modifiers, bone metabolism regulators, cardiovascular drugs, central nervous system stimulants, cholinesterases Steroid inhibitors, contraceptives, decongestants, dietary supplements, dopamine receptor agonists, Endometriosis management drugs, enzymes, erectile dysfunction treatments, infertility drugs, gastrointestinal drugs, homeopathic remedies, Lumon, hypercalcemia and hypocalcemia management drugs, immunomodulators, immunosuppressants, Headache preparations, motion sickness medicine, muscle relaxants, obesity management drugs, osteoporosis preparations, uterine contraction drugs, Sympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic drugs, respiratory drugs, Sedatives, smoking cessation aids, sympatholytics, tremor treatment preparations, urinary system medications, vasodilators, laxatives medicine, antacid, ion exchange resin, antipyretic, appetite suppressant, expectorant, anti-anxiety drug, anti-ulcer drug, anti Inflammatory substances, coronary vasodilators, cerebral vasodilators, peripheral vasodilators, psychotropic drugs, Stimulants, hypertension medications, vasoconstrictors, migraine medications, antibiotics, tranquilizers antipsychotics, antitumor drugs, anticoagulants, antithrombotic drugs, hypnotics, antiemetics, antinausea drugs, anticonvulsants Convulsants, Neuromuscular Agents, Hyperglycemic and Hypoglycemic Agents, Thyroid and Anti-thyroid Preparations, Diuretics , antispasmodics, uterine relaxants, anti-obesity drugs, erythropoiesis drugs, anti-asthmatic drugs, cough suppressants, mucolytic drugs, It can be DNA and gene modifying agents, and combinations thereof.

[0145] (Medical film) The pharmaceutical composition film that delivers octreotide and / or its components are water-soluble, water-swellable. The term "water soluble" includes, but is not limited to, water. It can refer to a substance that is at least partially soluble in an aqueous medium, but is not intended to be The term "water soluble" does not necessarily mean that a substance is 100% soluble in an aqueous medium. The term "water insoluble" includes, but is not limited to, water. It refers to a substance that is not soluble in an aqueous solvent. The solvent may include water or another solvent (preferably Polar solvents) either on their own or in combination with water.

[0146] The composition can include a polymer matrix. Any desired polymer matrix can be used. Any drug that is orally dissolvable or erodible may be used. The formulation has sufficient bioadhesiveness to not be easily removed and to form a gel-like structure when administered. They must be moderately soluble in the oral cavity and They are particularly suitable for the delivery of pharmaceutical active ingredients, including immediate release, delayed release, controlled release and sustained release. All sustained release compositions are also among the various embodiments contemplated.

[0147] Arrangement of permeation enhancers and active pharmaceutical ingredients (APIs) delivered to desired mucosal surfaces The ent, order, or sequence of the compounds may be chosen to achieve the desired pharmacokinetic profile. For example, it can be a film, a swab, a spray, a gel, The permeation enhancer is applied first, either by rinsing or by the first layer of film, and then Then, either by a single film, by a swab, or by a second layer of film, PI can be applied. This arrangement can be applied, for example, by film or by swab. The API is applied first by a first layer of film or a second layer of film, and then the API is applied by a film or a swab. Penetration enhancement can be achieved by a brush, spray, gel, rinse, or by a second layer of film. This can be reversed or changed by applying a filter. In the method, the permeation enhancer is applied through a film and the drug is delivered through another film. For example, depending on the desired pharmacokinetic profile, A permeation enhancer film or a film containing a permeation enhancer located under the film. The film contains the API and is placed under the

[0148] For example, a permeation enhancer can be used either as a pretreatment alone or in combination with at least one API. can be used in combination to precondition the mucosa for further absorption of the API. This treatment can be followed by another treatment with neat permeation enhancer to enhance the at least one This pretreatment can be followed by application of a variety of APIs to the mucosa. , solution, swab, etc.) or as a layer within a multi-layer film structure of one or more layers. Similarly, the pretreatment may include a first treatment with or without a permeation enhancer or API. Another aspect of the present invention is a single film designed to dissolve and release into the mucosa prior to the release of the second domain. The active ingredient may then be administered alone or in combination with a second treatment. It may be delivered in combination with additional penetration enhancers, in different ratios to each other, or with other treatments. Additional permeation enhancers and / or at least There may also be a third treatment or domain that delivers one or more APIs or prodrugs. This allows for a tailored pharmacokinetic profile to be obtained. The product is formulated to provide the desired absorption profile that achieves the intended pharmacokinetic profile and / or pharmacodynamic effect. Varying the order of application, composition, concentration, or total loading on the mucosa, which can lead to different amounts and / or rates of absorption The polypeptide may have a single or multiple domains that include a penetration enhancer and an API that can

[0149] This film format is preferably designed so that there are no distinct faces or that the film has co-terminous edges ( A multilayer film having or meeting at a shared border or limit It can be oriented to have at least one face.

[0150] (Branched polymer) The pharmaceutical composition films configured to deliver octreotide can be prepared in a variety of structural configurations. and dendritic polymers, including highly branched macromolecules having the architecture These include dendrimers, dendritic polymers (dendritic grafted polymers), linear These include dendritic hybrids, multi-arm star polymers, and hyperbranched polymers.

[0151] Hyperbranched polymers have imperfections in their structure, but are highly branched polymers. However, they can be synthesized in a single-step reaction, which is different from other dendritic This is an advantage over their spherical structure and therefore suitable for mass use. The properties of these polymers are abundant functional groups, intramolecular cavities, low viscosity and high solubility. Dendritic polymers are used in several drug delivery applications. Dendrimers as Drug Carriers: Application to Different Routes of Drug Administration ions in Different Routes of Drug Administration)”, J Pharm Sci, VOL. 97, 2008, 123-143).

[0152] Dendritic polymers have internal cavities in which drugs can be encapsulated. The steric hindrance caused by the polymer can prevent the drug from crystallizing. - Linearized glycerol is used to formulate physically metastable drugs that tend to crystallize in the matrix. There may be advantages to using branched polymers rather than polymers.

[0153] Examples of suitable dendritic polymers include poly(ether)-based dendrons, dendrimers, , and hyperbranched polymers, poly(ester)-based dendrons, dendrimers and hyperbranched polymers dendrons, dendrimers and hyperbranched polymers, poly(thioether)-based dendron ... Poly(arylamino acid)-based dendrons, dendrimers and hyperbranched polymers, poly(aryl (alkylene ether)-based dendrons, dendrimers and hyperbranched polymers, poly(alkoxy) Poly(amidoamine)-based dendrons, dendrimers and hyperbranched polymers ) based dendrons, dendrimers, and hyperbranched polymers.

[0154] Other examples of hyperbranched polymers include poly(amines), polycarbonates, poly(ethers), ketone), polyurethane, polycarbosilane, polysiloxane, poly(esteramine), Poly(sulfone amines), poly(urethane ureas), and polyether polyols, e.g., poly Glycerin, etc.

[0155] The pharmaceutical composition film is a liquid containing at least one polymer and, optionally, other ingredients. The solvent may be water, but is not limited to ethanol, isopropanol, or the like. The solvent may be a polar organic solvent, including alcohol, acetone, or any combination thereof. In an embodiment, the solvent may be a non-polar organic solvent, such as methylene chloride. The system utilizes a selected casting or deposition method and a controlled drying process. For example, the film can be prepared by using a method for forming a viscoelastic structure. , a controlled process involving the application of heat and / or radiation energy to a wet film matrix. The film may be prepared through a controlled drying process, which allows for controlled content uniformity of the film. The controlled drying process can be performed on the top side of the film, the bottom side of the film, or on the casting side. or in contact with a substrate supporting a deposited or extruded film; Contact with two or more surfaces at the same or different times during the drying process, air only, heat only It can contain heat or heat and air together (this is a bit awkward and needs some elaboration). (Some such processes are described in U.S. Pat. Nos. 8,765,167 and 8,313,743.) No. 8,652,378, which are incorporated herein by reference. Alternatively, the film may be any of the films disclosed in U.S. Pat. It may be extruded as described in Publication No. 2005 / 0037055A1.

[0156] The polymers contained in the film may be water soluble, water swellable, water insoluble, or water soluble. The polymer may be any one or more of water-swellable, water-insoluble, water-swellable, water-insoluble polymers. Examples of useful water soluble polymers include cellulose, cellulose derivatives, or gums. , polyethylene oxide, pullulan, hydroxypropyl methylcellulose, hydroxy Ethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxy Methylcellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol Gum acacia, gum arabic, xanthan gum, tragacanth gum, guar gum, Polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, dendrimer Examples of suitable granules include, but are not limited to, granules, gelatin, and combinations thereof. Specific examples of water-insoluble polymers include ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and These include, but are not limited to, combinations of the above. It may be desirable to incorporate polymers that provide a high level of viscosity relative to the dose. .

[0157] As used herein, the phrase "water soluble polymer" and variations thereof refer to a polymer that is at least partially water soluble. A polymer that is soluble in water, preferably completely or mostly soluble in water or that absorbs water. Polymers that absorb water are often referred to as water-swellable polymers. Useful materials are water-soluble or water-swellable at room temperature and at other temperatures, e.g., above room temperature. Additionally, these materials may be water-soluble or water-swellable at subatmospheric pressures. In some embodiments, the films formed from such water-soluble polymers may , may be sufficiently water soluble to be dissolved upon contact with body fluids.

[0158] Other polymers useful for incorporation into the film include biodegradable polymers, copolymers, and copolymers. The term "biodegradable" includes those that are physically disintegrable, such as polymers, polymeric ... Contains substances that chemically decompose, as opposed to substances that are destroyed (i.e., bioerodible substances). It is understood that the polymers incorporated into the film are also intended to be biodegradable. or a combination of bioerodible materials. Polymer or polymer classes include: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), poly(diol) xanthane, polyoxalate, poly(α-ester), polyanhydride, polyacetate, poly Caprolactone, poly(orthoester), polyamino acid, polyaminocarbonate, poly Urethanes, polycarbonates, polyamides, poly(alkyl cyanoacrylates), and Mixtures and copolymers thereof are included. Additional useful polymers include the stearate of L- and D-lactic acid. Teleopolymer, copolymer of bis(p-carboxyphenoxy)propanoic acid and sebacic acid , Sebacic acid copolymer, Caprolactone copolymer, Poly(lactic acid) / Poly(glycolic acid) ) / polyethylene glycol copolymers, polyurethane and (poly(lactic acid)) copolymers, poly copolymers of urethane and poly(lactic acid), copolymers of α-amino acids, copolymers of α-amino acids and carboxylates Copolymer of proline acid, α-benzyl glutamate and polyethylene glycol copolymers of succinic acid esters and poly(glycols); polyphosphazenes , polyhydroxy-alkanoates, and mixtures thereof. The polymer matrix is , 1, 2, 3, 4 or more components.

[0159] A variety of different polymers may be used, but it is important to provide the film with mucoadhesive properties as well as the desired It is desirable to select a polymer that provides a high dissolution and / or disintegration rate. The time for which it is desirable to maintain contact of the composition with the mucosal tissue is determined by the amount of the medicament active ingredient contained in the composition. Some active pharmaceutical ingredients require only a few minutes for delivery through mucosal tissue. Whereas other pharmaceutical active ingredients may not require a stimulant for up to a few hours or even longer. Therefore, in some embodiments, one or more of the above-mentioned aqueous solutions may be used. A polymer having a refractive index of 10 or less may be used to form the film. The water-soluble polymer and the water-swellable, water-insoluble and / or biodegradable polymer as provided above. It may be desirable to use a combination of water-swellable, water-insoluble and / or biocompatible polymers. The inclusion of one or more polymers that are degradable allows for a filtrate formed solely of water-soluble polymers to be It is possible to provide a film that has a slower dissolution or disintegration rate than a film. Therefore, the film adheres to the mucosal tissue for a relatively long period of time, up to several hours, and This can be desirable for the delivery of certain pharmaceutical active ingredients.

[0160] Desirably, the individual film dosages of the pharmaceutical film have a small size. This is approximately 0.0625 to 3 inches (1.5875 mm x 76.2 mm) by approximately 0.0625 to 3 inches. The film size, in at least one embodiment, is also greater than 0.25 inches (6.35 mm), less than 0.5 inches (1.5 mm), and more than 0.5 inches (1.5 mm). Over 1 inch (12.7 mm), over 1 inch (25.4 mm), over 2 inches (50.8 mm), about 3 inches (76.2 mm), and 3 inches Over 3 inches, Less than 2 inches, Less than 1 inch, Less than 0.5 inches, 0.0625 inches (1.5875 m In another embodiment, the range is greater than 0.0625 inches, greater than 0.5 inches, greater than 1 inch, or less than 2 inches. Over 3 inches, over 3 inches, about 3 inches, under 3 inches, under 2 inches, under 1 inch, under 0.5 inches The aspect ratio, including thickness, length and width, is the same as that of the polymer matrix. The chemical and physical properties of the drug, the active pharmaceutical ingredient, dosage, enhancers, and other This can be optimized by one skilled in the art based on the additive and the desired dimensions of the distribution unit. The film dosage form has good adhesion when placed in the buccal or sublingual area of ​​a user. Furthermore, the film formulation must be able to disperse at a moderate rate and have good adhesion. The composition should dissolve quickly and, most preferably, should disperse within about 1 minute and dissolve within about 3 minutes. In some embodiments, the film formulation is allowed to dry for about 1 to about 30 minutes, for example, about 1 to about 20 minutes. or more than 1 minute, more than 5 minutes, more than 7 minutes, more than 10 minutes, more than 12 minutes, more than 15 minutes, more than 20 minutes, more than 30 minutes, about 30 minutes, and 30 minutes Less than 20 minutes, less than 15 minutes, less than 12 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, and less than 1 minute The sublingual rate is shorter than the buccal rate. It's possible.

[0161] For example, in some embodiments, these films may be made of polyethylene oxide alone. The second polymer may be contained in the aqueous dispersion or in combination with another aqueous dispersion. a water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer, or any of them Suitable water-soluble polymers include any of those provided above. In some embodiments, the water soluble polymer may be, but is not limited to, a Water-based cellulosic polymers, such as hydroxypropyl cellulose and / or hydroxy In some embodiments, one or more water-swellable, Water-insoluble and / or biodegradable polymers may also be incorporated into polyethylene oxide-based films. Any of the water-swellable, water-insoluble or biodegradable polymers provided above may be included. The second polymer component may be used in an amount of about 0% to about 80% by weight of the polymer component. More specifically, it may be used in an amount of from about 30% to about 70% by weight, and even more specifically, from about 40% to about 60% by weight. may be used.

[0162] Additives may be included in these films. Examples of classes of additives are preservatives, antimicrobials, and the like. Biological agents, excipients, lubricants, buffers, stabilizers, foaming agents, pigments, colorants, fillers, extenders, Sweeteners, flavorings, fragrances, release modifiers, adjuvants, plasticizers, glidants, release agents, poly All, granulating agent, diluent, binder, buffer, absorbent, lubricant, adhesive, anti-adhesive agent, acidulant , fabric softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, anti-adhesive agents, antistatic agents These additives include antimicrobial agents and mixtures thereof. Stabilizers may include radical scavengers, antioxidants, buffers, antimicrobials, antibacterials, and the like. It may be a fungicide, a chelating agent, or a preservative, such as sodium metabisulfite. Cut.

[0163] As used herein, the term "stabilizer" refers to an active pharmaceutical ingredient, another excipient, or a combination thereof. Excipients capable of preventing aggregation or other physical degradation, as well as chemical degradation, of the combination This means an agent.

[0164] The stabilizer may also be an antioxidant, a sequestering agent, a pH regulator, an emulsifier and / or a surfactant. They can be classified as photoinhibitors, photoinhibitors, and ultraviolet light stabilizers.

[0165] Antioxidants (i.e., those that slow, inhibit, interrupt and / or stop the oxidative process, as medicines) The compatible compound(s) or composition(s) may in particular be the following substances: tocopherol and their esters, sesamol from sesame oil, coniferyl benzoate from benzoin resin, Nordihydroguaiaretic acid resin and nordihydroguaiaretic acid (NDGA), gallate ( In particular, methyl, ethyl, propyl, amyl, butyl, lauryl gallate, butylated Hydroxyanisole (also known as BHA / BHT, butyl-p-cresol); ascorbic acid and its Salts and esters (e.g., ascorbyl palmitate), erythorbic acid (isoascorbic acid acid) and its salts and esters, monothioglycerol, sodium formaldehyde Sulfoxylates, Sodium Metabisulfite, Sodium Hydrogen Sulfite, Sodium Sulfite , potassium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene Representative antioxidants include tocopherols, e.g., α-tocopherol ... ol and its esters, butylated hydroxytoluene and butylated hydroxyanisole The term "tocopherol" also includes esters of tocopherol. The term "α-tocopherol" refers to α-tocopherol. Examples of tocopherol include esters of tocopherol (eg, α-tocopherol acetate).

[0166] A sequestering agent (i.e., a compound, such as an active ingredient or another excipient, combined with a host-gel Any compound capable of participating in the formation of a calcium ion complex (also called a sequestering agent) is calcium chloride. Calcium disodium ethylenediaminetetraacetate, Glucono delta-lactone, Sodium Gluconate, Potassium Gluconate, Sodium Tripolyphosphate, Hexamethaline Sequestering agents also include cyclic oligosaccharides, e.g. For example, cyclodextrin, cyclomannin (five or more cyclodextrins linked at the 1,4 positions by α bonds) α-D-mannopyranose units), cyclogalactin (linked at the 1,4 positions by β bonds, 5 or more β-D-galactopyranose units), cycloartrin (linked at the 1,4 positions by α bonds) and combinations thereof.

[0167] The pH regulator may be an acid (e.g., tartaric acid, citric acid, lactic acid, fumaric acid, phosphoric acid, ascorbic acid, acid, acetic acid, succinic acid, adipic acid and maleic acid), acidic amino acids (e.g., glutamic acid , aspartic acid, etc.), inorganic salts of such acidic substances (alkali metal salts, alkaline earth metal salts, etc.), metal salts, ammonium salts, etc.), organic bases of such acidic substances (e.g., basic amino acids, salts with, for example, lysine, arginine, and the like, meglumine, and the like; Other examples of pH adjusters include silicided microcrystalline cellulose, ... Calcium salts of phosphoric acid (e.g., hydrogen phosphate) Calcium anhydride or hydrate, calcium carbonate or hydrogen carbonate, sodium or potassium, and calcium lactate or mixtures thereof), sodium carboxymethylcellulose thorium and / or calcium salts, cross-linked carboxymethylcellulose (e.g., chloroform, Scarmellose sodium and / or calcium), polacrilin potassium, sodium alginate Sodium and / or calcium docusate, magnesium stearate, calcium calcium, aluminum, or zinc, magnesium palmitate, and magnesium oleate Magnesium, sodium stearyl fumarate, and combinations thereof.

[0168] Examples of emulsifiers and / or surfactants are poloxamers or pluronics, polyethylene glycols, Recall, polyethylene glycol monostearate, polysorbate, sodium lauryl sulfate thorium, polyethoxylated and hydrogenated castor oil, alkyl polyosides, hydrophobic base Water-soluble proteins grafted onto the chain, lecithin, glyceryl monostearate, Glyceryl Monostearate / Polyoxyethylene Stearate, Ketostearyl Alcohol Sodium lauryl sulfate, carbomer, phospholipids, (C 10 ~C 20 )-Alkyl and Alkyl olefin carboxylates, alkyl ether carboxylates, fatty alcohol sulfates, fatty Alcohol ether sulfates, alkylamide sulfates and sulfonates, fatty acid alkyl Midopolyglycol ether sulfates, alkanesulfonates and hydroxyalkanesulfates Sulfonates, olefin sulfonates, acyl esters of isethionic acid, α-sulfo fatty acids Esters, alkylbenzene sulfonates, alkylphenol glycol ether sulfonates Sulfonates, sulfosuccinates, monoesters and diesters of sulfosuccinic acid, aliphatic aldehydes, Alcohol ether phosphate, protein / fatty acid condensation products, alkyl monoglyceride sulfur Acid salts and sulfonates, alkyl glyceride ether sulfonates, fatty acid methyl taurides amides, fatty acid sarcosinates, sulforicinolates, and acyl glutamates, quaternary acylates, Ammonium salts (e.g., di-(C 10 ~C 24 )-Alkyl-dimethylammonium chloride or bromine Mid), (C 10 ~C 24 )-Alkyl-dimethylethyl ammonium chloride or bromide, (C 10 ~C 24 )-Alkyl-trimethylammonium chloride or bromide (e.g., cetyltrimethylammonium Cethylammonium chloride or bromide), (C 10 ~C 24 )-Alkyl-dimethylbenzyl ane monium chloride or bromide (e.g., (C 12 ~C 18 )-Alkyl-dimethylbenzylammonium nium chloride), N-(C 10 ~C 18 )-alkyl-pyridinium chloride or bromide (e.g., N-(C 12 ~C 16 )-alkyl-pyridinium chloride or bromide), N-(C 10 ~C 18 )-Alkyl- Isoquinolinium chloride, bromide or monoalkyl sulfate, N-(C 12 ~C 18 )-Alkyl- Polyoylaminoformylmethylpyridinium chloride, N-(C 12 ~C 18 )-Alkyl-N-methyl Morpholinium chloride, bromide or monoalkyl sulfate, N-(C 12 ~C 18 )-Alkyl- N-Ethylmorpholinium chloride, bromide or monoalkyl sulfate, (C 16 ~C18 )-Al Kyl-Pentaoxetyl Ammonium Chloride, Diisobutylphenoxyethoxyethyl Dimethylbenzylammonium chloride, N,N-diethylaminoethylstearylamide and -oleylamide salts with hydrochloric acid, acetic acid, lactic acid, citric acid, and phosphoric acid, N-acylamino esters ethyl-N,N-diethyl-N-methylammonium chloride, bromide or monoalkyl sulfate, and N-acylaminoethyl-N,N-diethyl-N-benzylammonium chloride, bromide or monoalkyl sulfates (in the above, "acyl" means, for example, stearyl or oleyl). This includes all of the above, as well as combinations thereof.

[0169] Examples of UV stabilizers include UV absorbers (e.g., benzophenone), UV quenchers (i.e., UV Instead of decomposing the energy, it dissipates the energy as heat. any compound), scavengers (i.e., compounds that suppress free radicals resulting from exposure to UV radiation), any compound that removes iodine, iodine-1, iodine-2, iodine-3, iodine-4, iodine-5, iodine-6, iodine-7, iodine-8, iodine-9, iodine-10, iodine-11, iodine-12, iodine-13, iodine-14, iodine-15, iodine-1

[0170] In another embodiment, the stabilizer is ascorbyl palmitate, ascorbic acid, Luphatocopherol, Butylated Hydroxytoluene, Butylated Hydroxyanisole, Cysteine ​​HC1, Citric Acid, Ethylenediaminetetraacetic acid (EDTA), Methionine, Sodium Citrate Sodium, Sodium Ascorbate, Sodium Thiosulfate, Sodium Metabisulfite, Sodium Sodium bisulfate, propyl gallate, glutathione, thioglycerol, singlet oxygen Quencher, Hydroxyl radical scavenger, Hydroperoxide scavenger, Reducing agent, Gold "Singlet oxygen quenching agents include chelating agents, detergents, chaotropes, and combinations thereof. The "agents" include alkylimidazoles (e.g., histidine, L-camocine, histamine, imidazoline, 4-acetic acid), indoles (e.g., tryptophan and its derivatives, e.g., N-acetylglucosamine, -5-Methoxytryptamine, N-acetylserotonin, 6-Methoxy-1,2,3,4-tetrahydro- beta-carbolines), sulfur-containing amino acids (e.g., methionine, ethionine, diethylamino acids, Lanthionine, N-formylmethionine, felinine, S-allylcysteine, S-aminoethyl L-cysteine), phenolic compounds (e.g., tyrosine and its derivatives), aromatic acids ( ascorbate, salicylic acid, and their derivatives), azides (e.g., sodium), tocopherols and related vitamin E derivatives, and carotenes and related vitamins Hydroxyl radical scavenger The "rangers" are azide, dimethyl sulfoxide, histidine, mannitol, sucrose, and glucose. These include, but are not limited to, glucose, salicylate, and L-cysteine. "Hydroperoxide scavengers" include catalase, pyruvate, glutathione, and glutamine. "Reducing agents" include, but are not limited to, glutathione peroxidase. , cysteine ​​and mercaptoethylene, but are not limited to these. "Genus chelating agents" include, but are not limited to, EDTA, EGTA, o-phenanthroline, and citrate. "Detergent" includes, but is not limited to, SDS and sodium lauroyl sarcosine. "Chaotropes" include, but are not limited to, guanidinium hydrochloride. , isothiocyanates, urea, and formamide. do not have.

[0171] Useful additives include, for example, gelatin, vegetable proteins, such as sunflower seeds, and the like. Protein, soy protein, cottonseed protein, peanut protein, grapeseed protein Proteins such as whey protein, whey protein isolate, blood proteins, egg proteins Proteins, acrylated proteins, water-soluble polysaccharides, e.g. alginates, carrageenans, guar gum , agar, xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, Water-soluble derivatives of cellulose, such as gum karaya, gum tragacanth, and pectin: alkyl Cellulose, hydroxyalkyl cellulose and hydroxyalkyl alkyl cellulose , for example, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose , Hydroxypropyl cellulose, Hydroxyethyl methyl cellulose, Hydroxypro Cellulose esters such as butyl methylcellulose and hydroxybutyl methylcellulose and hydroxyalkyl cellulose esters, such as cellulose acetate phthalate (CAP), hydroxyalkyl cellulose esters, such as cellulose acetate phthalate (CAP), Hydroxypropyl methylcellulose (HPMC); Carboxyalkyl cellulose, Carboxyalkyl alkyl alkyl cellulose, carboxy alkyl cellulose esters, e.g. carboxy Methylcellulose and their alkali metal salts; water-soluble synthetic polymers, e.g. polyacrylic Polyacrylic acid and polymethacrylic acid esters, poly Polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), Contains polyvinylpyrrolidone (PVP), PVY / vinyl acetate copolymer, and polycrotonic acid. Also, phthalate gelatin, succinate gelatin, cross-linked gelatin, shellac, de Water-soluble chemical derivatives of starch, such as those having tertiary or quaternary amino groups, e.g., Cationically modified acrylates, such as those containing quaternized diethylaminoethyl groups. and methacrylates; and other similar polymers are also suitable.

[0172] The additional components may be present in an amount of up to about 80% by weight based on the weight of all the composition components, preferably It can be in the range of about 0.005% to 50%, more preferably 1% to 20%, which is greater than 1%, 5 More than %, More than 10%, More than 20%, More than 30%, More than 40%, More than 50%, More than 60%, More than 70%, About 80%, More than 80%, 80 Less than 70%, Less than 60%, Less than 50%, Less than 40%, Less than 30%, Less than 20%, Less than 10%, Less than 5 %, about 3%, and less than 1%. Other additives include anti-adhesive agents, flow agents, and opacifiers, For example, oxides of magnesium, aluminum, silicon, titanium, etc., may be used, if desired. Concentrations ranging from about 0.005% to about 5% by weight based on the weight of the film components, and if desired It can contain from about 0.02% to about 2% by weight, including greater than 0.02%, greater than 0.2%, greater than 0.5%, greater than 1%, More than 1.5%, More than 2%, More than 4%, About 5%, More than 5%, Less than 4%, Less than 2%, Less than 1%, Less than 0.5%, 0.2% Other additives include anti-adhesive agents, flow agents, and opacifiers, e.g. For example, oxides of magnesium, aluminum, silicon, titanium, etc., preferably entirely Based on the weight of the film components, about 0.01% to about 5% by weight, preferably about 0.02% to about 1% It can be included in a range of concentrations.

[0173] In certain embodiments, the composition can include a plasticizer, which can be a polyalkylene. Polyethylene glycol, polypropylene glycol, polyethylene -Low molecular weight organic plasticizers, e.g. glycerol, glycerol, etc. Monoacetate, diacetate or triacetate, triacetin, polysol Butyl alcohol, cetyl alcohol, propylene glycol, sugar alcohol sorbitol, diethyl Sodium sulfosuccinate, triethyl citrate, tributyl citrate, plant extracts, These may include fatty acid esters, fatty acids, oils, and the like, based on the weight of the composition. As such, it is added at a concentration in the range of about 0.1% to about 40%, preferably in the range of about 0.5% to about 20%. Compounds that improve the textural properties of the film material, e.g. animal or vegetable Fats and the like may also be added, preferably in their hydrogenated form. It may also contain compounds that improve the textural properties of the product. Binders that contribute to the ease of formation and overall quality of the film. Non-limiting examples of binders include: Starch, natural rubber, alpha starch, gelatin, polyvinylpyrrolidone, methylcellulose Rosemary, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide Polyvinyl oxazolidones, polyvinyl alcohols, and the like.

[0174] Further possible additives are solubility enhancing agents, such as substances that form inclusion compounds with the active ingredient. Such substances are useful in treating highly insoluble and / or unstable active substances. Generally, these materials can be useful for improving the hydrophobic interior cavities and It is a doughnut-shaped molecule with a hydrophilic exterior and a hydrophilic outer layer. Insoluble and / or unstable pharmaceutical active ingredients fits into the hydrophobic cavity, resulting in an inclusion complex that is soluble in water. The formation of inclusion complexes increases the water solubility of highly insoluble and / or unstable pharmaceutical active ingredients. Particularly desirable examples of such materials are cyclodextrins, which is a cyclic carbohydrate derived from starch. However, other similar substances are within the scope of the present invention. It is expected to fit within.

[0175] Suitable colorants include those listed under Food, Drug, and Cosmetic Colors (FD&C), Drug and Cosmetic Colors, and (D&C), or topical drug and cosmetic colorants (Ext. D&C). These colorants include pigments, These include their corresponding lakes, as well as certain natural and derived colorants. Lakes are water-based colorants. Other examples of colorants include known azo dyes, organic or inorganic pigments, or colorants of natural origin. Inorganic pigments, such as oxides or iron The oxides of titanium are preferably in an amount of about 0.001 to about 10% by weight based on the weight of the total components. %, preferably at a concentration in the range of about 0.5 to about 3%.

[0176] Flavoring agents may be selected from natural and synthetic flavored liquids. Exemplary of such materials are: The complete list includes volatile oils, synthetic flavor oils, flavored aromatics, oils, liquids, oleoresins, or botanicals. Non-limiting examples of extracts include those derived from the leaves, flowers, fruits, stems, and combinations thereof. A representative list would include mint oil, cocoa, and citrus oils such as lemon, orange, grape, laurel, and thyme. and grapefruit, as well as apples, pears, peaches, grapes, strawberries, raspberries - Fruit essences including cherry, plum, pineapple, apricot, or other Other useful flavoring agents include aldehydes and esters, such as benzaldehyde, stearyl alcohol, glyceryl alcohol, glyceryl alcohol, ethyl ... Hid (cherries, almonds), citral, i.e. alpha citral (lemon, la im), neral, i.e. beta-citral (lemon, lime), decanal (oleic acid), Aldehyde C-8 (citrus fruits), Aldehyde C-9 (citrus fruits), Aldehyde C-12 (citrus fruits), Tachibana fruit), tolualdehyde (cherries, almonds), 2,6-dimethyloctanol (green green fruits), and 2-dodecenal (citrus fruits, mandarin), and combinations thereof.

[0177] Sweeteners include the following non-limiting list: glucose (corn syrup), dextrose, inositol, glycerol ... saccharides, fructose, and combinations thereof; saccharin and its various salts, such as sodium dipeptide-based sweeteners, e.g. aspartame, neotame, advantage Dihydrochalcone compounds, glycyrrhizin, stevia (Stevia Rebaudiana) (steviosin) chlorine derivatives of sucrose, e.g. sucralose; sugar alcohols, e.g. sorbitol, malic acid The glycerol may be selected from the group consisting of diglycerol, glycerol, acetone, glycerol, sorbitol, xylitol, and the like. Starch hydrolysate and synthetic sweetener 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazine-4- acesulfame-2,2-dioxide, especially the potassium salt (acesulfame-K), as well as their sodium salts and calcium salts, as well as natural intensive sweeteners, such as Lo Han Kuo. Other sweeteners may also be used.

[0178] Defoamers and / or defoamers components may also be used in the film. The present invention also aids in the removal of air, such as trapped air, from the foam-forming composition. Entrapped air can lead to an uneven film. Simethicone is one particularly useful The present invention is not so limited, however, and includes other antifoaming and / or defoaming agents. Simethicone and related substances are used for densification purposes. More specifically, such materials may be utilized to absorb voids, air, moisture, and similar This can facilitate the removal of undesirable components, which allows for a denser film to be produced. The material or component that performs this function is the densifier (d These substances are called densification agents or densifying agents. As such, trapped air or undesirable components can lead to non-uniform films.

[0179] The previously mentioned U.S. Pat. Nos. 7,425,292 and 8,765,167, which are assigned to the assignee of the present invention. Any other optional ingredients described in may also be included in the films described herein.

[0180] The film composition may further contain a buffer to control the pH of the film composition. Any desired level of buffering agent may be used to stabilize the pharmaceutical active ingredient as it is released from the composition. This buffer is incorporated into the film composition to provide the desired pH level encountered. The agent is present in an amount sufficient to control the release of the medicament active ingredient from the film and / or its absorption into the body. In some embodiments, the buffer is sodium citrate. , citric acid, bitartrate and combinations thereof.

[0181] The pharmaceutical films described herein may be formed by any desired process. The process is described in U.S. Patent Nos. 8,652,378, 7,425,292 and 7,357,891. The entire contents of which are incorporated herein by reference. In one embodiment, The film formulation composition is formed by first preparing a wet composition, which The article comprises a polymeric carrier matrix and a therapeutically effective amount of a medicament active ingredient. The composition is cast into a film and then thoroughly dried to form a free-standing film composition. The wet composition is cast into individual dosage forms or it is cast into sheets. The sheet is then cut into individual dosage forms.

[0182] The pharmaceutical composition is capable of adhering to a mucosal surface. The present invention is directed to the oral, vaginal, visceral, or other mucosal surfaces. Any body tissue, patient, having a moist surface and susceptible to bodily fluids, such as any type of mucosal surface. The device is particularly useful for the topical treatment of mucosal lesions, ulcers, and wounds. Upon application and attachment, the drug provides a protective layer and protects the treatment site, surrounding tissue, and other body fluids. Deliver drugs. Control of erosion in aqueous solutions or body fluids such as saliva, and simultaneous or subsequent delivery. Given the slow natural erosion of the film, this device provides effective drug delivery at the treatment site. Provide adequate residence time for the

[0183] The residence time of the composition in the device depends on the erosion rate of the water-erodible polymer used in the formulation and The erosion rate depends on the composition and their respective concentrations. Chemically distinct polymers, such as hydroxyethyl cellulose and hydroxypropyl cellulose. By mixing cellulose and hydroxyethyl cellulose together, low and medium molecular weights were obtained. By using different molecular weight grades of the same polymer, such as blends of different lipophilicity values; or by using excipients or plasticizers with water solubility characteristics (including essentially insoluble components). By using water-soluble organic and inorganic salts, hydroxyethyl by using a polymer such as polycellulose and a cross-linking agent such as glyoxal; or or, once obtained, altering the physical state of the film, including its crystallinity or phase transition. These strategies include: They may be utilized alone or in combination to alter the erosion kinetics of the device. The drug delivery device adheres to the mucosal surface and is held in place. Absorption of water softens the device. While the device is placed on the mucosal surface, drug delivery is The residence time depends on the desired timing of delivery of the selected drug and the desired life of the carrier. However, in general, the residence time can be adjusted to anywhere from about a few seconds to about a few days. Preferably, the residence time for most pharmaceuticals is adjusted to be between about 5 seconds and about 24 hours. More preferably, the residence time is adjusted to about 5 seconds to about 30 minutes. Once the device is attached to the mucosal surface, it also provides protection for the treatment area and acts as an erodible dressing. The lipophilic material is designed to retard erosion in order to reduce disintegration and dissolution. It can be calculated.

[0184] Excipients that are sensitive to enzymes such as amylase and are highly soluble in water, e.g. The erodibility of the device can be adjusted by adding water-soluble organic and inorganic salts. Suitable excipients include chloride, carbonate, bicarbonate, citrate, trifluoroacetate, and the like. Sodium salts of fluoroacetates, benzoates, phosphates, fluorides, sulfates, or tartrates and potassium salts. The amount added will determine how much the erosion kinetics are altered, as well as and the amounts and nature of other ingredients in the device.

[0185] The emulsifiers typically used in the water-based emulsions described above are preferably , linoleic acid, palmitic acid, myristoleic acid, lauric acid, stearic acid, cetearyl acid When the acid is selected from the group consisting of oleic acid, sodium hydroxide, and potassium hydroxide, lauric acid esters of sorbitol and sorbitol anhydrides, palladium esters, etc., obtained in situ or Mitate ester, stearate ester, or oleate ester, monooleate Polyoxyethylene derivatives including monostearate, monopalmitate, and monolaurate Conductors, aliphatic alcohols, alkylphenols, allyl ethers, alkylaryl ethers sorbitan monostearate, sorbitan monooleate, and sorbitan monopasterate lumitate.

[0186] The amount of pharmaceutical active ingredient used will depend on the desired therapeutic strength and the composition of these layers. However, preferably, the pharmaceutical ingredient comprises from about 0.001% to about 99%, more preferably from about 0.003 to about 99%, of the composition. About 75%, and most preferably about 0.005% to about 50% by weight, which is greater than 0.005%, 0.05% Very, more than 0.5%, more than 1%, more than 5%, more than 10%, more than 15%, more than 20%, more than 30%, about 50%, more than 50%, 50% Less than, Less than 30%, Less than 20%, Less than 15%, Less than 10%, Less than 5%, Less than 1%, Less than 0.5%, 0.05 %, and less than 0.005%. The amount of other ingredients varies depending on the drug or other ingredients. Typically, these components will not exceed 50% by weight of the total device, and preferably will not exceed 30%. and most preferably not more than 15%.

[0187] The thickness of the film may vary depending on the thickness of each layer and the number of layers. Both the thickness and amount of may be adjusted to vary the erosion kinetics. When the film has only two layers, the thickness is 0.005 mm to 2 mm, preferably 0.01 to 1 mm, more preferably The range is 0.1 to 0.5 mm, which means more than 0.1 mm, more than 0.2 mm, about 0.5 mm, more than 0.5 mm, less than 0.5 mm, 0 The thickness of each layer should be between 10 and 90% of the total thickness of the layered device. %, preferably 30-60%, which may be greater than 10%, greater than 20%, greater than 30%, greater than 40%, More than 50%, more than 70%, more than 90%, about 90%, less than 90%, less than 70%, less than 50%, less than 40%, 30 %, less than 20%, and less than 10%. Therefore, the preferred thickness of each layer is 0.01 mm to 0.9 mm. m, and may vary from 0.03 to 0.5 mm.

[0188] As will be appreciated by those of skill in the art, where systemic delivery is desired, e.g., transmucosal or transdermal delivery, the therapeutic The site is configured so that the film delivers a desired level of medication into blood, lymph, or other bodily fluids and Typically, such treatment areas include any area capable of maintaining or maintaining a desired condition. The sites include the mucosal tissues of the mouth, esophagus, ear, eye, anus, nose, and vagina, as well as the skin. When used as a site, typically the upper arm or thigh, where movement will not interfere with attachment of the device. A relatively large area of ​​skin that is not sensitive to light is preferred.

[0189] The pharmaceutical composition can also be used as a wound dressing. By providing a physical, compliant, oxygen and moisture permeable, flexible barrier that The membrane not only protects the wound but also promotes healing, sterility and scarification. to promote the development of a medical condition, to relieve pain, or to improve the overall condition of the affected person. Some of the examples provided below are suitable for application to the skin or wounds. As one skilled in the art will appreciate, the present formulations are well suited for treating dry skin over an extended period of time. The present invention incorporates specific hydrophilic / hygroscopic excipients that will help maintain good adhesion on the Another advantage of the present invention when utilized in this manner is that If it is not desired that the formula be noticeable on the skin, the use of pigments or coloring substances is unnecessary. On the other hand, if it is desired that the film be conspicuous, a dye or coloring substance may be utilized. It is possible.

[0190] The pharmaceutical composition is capable of adhering to mucosal tissue, which is a naturally moist tissue, while It can also be used on other surfaces, such as skin or wounds. Prior to application, the device is moistened with an aqueous-based fluid such as water, saliva, wound drainage, or sweat. The film can be attached to the skin even when it is not in contact with the skin. It can remain on the skin until it is eroded by contact with water, such as by bathing or washing. The film also can be easily removed by peeling without significant damage to the tissue. It can be done.

[0191] All references cited herein are incorporated by reference in their entirety. Other embodiments are within the scope of the following claims.

Claims

[Claim 1] Novel products, methods, and methods of manufacture substantially described in this specification.

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