Macrolides for use in methods of preventing or treating immune diseases or conditions

Abstract

The present invention relates to a macrolide for use in a method of preventing or treating an immune disease or condition, preferably transplant rejection, comprising administering said macrolide at least twice a day wherein said at least twice a day administration comprises administering a first dose at a first point in time and administering a second dose at a second point in time, wherein the second time point is a time point in the range of from about 1 hour to about 7 hours, preferably from about 2 hours to about 5 hours, more preferably from about 2.5 hours to about 3.5 hours, even more preferably from about 3 hours after the first time point. The invention also relates to a tacrolimus mucoadhesive film suitable for buccal administration.

Description

Technical Field

[0001] This invention relates to a macrolide in a method for preventing or treating immune diseases or conditions (preferably transplant rejection), the method comprising administering the macrolide at least twice daily, wherein the at least twice daily administration comprises administering a first dose at a first time point and administering a second dose at a second time point, wherein the second time point is a time point within the range of about 1 hour to about 7 hours after the first time point, preferably about 2 hours to about 5 hours, more preferably about 2.5 hours to about 3.5 hours, and even more preferably about 3 hours. Background Technology

[0002] Poor water solubility of active pharmaceutical ingredients (APIs) has always been a challenge in drug formulation development. In fact, most active pharmaceutical ingredients exhibit low water solubility. For an API to produce a therapeutic effect, it must dissolve at a sufficient concentration and reach the bloodstream. Therefore, APIs with low water solubility (such as macrolides) typically have poor bioavailability, meaning that only a small fraction of the administered API reaches the bloodstream after ingestion. Low bioavailability can be associated with incomplete absorption and / or metabolism in the gastrointestinal tract. Due to poor water solubility, oral macrolide formulations (such as tacrolimus formulations) have highly variable absorption profiles; for example, the absolute bioavailability of oral tacrolimus formulations ranges from 5% to 93%. Macrolides such as tacrolimus undergo extensive pre-systemic metabolism in the gastrointestinal tract, which limits their oral bioavailability; for example, in the case of tacrolimus, the average is approximately 25%.

[0003] Tacrolimus is an exemplary macrolide, a class of macrolides with potent immunosuppressive properties that inhibit cellular and humoral immune responses through several mechanisms of action, with the central effect involving the inhibition of calcineurin. Tacrolimus is approved as a first-line immunosuppressant for the prevention of transplant rejection in recipients of liver, kidney, or heart allogeneic transplants and for the treatment of allogeneic transplant rejection resistant to other immunosuppressive pharmaceutical products. Since Prograf was first approved in 1994, orally administered tacrolimus has become a cornerstone of immunosuppression in adults and children receiving solid organ transplants (SOTs). Approved oral dosage forms of tacrolimus include immediate-release capsules (e.g., [missing information]). Hard capsules), sustained-release capsules (e.g., Sustained-release hard capsules), sustained-release tablets (e.g., Sustained-release tablets and granules (e.g., for oral suspensions) (Particles). Oral administration of tacrolimus is now considered the global standard of care for preventing rejection after solid organ transplantation. Tacrolimus therapy is a daily, lifelong treatment.

[0004] Macrolides such as tacrolimus have a narrow therapeutic index, exhibit poor oral bioavailability due to their poor solubility, and further demonstrate high variability in pharmacokinetic parameters both between and within individuals. Therefore, close monitoring of the dose administered to patients is essential. Due to the patient-specific dosage (mg / kg body weight / day) of the macrolide tacrolimus, readily available capsule preparations are typically opened to prepare a solution of the active ingredient before administration to the patient; this process is known as “drug dispensing.” Drug dispensing does not meet the high-quality requirements of the drug product and may even jeopardize drug safety by increasing the risk of incorrect dosing. Furthermore, drug dispensing may lead to decreased drug stability or microbial contamination of the prepared solution.

[0005] Therefore, there remains a need for enhanced therapies using macrolides (especially those used for increased efficacy and / or enhanced bioavailability). In particular, there is a need for treatments that allow for the effective administration of sufficient doses of macrolides to patients. There is also a need for dosing regimens and / or formulations that allow for the effective delivery of macrolides to patients. Specifically, there remains a need for enhanced therapies that allow for the achievement of sufficient macrolide blood concentrations. There is also a need to reduce the variability in the bioavailability of macrolides, particularly the variability in macrolide blood levels. Furthermore, there is a need to enhance the bioavailability of macrolides such as tacrolimus. In addition, there is a need for enhanced means, such as dosing regimens for administering macrolides, for example, therapeutic systems that allow for the effective administration of active agents (e.g., macrolides). The aim is also to reduce the macrolide dose required to achieve therapeutic effects. Furthermore, there remains a need for effective methods for the prevention or treatment of immune diseases or conditions such as transplant rejection. Summary of the Invention

[0006] The elements of the invention will now be described. These elements are listed together with specific embodiments; however, it should be understood that they can be combined in any manner and in any number to create additional embodiments. The various examples and preferred embodiments described should not be construed as limiting the invention to only the explicitly described embodiments. This specification should be understood to support and cover embodiments that combine two or more of the explicitly described embodiments, or embodiments that combine one or more of the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutation and combination of all elements described in this application should be considered as disclosed in the description of this application, unless the context otherwise indicates.

[0007] In a first aspect, the present invention relates to a macrolide in a method for preventing or treating immune diseases or conditions (preferably transplant rejection), the method comprising administering the macrolide at least twice daily.

[0008] The application of at least twice a day includes administering a first dose at a first time point and administering a second dose at a second time point, wherein the second time point is within the range of about 1 hour to about 7 hours after the first time point, preferably about 2 hours to about 5 hours, more preferably about 2.5 hours to about 3.5 hours, or even more preferably about 3 hours after the first time point.

[0009] Preferably, the macrolide is administered via buccal administration.

[0010] In one embodiment, the macrolide is applied in the form of a mucosal adhesive layer (preferably a mucosal adhesive buccal layer);

[0011] Preferably, the application includes adhering the mucosal adhesive layer to the patient's body cavity, preferably to the patient's buccal cavity and / or the patient's mucosa.

[0012] The present invention also relates to a method for preventing or treating immune diseases or conditions (preferably transplant rejection), the method comprising administering macrolides at least twice daily.

[0013] The application of at least twice a day includes administering a first dose at a first time point and administering a second dose at a second time point, wherein the second time point is within the range of about 1 hour to about 7 hours after the first time point, preferably about 2 hours to about 5 hours, more preferably about 2.5 hours to about 3.5 hours, or even more preferably about 3 hours after the first time point.

[0014] Preferably, the macrolide is administered via buccal administration.

[0015] In one embodiment, the application includes applying each of the first dose and the second dose, preferably in the form of a mucosal adhesive layer, for a duration ranging from about 1 minute to about 7 hours, preferably from about 10 minutes to about 3 hours, more preferably from about 20 minutes to about 2 hours, even more preferably from about 30 minutes to about 90 minutes, and even more preferably from about 60 minutes.

[0016] In one embodiment, the administration includes administering the first dose for a period of about 30 minutes to about 90 minutes, preferably about 60 minutes; and administering the second dose at a time point about 2.5 hours to about 3.5 hours, preferably about 3 hours after the first time point, for a period of about 30 minutes to about 90 minutes, preferably about 60 minutes.

[0017] In one embodiment, the first dose and the second dose (preferably prior to their administration) each comprise an amount in the range of about 0.001 mg to about 250 mg, preferably in the range of about 0.01 mg to about 50 mg, more preferably in the range of about 0.05 mg to about 25 mg, even more preferably in the range of about 0.1 mg to about 15 mg, even more preferably in the range of about 0.5 mg to about 13 mg, optionally in the range of about 8 mg to about 12 mg of the macrolide; and / or

[0018] The macrolide is administered via buccal administration, and the administration of the macrolide at least twice daily comprises administering the macrolide at about ≤40%, preferably about ≤30%, more preferably about ≤25%, and even more preferably about ≤20% of the total daily dose administered orally.

[0019] In one embodiment, prior to the application, the macrolide is administered at a concentration relative to 1 cm. 2 The amount of the mucosal adhesive layer is in the range of about 0.01 mg to about 10 mg, preferably in a quantity relative to 1 cm. 2 The mucosal adhesive layer is in the range of about 0.1 mg to about 5 mg, more preferably relative to 1 cm. 2 The mucosal adhesive layer is in the range of approximately 1.5 mg to approximately 3.5 mg, or even more preferably relative to 1 cm. 2 The amount of the mucosal adhesive layer is in the range of about 1.8 mg to about 2.5 mg.

[0020] In one embodiment, the macrolide is applied in the form of a mucosal adhesive layer comprising the following:

[0021] - Mucosal adhesive polymers, preferably selected from the following polymers: a) amphiphilic polymers and hydrophilic polymers, b) poly(methacrylate), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers comprising polyvinyl acetate and / or polyvinylpyrrolidone, and combinations thereof;

[0022] Preferably,

[0023] The amphiphilic polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyoxyethylene castor oil, and D-α-tocopherol-polyethylene glycol-succinate (TPGS), and / or

[0024] The poly(methacrylate) is selected from neutral protonable poly(methacrylate) and cationic poly(methacrylate), preferably selected from copolymers of dialkylaminoethyl methacrylate and methacrylate and copolymers of trialkylaminoethyl methacrylate and methacrylate, especially copolymers of dimethylaminoethyl methacrylate and methacrylate and copolymers of trimethylaminoethyl methacrylate and methacrylate.

[0025] Optionally, the mucosal adhesive layer further comprises:

[0026] - Cellulose derivatives, preferably selected from hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), hydroxyethyl methyl cellulose (HEMC), ethyl cellulose (EC), and combinations thereof;

[0027] - A plasticizer, preferably selected from glycerol, polyethylene glycol (e.g., low molecular weight polyethylene glycols such as PEG 200 or PEG400), propylene glycol, sorbitol, triacetin, and tributyl citrate; more preferably glycerol; and / or

[0028] - Colorant, preferably TiO2;

[0029] Optionally, the macrolide is in the form of a micronized macrolide, preferably a micronized crystalline macrolide, and / or...

[0030] Or it may exist in the layer in the form of molecularly dissolved non-nanoparticles.

[0031] In one embodiment, the at least twice daily administration provides a first peak in whole blood concentration of macrolide at a time point approximately 2 to 4 hours after the first time point, preferably approximately 2.5 to 3.5 hours, more preferably approximately 3 hours, and provides a second peak in whole blood concentration of macrolide at a time point approximately 7 to 9 hours after the first time point, preferably approximately 7.5 to 8.5 hours, more preferably approximately 8 hours.

[0032] Optionally, the administration of the macrolide at least twice daily at a time point approximately 3 to 5 hours after the second time point, preferably approximately 3.5 to 4.5 hours, and more preferably approximately 4 hours after the second time point, provides the second peak concentration of the macrolide in whole blood.

[0033] In one embodiment, the administration at least twice daily provides a whole blood concentration of the macrolide in the range of about 0.01 ng / mL to about 50 ng / mL, preferably in the range of about 3 ng / mL to about 20 ng / mL, more preferably in the range of about 5 ng / mL to about 20 ng / mL, for a duration of about 24 hours.

[0034] In one embodiment, the at least twice-daily application provides a coefficient of variation of less than 40%, preferably less than 35%, more preferably less than 32%, and even more preferably 30% or less, such as in the range of 20% to 30% or in the range of 25% to 30%.

[0035] In one implementation, the at least twice-daily application is provided:

[0036] - Within approximately 3 to 10 hours after the first time point, preferably within approximately 7 to 9 hours after the first time point, more preferably within approximately 7.5 to 8.5 hours after the first time point. max ; and / or

[0037] - Within approximately 1 hour to approximately 6 hours after the second time point, preferably within approximately 2 hours to approximately 5 hours after the second time point, more preferably within approximately 3.5 hours to approximately 4.5 hours after the second time point, for example, within approximately 4 hours after the second time point. max .

[0038] In one implementation, the at least twice-daily application is provided:

[0039] - In the range of about 0.05 ng / mL to about 50 ng / mL, preferably in the range of about 0.1 ng / mL to about 30 ng / mL, more preferably in the range of about 0.7 ng / mL to about 20 ng / mL, and even more preferably in the range of about 5.5 ng / mL to about 20 ng / mL.

[0040] C in the range of ng / mL max ; and / or

[0041] - In the range of about 0.01 ng / mL to about 18 ng / mL, preferably in the range of about 0.5 ng / mL to about 16 ng / mL, more preferably in the range of about 3 ng / mL to about 15 ng / mL, such as in the range of about 3 ng / mL to about 7 ng / mL or in the range of about 5 ng / mL to about 7 ng / mL, C trough .

[0042] In one implementation, the at least twice-daily application is performed for at least two days, preferably at least one week, more preferably at least one month, and even more preferably at least one year.

[0043] Optionally, if the macrolide is used to prevent or treat transplant rejection, the at least twice-daily administration is performed on the patient for life.

[0044] In one embodiment, the macrolide is administered to a human patient; wherein, preferably, the patient is not a fasting patient.

[0045] In one embodiment, the macrolide is selected from macrolide immunosuppressants, macrolide antibiotics, and macrolide antifungals;

[0046] Preferably,

[0047] -The macrolide immunosuppressants are selected from tacrolimus, sirolimus, everolimus, and pimecrolimus;

[0048] - The macrolide antibiotics are selected from erythromycin, clarithromycin, azithromycin, roxithromycin, josamycin, spiramycin, telithromycin, tylosin, and fedamycin; and / or

[0049] The macrolide antifungal agents mentioned are selected from polyenes, particularly nystatin, natamycin, and amphotericin B.

[0050] More preferably, the macrolide is tacrolimus or sirolimus, or even more preferably tacrolimus.

[0051] In one embodiment, the mucosal adhesive layer is provided in the form of a mucosal adhesive film comprising the mucosal adhesive layer, preferably in the form of a mucosal adhesive buccal membrane comprising the mucosal adhesive layer.

[0052] On the other hand, the present invention relates to a method for preventing and / or treating immune diseases or conditions (preferably transplant rejection), comprising administering macrolides, particularly therapeutically effective amounts of macrolides, to a patient in need at least twice daily, wherein the at least twice daily administration comprises administering a first dose at a first time point and administering a second dose at a second time point, wherein the second time point is a time point within the range of about 1 hour to about 7 hours after the first time point, preferably about 2 hours to about 5 hours, more preferably about 2.5 hours to about 3.5 hours, and even more preferably about 3 hours.

[0053] Preferably, the macrolide is administered via buccal administration.

[0054] In one embodiment, the macrolide is applied as a mucosal adhesive layer, preferably a mucosal adhesive buccal layer; wherein, preferably, the application comprises adhering the mucosal adhesive layer to a patient's body cavity, preferably to the patient's buccal cavity and / or the patient's mucosa.

[0055] In one implementation, the administration, the first dose, the second dose, the macrolide, the mucosal adhesive layer, and the patient are as defined herein.

[0056] On the other hand, the present invention relates to the use of macrolides in the manufacture of medicaments for the prevention or treatment of immune diseases or conditions (preferably transplant rejection), comprising administering the macrolides at least twice daily.

[0057] The application of at least twice a day includes administering a first dose at a first time point and administering a second dose at a second time point, wherein the second time point is within the range of about 1 hour to about 7 hours after the first time point, preferably about 2 hours to about 5 hours, more preferably about 2.5 hours to about 3.5 hours, or even more preferably about 3 hours after the first time point.

[0058] Preferably, the macrolide is administered via buccal administration.

[0059] In one embodiment, the macrolide is applied as a mucosal adhesive layer, preferably a mucosal adhesive buccal layer; wherein, preferably, the application comprises adhering the mucosal adhesive layer to a patient's body cavity, preferably to the patient's buccal cavity and / or the patient's mucosa.

[0060] In one implementation, the administration, the first dose, the second dose, the macrolide, the mucosal adhesive layer, and the patient are as defined herein.

[0061] Sometimes in this document, the composition of a membrane or layer is described by indicating the presence of individual components contained therein, and by exemplarily representing their respective amounts or percentages (e.g., weight percentages) within such a membrane or layer. Such amounts or percentages are typically expressed in ranges that may be adopted. In this context, it should be noted that the specific and particular values ​​of the individual components will and should be selected from the corresponding ranges, such that in any case, the sum of the corresponding components will total exactly 100% or less than 100%, but not exceeding 100%. Nevertheless, as examples for components A, B, C, and D, the range for each component is expressed in terms of a maximum and a minimum value: A min To A max B min To B max C min To C max and D min To Dmax The corresponding values ​​for each component will and should be selected from the corresponding ranges such that, in any case, the sum of the corresponding components will total exactly 100% or less than 100%. When the sum of the corresponding values ​​is not equal to 100%, but equal to or less than 100%, there will be additional components such as one or more solvents, fillers, fillers, etc., which will and should be added in appropriate amounts, i.e., up to the amount required to make up 100%.

[0062] The present invention also relates to a tacrolimus mucosal adhesive film suitable for buccal administration, comprising a mucosal adhesive layer and a backing layer, wherein:

[0063] A) The adhesive membrane layer comprises:

[0064] Tacrolimus, approximately 12 to approximately 25 percent by weight;

[0065] Ethyl cellulose, approximately 27 to approximately 31 percent by weight;

[0066] Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 300-600 mPa·s, approximately 28 to about 36% by weight;

[0067] About 6 to about 10% by weight of hydroxypropyl cellulose [weight-average molecular weight about 370,000-Klucel GF] having a viscosity of about 150-400 mPa·s; and

[0068] About 2 to about 5% by weight of a calcium / sodium copolymer of methyl vinyl ether and maleic anhydride; and

[0069] The weight percentages are based on the dry weight of the adhesive layer.

[0070] Or one of them:

[0071] B) The adhesive membrane layer comprises:

[0072] Tacrolimus, approximately 18 to approximately 25 percent by weight;

[0073] Ethyl cellulose, approximately 3 to approximately 13 percent by weight;

[0074] Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 300-600 mPa·s, approximately 29 to about 42% by weight;

[0075] Hydroxypropyl cellulose [weight-average molecular weight of about 370,000-Klucel GF] with a viscosity of about 1 to about 28% by weight and a viscosity of about 150-400 mPa·s; and

[0076] About 2 to about 10% by weight of crosslinked poly(acrylic acid); and

[0077] The weight percentages are based on the dry weight of the adhesive layer.

[0078] In one embodiment of the tacrolimus adhesive membrane (particularly according to any one of the foregoing embodiments), the backing layer comprises ethyl cellulose.

[0079] In one embodiment of the tacrolimus-based adhesive membrane (particularly according to the foregoing embodiments), the backing layer comprises ethyl cellulose in the range of about 50 to about 62% by weight based on the dry weight of the backing layer.

[0080] In another embodiment of the tacrolimus adhesive membrane, the backing layer comprises ethyl cellulose in the range of about 25 to about 27% by weight based on the dry weight of the backing layer.

[0081] In one embodiment of the tacrolimus mucosal adhesive membrane (particularly according to any one of the foregoing embodiments), the membrane contains 8 mg to 17 mg of tacrolimus.

[0082] In one embodiment of the tacrolimus mucosal adhesive membrane (particularly according to any one of the foregoing embodiments), the tacrolimus membrane contains 8.8 mg, 12 mg, 14.4 mg, or 16.5 mg of tacrolimus.

[0083] In one embodiment of a tacrolimus adhesive membrane (particularly according to any one of the foregoing embodiments), such a membrane further comprises an adhesive layer disposed between the adhesive membrane layer and the backing layer.

[0084] In another embodiment of the tacrolimus mucosal adhesive membrane, the adhesive layer and the backing layer are in direct contact with each other, and in this embodiment of tacrolimus mucosal adhesion, no layer is provided between the adhesive layer and the backing layer.

[0085] In another aspect, the present invention relates to a tacrolimus mucosal adhesive membrane suitable for buccal administration, comprising an adhesive layer and a backing layer, wherein:

[0086] The adhesive membrane layer comprises:

[0087] About 12 to about 13 percent by weight of tacrolimus, or about 19 to about 23 percent by weight of tacrolimus;

[0088] Ethyl cellulose, approximately 27 to approximately 30 percent by weight;

[0089] Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 30-600 mPa·s, approximately 30-35% by weight;

[0090] About 7 to 8% by weight of hydroxypropyl cellulose [weight-average molecular weight about 370,000-Klucel GF] having a viscosity of about 150-400 mPa·s; and

[0091] A calcium / sodium copolymer of methyl vinyl ether and maleic anhydride, comprising approximately 3 to 4% by weight; and

[0092] The weight percentages are based on the dry weight of the adhesive layer.

[0093] In another aspect, the present invention relates to a tacrolimus mucosal adhesive membrane suitable for buccal administration, comprising an adhesive layer and a backing layer, wherein:

[0094] The adhesive membrane layer comprises:

[0095] Tacrolimus: approximately 19 to approximately 22 percent by weight;

[0096] Ethyl cellulose, approximately 3 to approximately 13 percent by weight;

[0097] Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 300-600 mPa·s, approximately 29 to about 42% by weight;

[0098] Hydroxypropyl cellulose [weight-average molecular weight of about 370,000-Klucel GF] with a viscosity of about 1 to about 28% by weight and a viscosity of about 150-400 mPa·s; and

[0099] About 2 to about 10% by weight of crosslinked poly(acrylic acid); and

[0100] The weight percentages are based on the dry weight of the adhesive layer.

[0101] In another aspect, the present invention relates to a tacrolimus mucosal adhesive membrane suitable for buccal administration, comprising an adhesive layer and a backing layer, wherein:

[0102] The adhesive membrane layer comprises:

[0103] Tacrolimus, approximately 5 to approximately 14% by weight;

[0104] Ethyl cellulose, approximately 29 to approximately 33 percent by weight;

[0105] Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 34 to about 41% by weight;

[0106] About 7 to about 10% by weight of hydroxypropyl cellulose [weight-average molecular weight about 370,000-Klucel GF] having a viscosity of about 150-400 mPa·s; and

[0107] A copolymer of about 2 to about 4 weight percent methyl vinyl ether and maleic anhydride; and

[0108] The weight percentages are based on the dry weight of the adhesive layer.

[0109] In another aspect, the present invention relates to a tacrolimus mucosal adhesive membrane suitable for buccal administration, comprising an adhesive layer and a backing layer, wherein:

[0110] The adhesive membrane layer comprises:

[0111] Tacrolimus, approximately 18 to 20 percent by weight;

[0112] Ethyl cellulose, approximately 11 to approximately 13 percent by weight;

[0113] Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 30-600 mPa·s, approximately 30-32% by weight;

[0114] Hydroxypropyl cellulose [weight-average molecular weight of about 370,000-Klucel GF] with a viscosity of about 11 to about 13% by weight;

[0115] The weight percentages are based on the dry weight of the adhesive layer; and

[0116] Such mucosal adhesive layers do not contain any polymer selected from the following mucosal adhesive polymers: copolymers of methyl vinyl ether and maleic anhydride; poly(acrylic acid); crosslinked poly(acrylic acid); poly(methacrylic acid); poly[(maleic anhydride)-co-(vinyl methyl ether)] or its salts; gelatin; polysaccharides, especially alginate, chitosan, xanthan gum, hyaluronic acid, pectin or pullulan; carboxymethyl cellulose; hydroxypropyl methyl cellulose; poly(vinylpyrrolidone), poly[(vinylpyrrolidone)-co-(vinyl acetate)]; mixtures of poly(vinyl acetate) and poly(vinylpyrrolidone); poly(vinyl alcohol); and poly(vinyl acetate).

[0117] In another aspect, the present invention relates to a tacrolimus mucosal adhesive membrane suitable for buccal administration, comprising an adhesive layer and a backing layer, wherein:

[0118] The adhesive membrane layer comprises:

[0119] Tacrolimus: approximately 9 to approximately 23 percent by weight;

[0120] Ethyl cellulose, approximately 10 to approximately 13 percent by weight;

[0121] Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 300-600 mPa·s, about 15 to about 32% by weight;

[0122] About 5 to about 12% by weight of hydroxypropyl cellulose [weight-average molecular weight about 370,000-Klucel GF] having a viscosity of about 150-400 mPa·s; and

[0123] Approximately 6 to 28 percent by weight of poly(methacrylate); and

[0124] The weight percentages are based on the dry weight of the adhesive layer.

[0125] In another aspect, the present invention relates to a tacrolimus mucosal adhesive membrane suitable for buccal administration, comprising an adhesive layer and a backing layer, wherein:

[0126] The adhesive membrane layer comprises:

[0127] Tacrolimus, approximately 18 to 20 percent by weight;

[0128] Ethyl cellulose, approximately 4 to 6 percent by weight;

[0129] Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 31 to about 32% by weight;

[0130] Hydroxypropyl cellulose [weight-average molecular weight of about 370,000-Klucel GF] with a viscosity of about 27 to about 28% by weight;

[0131] The weight percentages are based on the dry weight of the adhesive layer; and

[0132] Such mucosal adhesive layers do not contain any polymer selected from the following mucosal adhesive polymers: copolymers of methyl vinyl ether and maleic anhydride; poly(acrylic acid); crosslinked poly(acrylic acid); poly(methacrylic acid); poly[(maleic anhydride)-co-(vinyl methyl ether)] or its salts; gelatin; polysaccharides, especially alginate, chitosan, xanthan gum, hyaluronic acid, pectin or pullulan; carboxymethyl cellulose; hydroxypropyl methyl cellulose; poly(vinylpyrrolidone), poly[(vinylpyrrolidone)-co-(vinyl acetate)]; mixtures of poly(vinyl acetate) and poly(vinylpyrrolidone); poly(vinyl alcohol); and poly(vinyl acetate).

[0133] In another aspect, the present invention relates to a tacrolimus mucosal adhesive membrane suitable for buccal administration, comprising an adhesive layer and a backing layer, wherein:

[0134] The adhesive membrane layer comprises:

[0135] Tacrolimus, approximately 18 to 20 percent by weight;

[0136] Ethyl cellulose, approximately 4 to approximately 12 percent by weight;

[0137] Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 31 to about 42% by weight;

[0138] About 2 to about 23% by weight of hydroxypropyl cellulose [weight-average molecular weight about 370,000-Klucel GF] having a viscosity of about 150-400 mPa·s; and

[0139] About 2 to about 6 weights of crosslinked poly(acrylic acid); and

[0140] The weight percentages are based on the dry weight of the adhesive layer.

[0141] In another aspect, the present invention relates to a method for treating a human patient with an allogeneic solid organ transplant, wherein the patient requires prevention of transplant rejection, comprising:

[0142] Twice daily, a mucosal adhesive film as described in any of the embodiments and aspects herein, preferably a mucosal adhesive film as described in any of the foregoing embodiments, is applied to the patient's cheek.

[0143] In one embodiment of a method for treating human patients with allogeneic solid organ transplants, buccal application involves applying a first mucosal adhesive membrane as described herein for about 30 to 60 minutes, preferably 60 minutes, or equally preferably 30 minutes, followed by no application for about 3 to 5 hours, after which a second mucosal adhesive membrane as described herein is applied buccally to the patient for about 30 to 60 minutes, preferably 60 minutes, or equally preferably 30 minutes.

[0144] In one embodiment of a method for treating human patients with allogeneic solid organ transplants, 24 hours after twice-daily buccal application, the human patient's C... trough Blood levels of tacrolimus C max The value is approximately 30%-40%.

[0145] Detailed description

[0146] This invention aims to provide, for example, enhanced administration of macrolides, for the prevention and / or treatment of transplant rejection after organ transplantation, particularly after solid organ transplantation. A further objective of this invention is to provide an effective administration of macrolides. Another object of this invention is to provide a macrolide for a therapy that allows for the efficient achievement of therapeutic blood levels of macrolides. Furthermore, an object of this invention is to provide a dosing regimen that allows for early onset of therapeutic effects. Another object of this invention is to reduce side effects. Another object of this invention is to reduce the dosage required to achieve desired macrolide blood levels (such as blood levels within a therapeutic window). This invention also aims to prevent and treat immune diseases and conditions such as solid organ transplant rejection. For example, the macrolides used in this invention can be administered in the form of mucosal adhesive films (e.g., mucosal adhesives, unidirectional, insoluble buccal films). This invention aims to provide effective therapies, for example, those more effective than standard oral macrolide therapies (such as standard tacrolimus therapy, e.g., standard therapies involving capsules, tablets, or granules). Although macrolides such as tacrolimus typically have very low water solubility, the macrolides used in this invention (e.g., administered in the form of a layer or film) effectively achieve therapeutic macrolide blood concentrations. Surprisingly, clinically relevant macrolide blood levels have been achieved using the macrolides used in this invention.

[0147] As used herein, the term "macrolide" refers to a class of natural product compounds that comprise or consist of one or more deoxyglucosides (typically clarithromycin and erythromycin deoxyglucosamine) linked to or composed of a large macrolide ring (e.g., a 14-, 15-, or 16-membered lactone ring); for example, tacrolimus, sirolimus, everolimus, pimecrolimus, erythromycin, clarithromycin, azithromycin, roxithromycin, josamycin, spiramycin, telithromycin, tylosin, and fidamycin, nystatin, natamycin, and amphotericin B. In one embodiment, the macrolide is selected from macrolide immunosuppressants, macrolide antibiotics, and macrolide antifungal agents. In one embodiment, the macrolide immunosuppressant is selected from tacrolimus, sirolimus, everolimus, and pimecrolimus. In one embodiment, the macrolide antibiotic is selected from erythromycin, clarithromycin, azithromycin, roxithromycin, josamycin, spiramycin, telithromycin, tylosin, and fidamycin. In one embodiment, the macrolide antifungal agent is selected from polyenes, particularly nystatin, natamycin, and amphotericin B. In a preferred embodiment, the macrolide is selected from tacrolimus, sirolimus, everolimus, and pimecrolimus, preferably from tacrolimus and sirolimus, and more preferably from tacrolimus. In one embodiment, the terms "active agent," "active ingredient," and "API" refer to macrolides. In one embodiment, the macrolide is formulated as a mucosal adhesive layer.

[0148] As used herein, the term "immune disease or condition" refers to any immune disease or condition known to those skilled in the art, particularly those that can be prevented or treated with macrolides such as tacrolimus. For example, an immune disease or condition may be selected from transplant rejection, preferably solid organ transplant rejection, such as liver, kidney, or heart allogeneic transplant rejection; autoimmune diseases, such as systemic lupus erythematosus, psoriasis, vitiligo, or lichen planus; infections, such as bacterial infections, such as Helicobacter pylori infection or Lyme disease; tumors, such as angiofibroma, lymphoma (e.g., T-cell lymphoma), renal cell carcinoma, neuroendocrine tumors, or breast cancer; and inflammatory diseases or conditions, such as atopic eczema, uveitis, dermatitis, Kimura disease, or inflammation associated with coronary heart disease. For example, the immune diseases or conditions for which macrolides such as tacrolimus are intended for prevention or treatment may be selected from transplant rejection, preferably solid organ transplant rejection, such as liver, kidney, or heart allogeneic transplant rejection; autoimmune diseases, such as psoriasis; infections; tumors; and inflammatory diseases, conditions, or illnesses, such as atopic eczema, uveitis, or Kimura disease. In one embodiment, the immune disease or condition is selected from transplant rejection, preferably solid organ transplant rejection, such as liver, kidney, or heart allogeneic transplant rejection; autoimmune diseases, such as systemic lupus erythematosus, psoriasis, vitiligo, or lichen planus; infections, such as bacterial infections, such as Helicobacter pylori infection or Lyme disease; tumors, such as angiofibroma, lymphoma (e.g., T-cell lymphoma), renal cell carcinoma, neuroendocrine tumors, or breast cancer; and inflammatory diseases or illnesses, such as atopic eczema, uveitis, dermatitis, Kimura disease, or inflammation associated with coronary heart disease. In a preferred embodiment, the immune disease or condition is transplant rejection. In one embodiment, the immune disease or condition is transplant rejection, preferably solid organ transplant rejection, such as allogeneic transplant rejection of the liver, kidney, or heart. In one embodiment, the terms "immune disease" and "immune condition" are used interchangeably. In a preferred embodiment, macrolides are used to prevent or treat transplant rejection.

[0149] In one embodiment, the administration of the macrolide at least twice daily comprises administration via a mucosal membrane, preferably via buccal administration. In another embodiment, the administration at least twice daily comprises administration via a mucosal membrane, preferably via buccal administration, for a first dose and a second dose, optionally an additional dose. For example, mucosal administration may involve application to the lining of a moist cavity such as the mouth or nose. Advantageously, mucosal administration, such as buccal administration, allows for reduced systemic side effects. Advantageously, mucosal routes, particularly buccal routes, avoid significant disadvantages associated with oral administration, such as first-pass metabolism in the liver, slow absorption, and drug degradation in the gastrointestinal tract. For example, buccal administration can be a local administration route, through which a drug held or applied to the buccal region diffuses through the oral mucosa and can directly enter the bloodstream. In a preferred embodiment, the mucosal administration, preferably buccal administration, comprises administration of the macrolide in the form of a mucosal adhesive layer, particularly in the form of a mucosal adhesive layer containing the macrolide. Advantageously, compared to oral administration, buccal administration provides better bioavailability and a faster onset of action, thus avoiding first-pass metabolism, because the drug does not pass through the digestive system. The inventors have discovered that, advantageously, when administered via a mucosa, such as buccal administration, particularly with two doses administered at an interval of 7 hours or less, preferably 5 hours or less, more preferably 4 hours or less, and even more preferably within a dosing interval of about 2.5 hours to about 3.5 hours, desired macrolide blood levels can be effectively achieved, and the dose required to achieve the desired macrolide blood levels can be significantly reduced, for example, by about 80%. Advantageously, buccal administration requires only 20%-25% of the dose required for standard oral therapy to achieve clinically relevant blood levels. In a preferred embodiment, the macrolide is administered to the buccal mucosa. From a drug delivery point of view, the buccal mucosa offers advantages over other epithelial tissues in the oral cavity (including a larger surface area) and is highly vascularized, resulting in direct entry into the systemic circulation via capillary and venous drainage, bypassing the hepatic first-pass effect.

[0150] As used herein, the term "at least twice daily" refers to administering macrolides in the form of at least two doses per day; for example, administering macrolides in the form of a first dose, a second dose, and optionally one or more additional doses (such as a third dose). The number of doses can be adjusted to meet the needs of the patient; thus, if desired, more than two doses may be administered per day, for example, to a patient with a high body weight. In one embodiment, at least twice daily refers to twice daily, three times daily, or four times daily, preferably twice daily. In a preferred embodiment, the macrolide is administered twice daily. In a preferred embodiment, the administration includes administering the macrolide twice daily. Optionally, more than two doses are administered to the patient per day. In one embodiment, the at least twice daily administration includes administering a first dose at a first time point and a second dose at a second time point, optionally administering a third dose at a third time point, wherein the second time point is within the range of about 1 hour to about 7 hours, preferably about 2 hours to about 5 hours, more preferably about 2.5 hours to about 3.5 hours, and even more preferably about 3 hours after the first time point. In one embodiment, the at least twice-daily administration comprises administering a first dose in the form of a mucosal adhesive layer and a second dose in the form of a mucosal adhesive layer, optionally administering a third dose in the form of a mucosal adhesive layer. Advantageously, when the second dose is administered after the first time point, i.e., after the administration of the first dose, within a time range of about 1 hour to about 7 hours, preferably about 2 hours to about 5 hours, more preferably about 2.5 hours to about 3.5 hours, and even more preferably about 3 hours, exceptionally high blood levels are achieved and the required dose is reduced. Advantageously, when the second dose is administered within a time range of about 1 hour to about 7 hours after the first time point, for example, at a second time point of about 3 hours after the first time point, the blood levels achieved are significantly higher than the expected blood levels. In particular, the blood levels achieved with the second dose are more than twice the blood levels achieved with the first dose. Therefore, a synergistic effect can be achieved when the second dose is administered within a time range of about 1 hour to about 7 hours after the first time point, preferably about 2 hours to about 5 hours, more preferably about 2.5 hours to about 3.5 hours, and even more preferably about 3 hours. The inventors have discovered, surprisingly, that when the second dose is administered within 7 hours, preferably 5 hours, more preferably 4 hours, and even more preferably 3 hours after the first dose, the dose required to achieve a specific blood level can be significantly reduced compared to when the second dose is administered more than 9 hours after the first dose, particularly more than 10 hours, such as about 12 hours. The inventors have also discovered that the highest synergistic effect is achieved when the second dose is administered at a second time point within the range of about 2.5 to about 3.5 hours after the first time point, such as about 3 hours.In particular, the inventors have discovered, surprisingly, that when the second dose is administered at a second time point within a range of approximately 2.5 to 3.5 hours after the first time point, such as approximately 3 hours, the blood level achieved with the second dose is more than twice that achieved with the first dose. Furthermore, the inventors have discovered, surprisingly, that when the second dose is administered at a second time point within a range of approximately 2.5 to 3.5 hours after the first time point, such as approximately 3 hours, the dose required to achieve a specific blood level is greatly reduced. The inventors have discovered that these advantages are strongest when the second dose is administered within 3 to 5 hours after the first time point, particularly within a range of approximately 2.5 to 3.5 hours after the first time point. In one embodiment, the terms "bid," "bid," and "twice daily" are used interchangeably. In one embodiment, the first dose is administered in the form of a first mucosal adhesive layer, and the second dose is administered in the form of a second mucosal adhesive layer. Optionally, additional doses may be administered in the form of additional mucosal adhesive layers.

[0151] As used herein, the terms "first time point" and "second time point" preferably refer to the time points at which the first and second doses are initially administered, respectively. For example, the first time point refers to the time point at which the mucosal adhesive layer initially adheres to the body cavity, and the second time point refers to the time point at which the second mucosal adhesive layer initially adheres to the body cavity. The mucosal adhesive layer can then remain adhered to the body cavity for, for example, from about 1 minute to about 7 hours, such as a duration of about 60 minutes. Preferably, the second time point is a time point within the range of about 1 hour to about 7 hours after the first time point, wherein the first time point relates to the initial administration of the first dose and is independent of the duration of administration of the first dose. For example, the first time point can refer to t=0, i.e., the time point at which the first dose is administered, such as the time point at which the mucosal adhesive layer adheres. The first time point preferably relates to the start of prevention or treatment. As used herein, the term "second time point" refers to a time point within the range of about 1 hour to about 7 hours after the first time point, preferably about 2 hours to about 5 hours, more preferably about 2.5 hours to about 3.5 hours, and even more preferably about 3 hours.

[0152] The inventors have discovered that this asymmetric administration of at least two doses—specifically, administering the second dose within approximately 7 hours after the first dose, preferably within approximately 5 hours, more preferably within approximately 4 hours, and even more preferably within approximately 3.5 hours, rather than administering the second dose within approximately 10 to approximately 12 hours—allows for higher macrolide blood levels. Advantageously, because the desired blood levels are achieved more effectively, the administered dose can be reduced. Therefore, for example, by administering a lower dose, side effects can be reduced.

[0153] In a preferred embodiment, the macrolide is administered via a mucosal route, preferably via buccal administration. A mucosal adhesive layer (e.g., a mucosal adhesive layer comprised of a mucosal adhesive membrane) can adhere to a patient's body cavity, such as the mouth, nose, or rectum. In a preferred embodiment, the mucosal adhesive layer adheres to the mucosa of a patient's body cavity. In one embodiment, the mucosal adhesive layer adheres to the buccal cavity, particularly the buccal mucosa. Advantageously, by adhering the mucosal adhesive layer to the mucosa, the macrolide is released directly into the mucosa, optionally forming a reservoir within the mucosa, thereby avoiding the first-pass effect. Advantageously, direct application of the macrolide to the mucosa allows for the attainment of desired blood levels by administering a reduced dose compared to the dose used for oral administration (e.g., compared to the dose administered in tablet or pill form). In a preferred embodiment, the body cavity to which the layer adheres is the oral cavity, particularly the buccal cavity. In one embodiment, the application involves adhering a mucosal adhesive layer (e.g., in the form of a mucosal adhesive membrane) to a patient's body cavity (preferably the buccal cavity), wherein the adhesion causes the mucosal adhesive membrane to contact the adhesion site in the body cavity (preferably the buccal cavity, particularly the mucosa) via the unadhered backing side of the polymer matrix layer.

[0154] In one embodiment, the application includes applying each of the first dose and the second dose, optionally the other doses, for a duration ranging from about 1 minute to about 7 hours, preferably from about 10 minutes to about 3 hours, more preferably from about 20 minutes to about 2 hours, even more preferably from about 30 minutes to about 90 minutes, even more preferably from about 60 minutes. For example, the first dose is applied at a first time point, for example, in the form of a mucosal adhesive layer, and then held at the application site, preferably at the mucosa, more preferably at the buccal cavity, for a duration ranging from about 1 minute to about 7 hours, preferably from about 10 minutes to about 3 hours, more preferably from about 20 minutes to about 2 hours, even more preferably from about 30 minutes to about 90 minutes, even more preferably from about 60 minutes. For example, the second dose is applied at a second time point, for example, in the form of a mucosal adhesive layer, and then held at the application site, preferably at the mucosa, more preferably at the buccal cavity, for a duration ranging from about 1 minute to about 7 hours, preferably from about 10 minutes to about 3 hours, more preferably from about 20 minutes to about 2 hours, even more preferably from about 30 minutes to about 90 minutes, even more preferably from about 60 minutes. Advantageously, by administering the dose, for example, in the form of a mucosal adhesive layer, for a duration ranging from about 1 minute to about 7 hours, such as from about 30 minutes to about 90 minutes, macrolides can be directly released into the mucosa, for example, in the buccal cavity, and can effectively enter the patient's bloodstream. After the duration, the application device, and in particular the mucosal adhesive layer, can be removed. In one embodiment, at the end of the duration, about 50% to about 95%, preferably about 70% to about 93%, of the initial amount of macrolide is contained in the mucosal adhesive layer. For example, when a first mucosal adhesive layer containing the first dose is removed after the duration, the first mucosal adhesive layer contains about 50% to about 95%, preferably about 70% to about 93%, of the initial amount of macrolide contained in the layer prior to the application. For example, when a second mucosal adhesive layer containing the second dose is removed after the duration, the second mucosal adhesive layer contains about 50% to about 95%, preferably about 70% to about 93%, of the initial amount of macrolide contained in the layer prior to the application.

[0155] In particular, the inventors have discovered that when the administration comprises administering the first dose for a period of approximately 30 minutes to approximately 90 minutes, preferably approximately 60 minutes; and administering the second dose at a time point approximately 2.5 hours to approximately 3.5 hours, preferably approximately 3 hours later, for a period of approximately 30 minutes to approximately 90 minutes, preferably approximately 60 minutes, efficient and synergistic administration of at least two doses can be achieved. Advantageously, very high blood levels can be achieved through this asymmetric administration, particularly even with relatively low doses.

[0156] In one embodiment, the first dose and the second dose, and optionally the additional dose (preferably before its administration), each comprise an amount in the range of about 0.001 mg to about 250 mg, preferably in the range of about 0.01 mg to about 50 mg, more preferably in the range of about 0.05 mg to about 25 mg, even more preferably in the range of about 0.1 mg to about 15 mg, even more preferably in the range of about 0.5 mg to about 13 mg, and optionally in the range of about 8 mg to about 12 mg of the macrolide. In one embodiment, the total daily dose comprises an amount in the range of about 0.001 mg to about 500 mg, preferably in the range of about 0.01 mg to about 100 mg, more preferably in the range of about 0.05 mg to about 50 mg, even more preferably in the range of about 0.1 mg to about 30 mg, even more preferably in the range of about 0.5 mg to about 26 mg, and optionally in the range of about 8 mg to about 24 mg of the macrolide. As used herein, the term "total daily dose" preferably refers to the total amount of macrolides administered daily, such as the total amount of the first dose and the second dose. In one embodiment, the terms "total daily dose" and "total daily amount" are used interchangeably. If two doses are administered daily, the total daily dose preferably refers to the sum of the first dose and the second dose. If more than two doses are administered daily, the total daily dose preferably refers to the sum of the first dose, the second dose, and any additional doses. Advantageously, by administering the second dose within 7 hours, preferably within 5 hours, more preferably within 3.5 hours, such as within 3 hours, particularly when the dose is administered in the form of a mucosal adhesive layer, the first dose, the second dose, and / or the total daily dose required to achieve the desired macrolide blood level is significantly reduced compared to when the second dose is administered at a time point within the range of about 10 hours to about 14 hours, for example, about 12 hours, after the first dose.

[0157] In one embodiment, the macrolide is administered via mucosal administration, preferably via buccal administration, and the administration of the macrolide at least twice daily comprises administering the macrolide at approximately ≤40%, preferably approximately ≤30%, more preferably approximately ≤25%, and even more preferably approximately ≤20% of the total daily dose administered orally. For example, if the recommended total daily oral dose is 100 mg, the macrolide used in this invention is administered at a total daily dose of ≤40 mg, preferably approximately ≤30 mg, more preferably approximately ≤25 mg, and even more preferably approximately ≤20 mg. Those skilled in the art will understand the specific application based on oral formulations such as… The recommended total daily oral dose is understood from the package insert. In one embodiment, the macrolide is administered via a mucosal dressing, preferably via buccal administration, and the administration of the macrolide at least twice daily comprises administering the macrolide at a total daily dose comprising or consisting of: about ≤40% of the recommended total daily oral dose, preferably about ≤30% of the recommended total daily oral dose, more preferably about ≤25% of the recommended total daily oral dose, and even more preferably about ≤20% of the recommended total daily oral dose. As used herein, the term “recommended total daily oral dose” preferably refers to the total daily dose listed in the package insert of an oral macrolide formulation that has been marketed and / or an oral macrolide formulation. When the term "oral" is used in the context of oral administration, oral formulations, and / or oral dosage, it preferably refers to administration / formulation / dosage involving swallowing, such as oral administration of tablets, capsules, granules, or pills, such that the macrolide enters the bloodstream via the gastrointestinal tract; conversely, "buccal" administration / formulation / dosage does not involve swallowing a significant amount of macrolide, but instead, macrolide is administered to the bloodstream via the mucous membrane of the cheek. In one embodiment, oral administration involves oral delivery. In one embodiment, oral dosage involves oral dosage. Advantageously, given the efficient administration, the macrolides used in this invention allow for the administration of much lower amounts, such as only about 20% of the recommended oral dosage, while still achieving therapeutic levels. Advantageously, the bioavailability of macrolides is greatly enhanced when administered via mucous membranes (particularly via the buccal) rather than orally, particularly when a second dose is administered within 7 hours after the first dose. Not wishing to be bound by any theory, the inventors believe that the first-pass effect and systemic pre-degradation following oral administration, independent of mucosal administration, particularly buccal administration, provide enhanced bioavailability of the macrolides used in this invention. Advantageously, particularly when the first and second doses are administered in the form of a mucosal adhesive layer, by administering the second dose within 7 hours, preferably within 5 hours, more preferably within 3.5 hours after the first dose, the patient's drug load can be reduced by approximately 80%. For example, this can reduce the side effects of macrolide therapy.

[0158] The inventors have discovered that, prior to the application, the macrolide is at a concentration relative to 1 cm. 2 The amount of the mucosal adhesive layer is in the range of about 0.01 mg to about 10 mg, preferably in a quantity relative to 1 cm. 2 The mucosal adhesive layer is in the range of about 0.1 mg to about 5 mg, more preferably relative to 1 cm. 2 The mucosal adhesive layer is in the range of approximately 1.5 mg to approximately 3.5 mg, or even more preferably relative to 1 cm. 2When the amount of macrolide present in the mucosal adhesive layer is in the range of about 1.8 mg to about 2.9 mg, the application of macrolide is further enhanced. As used herein in the context of the amount or dose of macrolide, the expressions “before the application” and “before its application” are intended to be understood to refer to the corresponding amount or dose contained in the mucosal adhesive layer after its preparation and before its application, in particular the initial amount / dose contained in the mucosal adhesive layer; when the mucosal adhesive layer is applied, for example when it adheres to the buccal cavity, the amount / dose of macrolide generally decreases over time as the macrolide is released from the mucosal adhesive layer into the buccal cavity.

[0159] The inventors have also discovered that the application of the macrolide (e.g., the tacrolimus) is further enhanced when it is present in the mucosal adhesive layer in an amount ranging from about 12 to about 25% by weight, preferably in an amount ranging from about 12 to about 13% by weight or in an amount ranging from about 19 to about 23% by weight prior to the application, wherein the weight percentage is based on the dry weight of the mucosal adhesive layer.

[0160] In a preferred embodiment, the at least twice daily administration at a time point within the range of approximately 2 to 4 hours, preferably approximately 2.5 to 3.5 hours, and more preferably approximately 3 hours after the first time point provides a first peak in macrolide whole blood concentration, and at a time point within the range of approximately 7 to 9 hours, preferably approximately 7.5 to 8.5 hours, and more preferably approximately 8 hours after the first time point provides a second peak in macrolide whole blood concentration. In one embodiment, the at least twice daily administration at a time point within the range of approximately 3 to 5 hours, preferably approximately 3.5 to 4.5 hours, and more preferably approximately 4 hours after the second time point provides the second peak in macrolide whole blood concentration. Preferably, the second peak is higher than the first peak. Preferably, the second peak is at least twice the height of the first peak. For example, the second peak is twice as high as or more than twice the height of the first peak. For example, the sum of the heights of the first and second peaks can be more than twice the height of the first peak. Advantageously, when administered within a time range of 7 hours or less, preferably 5 hours or less, and particularly 3.5 hours or less, the first and second doses have a synergistic effect. The inventors have discovered, surprisingly, that the second peak is higher than expected, as it significantly exceeds the first peak. In one embodiment, the terms "whole blood concentration" and "blood concentration" are used interchangeably. Preferably, when referring to "whole blood concentration," "blood concentration," or "blood level," it means macrolide blood concentration.

[0161] In one embodiment, the at least twice-daily administration provides a whole blood concentration of the macrolide in the range of about 0.01 ng / mL to about 50 ng / mL, preferably in the range of about 3 ng / mL to about 20 ng / mL, more preferably in the range of about 5 ng / mL to about 20 ng / mL, for a duration of about 24 hours. Advantageously, the macrolides used in this invention allow for the achievement of desired blood concentrations, such as those in the range of about 5 ng / mL to about 20 ng / mL. In one embodiment, the therapeutic window is in the range of about 5 ng / mL to about 20 ng / mL. In a preferred embodiment, the administration of the macrolides used in this invention results in a blood concentration within the therapeutic window.

[0162] The inventors have discovered, surprisingly, that, compared to standard oral macrolides (such as those administered twice daily at an interval of approximately 10 to 12 hours), Compared to standard oral macrolides (such as those administered twice daily at approximately 10 to 12-hour intervals), the coefficient of variation for macrolides used in this invention is significantly reduced. In particular, the coefficient of variation is further enhanced, i.e., reduced, when the macrolides used in this invention are administered as a mucosal adhesive layer. Advantageously, compared to standard oral macrolides (such as those administered twice daily at approximately 10 to 12-hour intervals), the coefficient of variation is significantly reduced. Compared to the previous method, the intra- and inter-subject coefficients of variation were observed to be lower for the macrolides used in this invention.

[0163] In one embodiment, the at least twice-daily administration provides a coefficient of variation of less than 40%, preferably less than 35%, more preferably less than 32%, and even more preferably 30% or less, such as in the range of 20% to 30% or in the range of 25% to 30%, preferably the coefficient of variation of macrolide blood levels. Physiological variations, particularly biological variations, are commonly present in patients, determined by factors such as hydration levels, diet, circadian rhythms, and exercise. Furthermore, drug responses vary between different patients. For example, variations within a subject (particularly intra-subject variations) and / or variations between subjects (particularly inter-subject variations) can be quantified using the coefficient of variation. As used herein, the term "coefficient of variation" preferably refers to intra-subject and / or inter-subject variability in pharmacokinetic parameters such as macrolide blood levels. In one embodiment, the variation is intra-subject variation; for example, intra-subject macrolide blood level variation. In one embodiment, the coefficient of variation is a coefficient of variation in macrolide blood levels, such as inter-subject macrolide blood level variation and / or intra-subject macrolide blood level variation. In one embodiment, the coefficient of variation is the within-subject and / or between-subject coefficient of variation as a pharmacokinetic measure, preferably the within-subject coefficient of variation as a pharmacokinetic measure. The coefficient of variation (CV) can be defined as the ratio of the standard deviation to the mean. Advantageously, compared with standard orally administered macrolides (such as...) Compared to other medications, the macrolides used in this invention exhibit reduced intra- and inter-subject variability. For example, inter-individual pharmacokinetic variability may be influenced by time elapsed since transplantation, patient demographics (age and race), liver and kidney function, hematocrit levels, food administration, concomitant medications (corticosteroids, antifungals, calcium channel blockers, etc.), and the genotype of metabolic enzymes.

[0164] In one implementation, the at least twice-daily application is provided:

[0165] - within a range of approximately 3 to approximately 10 hours after the first time point, such as within a range of approximately 4 to approximately 10 hours after the first time point, preferably within a range of approximately 7 to approximately 9 hours after the first time point, more preferably within a range of approximately 7.5 to approximately 8.5 hours after the first time point. max ;and /

[0166] or

[0167] - Within approximately 1 hour to approximately 6 hours after the second time point, preferably within approximately 2 hours to approximately 5 hours after the second time point, more preferably within approximately 3.5 hours to approximately 4.5 hours after the second time point, for example, within approximately 4 hours after the second time point. max .

[0168] T max This is typically the time it takes to reach peak drug concentration, especially when the drug reaches its maximum concentration (C) after administration. max The time spent. Advantageously, the macrolides used in this invention allow for very high blood levels to be achieved at relatively low doses (e.g., in the range of about 1 hour to about 6 hours after the second time point).

[0169] In one implementation, the at least twice-daily application is provided:

[0170] - In the range of about 0.05 ng / mL to about 50 ng / mL, preferably in the range of about 0.1 ng / mL to about 30 ng / mL, more preferably in the range of about 0.7 ng / mL to about 20 ng / mL, and even more preferably in the range of about 5.5 ng / mL to about 20 ng / mL.

[0171] C in the range of ng / mL max ; and / or

[0172] - In the range of about 0.01 ng / mL to about 18 ng / mL, preferably in the range of about 0.5 ng / mL to about 16 ng / mL, more preferably in the range of about 3 ng / mL to about 15 ng / mL, such as in the range of about 3 ng / mL to about 7 ng / mL or in the range of about 5 ng / mL to about 7 ng / mL, C trough .

[0173] In a preferred embodiment, C max 20 ng / mL or lower and / or C trough 5 ng / mL or higher. For example, if C max 20 ng / mL or lower and C trough At concentrations of 5 ng / mL or higher, effective and safe prevention and treatment can be achieved.

[0174] In one embodiment, the at least twice daily administration at time points ranging from about 1 hour to about 4 hours after the first time point, preferably from about 1.5 hours to about 3.5 hours, provides a whole blood concentration ranging from 0.1 ng / mL to about 20 ng / mL, preferably from 0.2 ng / mL to about 10 ng / mL, and more preferably from 0.3 ng / mL to about 7 ng / mL. In one embodiment, the at least twice daily administration provides:

[0175] - AUC in the range of about 0.5 h*ng / mL to about 7.0 h*ng / mL, preferably in the range of about 1.0 h*ng / mL to about 6.5 h*ng / mL. 0-4 ;

[0176] - In the range of about 0.7 h*ng / mL to about 15.0 h*ng / mL, preferably from about 1.5 h*ng / mL to about 12.0 h*ng / mL.

[0177] AUC in the range of h*ng / mL 4-8 ;

[0178] - In the range of about 4.0 h*ng / mL to about 200.0 h*ng / mL, preferably from about 5.0 h*ng / mL to about 60.0 h*ng / mL.

[0179] More preferably, the AUC is in the range of h*ng / mL, more preferably in the range of about 10.0 h*ng / mL to about 55.0 h*ng / mL. 0-24 ;

[0180] - In the range of about 4.0 h*ng / mL to about 250.0 h*ng / mL, preferably from about 5.0 h*ng / mL to about 70.0 h*ng / mL.

[0181] More preferably, the AUC is in the range of h*ng / mL, more preferably in the range of about 10.0 h*ng / mL to about 60.0 h*ng / mL. 0-tlast ;

[0182] - A half-life in the range of about 12 hours to about 16 hours, preferably about 13.5 hours to about 15.5 hours, more preferably about 14 hours to about 15 hours; and / or

[0183] - An elimination rate in the range of about 0.01 1 / h to about 0.08 1 / h, preferably in the range of about 0.04 1 / h to about 0.05 1 / h, and even more preferably in the range of about 0.045 1 / h to about 0.049 1 / h.

[0184] In one embodiment, the at least twice daily administration is performed for at least two days, preferably at least one week, more preferably at least one month, and even more preferably at least one year. Thus, for example, the first and second doses can be administered daily for at least two days, preferably at least one week, more preferably at least one month, and even more preferably at least one year. In one embodiment, if the macrolide is used for the prevention or treatment of chronic immune diseases or conditions (such as transplant rejection), the at least twice daily administration can be performed on the patient for life. Advantageously, because lower doses are required to achieve blood levels within the therapeutic window, the macrolide used via mucosal administration, particularly buccal administration, can reduce side effects and improve the patient's quality of life.

[0185] In one embodiment, the term "patient" refers to a person or animal, preferably a person. In one embodiment, the patient is not a fasting patient. Advantageously, even if the patient is not a fasting patient, the macrolide used (especially when applied via the buccal route) can achieve the desired blood levels, such as blood levels within the therapeutic window. In one embodiment, the patient is not a fasting patient. In one embodiment, the patient is a pediatric patient, an adolescent patient, or an adult patient. An adult patient may be an elderly patient. The terms "patient" and "subject" are used interchangeably.

[0186] As used herein, the term "mucosal adhesive layer" refers to a layer that adheres to and / or is configured to adhere to a mucosa (e.g., oral and / or buccal mucosa). In a preferred embodiment, the mucosal adhesive layer is provided in the form of a mucosal adhesive film, particularly in the form of a mucosal adhesive film comprising the mucosal adhesive layer and optionally additional layers. Preferably, the mucosal adhesive layer contains the macrolide. For example, the layer may contain macrolides in the form of nanoparticles or non-nanoparticle macrolides. In one embodiment, the mucosal adhesive layer optionally contains a surfactant, such as polysorbate. In one embodiment, the mucosal adhesive layer is swellable in an aqueous liquid but insoluble in an aqueous liquid and / or has negligible solubility in an aqueous liquid. Insolubility or low solubility increases the adhesion time on the mucosa, thus allowing the active ingredient to be released over a long period, such as at least 60 minutes. As used herein, the term "mucosal adhesive buccal layer" refers to a mucosal adhesive layer configured for buccal application. In one embodiment, the macrolide is present in the mucosal adhesive layer at a concentration of at least 2% by weight, preferably at least 3% by weight, for example, 3.2% by weight, wherein the weight percentage is based on the dry weight of the mucosal adhesive layer. In one embodiment, the macrolide is present in the mucosal adhesive layer at a concentration of about 12% to about 25% by weight, wherein the weight percentage is based on the dry weight of the mucosal adhesive layer. In one embodiment, the macrolide is present in the mucosal adhesive layer at a concentration of about 12% to about 13% by weight or about 19% to about 23% by weight, wherein the weight percentage is based on the dry weight of the mucosal adhesive layer. In one embodiment, the macrolide is present in the mucosal adhesive layer at a concentration of about 18% to about 25% by weight, wherein the weight percentage is based on the dry weight of the mucosal adhesive layer. In one embodiment, the macrolide is present in the mucosal adhesive layer at a concentration of about 19% to about 22% by weight, wherein the weight percentage is based on the dry weight of the mucosal adhesive layer. In one embodiment, the macrolide is applied in the form of a mucosal adhesive layer comprising a mucosal adhesive polymer. In one embodiment, the mucosal adhesive layer comprises a mucosal adhesive polymer. In one embodiment, the mucosal adhesive layer or mucosal adhesive membrane comprises a therapeutically effective amount of the macrolide.

[0187] As used herein, the term "tacrolimus mucosal adhesive membrane" is intended to refer to a mucosal adhesive membrane suitable for buccal administration, comprising a mucosal adhesive layer and a backing layer, wherein the mucosal adhesive layer comprises tacrolimus and optionally a mucosal adhesive polymer.

[0188] In one embodiment, the mucosal adhesive layer comprises a mucosal adhesive polymer and / or a cellulose derivative, and further comprises the macrolide, such as a nanoparticle macrolide or a non-nanoparticle macrolide. In one embodiment, the mucosal adhesive layer comprises a mucosal adhesive polymer such as alginate. In one embodiment, the mucosal adhesive layer comprises alginate. In one embodiment, the mucosal adhesive layer is an alginate layer. In one embodiment, the mucosal adhesive layer comprises a non-nanoparticle macrolide, preferably a micronized crystalline non-nanoparticle macrolide, and / or a molecularly dissolved non-nanoparticle macrolide. In one embodiment, the non-nanoparticle macrolide is present in the layer in the form of a micronized macrolide, preferably a micronized crystalline macrolide, and / or in the form of molecularly dissolved non-nanoparticles. In one embodiment, the average particle size of the micronized macrolide is 1 to 100 μm, preferably 1.5 to 50 μm, more preferably 2 to 25 μm. In one embodiment, the non-nanoparticle macrolide exists in the mucosal adhesive layer in the form of molecularly dissolved non-nanoparticles; and optionally, the mucosal adhesive polymer and / or the cellulose derivative (if present) are polymers soluble in organic solvents.

[0189] In one embodiment, (in addition to macrolides as described herein) the mucosal adhesive layer comprises:

[0190] a) a mucosal adhesive polymer, preferably an amphiphilic polymer; hydroxypropyl cellulose (HPC); carboxymethyl cellulose (CMC); a plasticizer, preferably glycerol; and optionally a colorant, preferably TiO2;

[0191] Preferably, 10%-30% by weight of the mucosal adhesive polymer; 25%-35% by weight of hydroxypropyl cellulose (HPC); 10%-25% by weight of carboxymethyl cellulose (CMC); 10%-16% by weight of the plasticizer; and optionally 1%-4% by weight of the colorant; or

[0192] b) A mucosal adhesive polymer, preferably selected from cross-linked polyacrylic acid polymers and copolymers of methyl vinyl ether and maleic anhydride; hydroxypropyl cellulose (HPC); ethyl cellulose (EC); a plasticizer, preferably glycerol; and optionally a colorant, preferably TiO2;

[0193] Preferably, 2%-17% by weight of the mucosal adhesive polymer; 30%-70% by weight of hydroxypropyl cellulose (HPC); 5%-40% by weight of the ethyl cellulose; and 3%-20% by weight of the [unspecified ingredient].

[0194] Plasticizer; and optionally 1% to 5% by weight of the colorant.

[0195] In one embodiment, (in addition to macrolides as described herein) the mucosal adhesive layer comprises:

[0196] a) Mucosal adhesive polymers, preferably selected from cross-linked polyacrylic acid polymers and copolymers of methyl vinyl ether and maleic anhydride; ethyl cellulose; hydroxypropyl cellulose (e.g., Klucel EF) having a viscosity of about 300-600 mPa·s; hydroxypropyl cellulose (e.g., Klucel GF) having a viscosity of about 150-400 mPa·s.

[0197] And a plasticizer, preferably glycerin; and optionally a colorant, preferably TiO2 or iron oxide yellow;

[0198] Preferably, 2% to 10% by weight of the mucosal adhesive polymer; 30% to 70% by weight of hydroxypropyl cellulose (HPC), wherein optionally the hydroxypropyl cellulose consists of at least two different types of hydroxypropyl cellulose; 3% to 13% by weight of the ethyl cellulose or 27% to 31% by weight of the ethyl cellulose; 4% to 6% by weight of the plasticizer; and optionally 1% to 4% by weight of the colorant.

[0199] As used herein, the term "nanoparticle macrolide" refers to macrolides in nanoparticle form, particularly nanoparticles with sizes ranging from 1 nm to 1000 nm. In one embodiment, the mucosal adhesive layer comprises nanoparticles, such as said macrolides in the form of nanoparticles with a particle size of about 10 nm to about 400 nm. In one embodiment, the mucosal adhesive layer comprises macrolide nanoparticles. For example, the nanoparticles may have a polydispersity index ≤ about 0.4. The nanoparticles may contain stabilizers and / or surfactants. For example, stabilizers may include polyvinylpyrrolidone, vinylpyrrolidone- / vinyl acetate-polymer, polyethylene glycol, and / or cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), and / or carboxymethyl cellulose (CMC). In one embodiment, the mucosal adhesive layer comprises nanoparticle macrolides and / or non-nanoparticle macrolides.

[0200] As used herein, the term "non-nanoparticle macrolide" refers to macrolides that are not in nanoparticle form. In one embodiment, a non-nanoparticle macrolide refers to a macrolide that is not formulated as nanoparticles, particularly not formulated as nanoparticles with a size in the range of 1 nm to 1000 nm. In one embodiment, a non-nanoparticle macrolide is a macrolide formulated as a molecularly dissolved macrolide and / or a micronized crystalline macrolide. In one embodiment, a molecularly dissolved macrolide is not a molecularly dissolved macrolide in nanoparticle form, for example, not a molecularly dissolved macrolide present in micelles or liposomes. In one embodiment, a molecularly dissolved macrolide does not refer to nanoparticles containing a molecularly dissolved macrolide. In one embodiment, a molecularly dissolved macrolide is formulated in the form of a solid solution, such as embedded and / or dissolved in a polymer matrix. In one embodiment, a micronized crystalline macrolide is not in nanoparticle form, for example, not in the form of nanoparticles containing a micronized crystalline macrolide. In one embodiment, a micronized crystalline macrolide has an average particle size >1000 nm. In one embodiment, the micronized crystalline macrolide is in the form of microparticles, preferably having an average particle size of 1 μm to 1000 μm, preferably >1000 nm. In one embodiment, the non-nanoparticle macrolides contained in the mucosal adhesive layer and / or mucosal adhesive membrane are not in the form of nanoparticles and / or are not contained in nanoparticles. In one embodiment, the non-nanoparticle macrolide exists in the layer in the form of micronized macrolides, preferably micronized crystalline macrolides, in the form of molecularly dissolved non-nanoparticles, and / or in the form of crystalline macrolides; preferably, the non-nanoparticle macrolide exists in the layer in the form of micronized macrolides, preferably micronized crystalline macrolides, and / or in the form of molecularly dissolved non-nanoparticles. In one embodiment, the mucosal adhesive layer containing micronized macrolides, preferably micronized crystalline macrolides, and / or molecularly dissolved non-nanoparticle macrolides further contains crystalline macrolides.

[0201] As used herein, the term "average particle size" refers to the average diameter of particles in an analyzed batch, such as micronized macrolides. For example, average particle size can be the average diameter of a batch of particles, where, if the particles are not spherical, the longest extended dimension of each particle is considered the diameter. In one embodiment, the average particle size is in the range of 1 to 100 μm, preferably 1.5 to 50 μm, more preferably 2 to 25 μm. In one embodiment, the average particle size of, for example, micronized macrolides is measured using any technique known to those skilled in the art, such as laser diffraction analysis or dynamic light scattering, preferably laser diffraction analysis. Average particle size is defined as the average diameter of the analyzed particles determined by a suitable method (e.g., using dynamic light scattering). In one embodiment, the average particle size of the micronized macrolide is 2 μm to 25 μm. In one embodiment, the micronized macrolide has a D... 10 2μm, D 50 10μm and D 90 A particle size distribution of 25 μm. In one embodiment, 10% of all particles have a particle size of <2 μm, 50% of all particles have a particle size of <10 μm, and 90% of all particles have a particle size of <10 μm. In one embodiment, all particles have a particle size of >1 μm. In one embodiment, the micronized macrolide is not in the form of nanoparticles. In one embodiment, the average particle size is D. 50 In one embodiment, the average particle size of the micronized macrolide is >1 μm. It should be understood that, preferably, the particles are not nanoparticles. In one embodiment, the particle size of the micronized macrolide is >1 μm. In one embodiment, the particle size of each micronized macrolide particle is >1 μm. As used herein, the term "micronization" refers to an average particle size in the micrometer range and / or (preferably by micronization) reduced to the micrometer range. In one embodiment, "micronized crystalline macrolide" refers to crystalline macrolides with an average particle size in the micrometer range.

[0202] In one embodiment, the macrolide is formulated as a mucosal adhesive membrane; preferably, it is formulated as a mucosal adhesive membrane comprising a mucosal adhesive layer containing the macrolide and including additional layers such as a backing layer. In one embodiment, the mucosal adhesive layer is provided as a mucosal adhesive membrane. In one embodiment, the macrolide is applied as a mucosal adhesive membrane, preferably a mucosal adhesive buccal membrane. In one embodiment, as used herein, the term "mucosal adhesive membrane" refers to a membrane that adheres to and / or is configured to adhere to a mucosa (e.g., oral and / or buccal mucosa). In one embodiment, the terms "membrane," "mucosal adhesive membrane," "mucosal adhesive buccal membrane," and "MBF" are used interchangeably. In one embodiment, when referring to "mucosal adhesive buccal membrane" or "MBF," such abbreviations refer not only to a mucosal adhesive buccal membrane but also to a mucosal adhesive membrane for applications other than buccal applications. In one embodiment, the mucosal adhesive membrane (preferably a mucosal adhesive buccal membrane) comprises a mucosal adhesive layer containing macrolides, preferably as defined above; and further comprises a backing layer, preferably a backing layer impermeable to macrolides and / or impermeable to water. In one embodiment, the backing layer comprises a plasticizer, preferably selected from glycerol, polyethylene glycol (e.g., low molecular weight polyethylene glycols such as PEG 200 or PEG 400), propylene glycol, sorbitol, triacetin, and tributyl citrate, more preferably glycerol; and a water-insoluble polymer and / or cellulose derivative, such as hydroxyethyl cellulose, preferably a water-insoluble cellulose derivative, more preferably ethyl cellulose. The advantage of the mucosal adhesive layer or membrane is that the rich blood circulation of the oral and / or buccal mucosa ensures rapid transfer of the active substance into the bloodstream. Advantageously, the active ingredient is mostly absorbed through the mucosa, thus avoiding the "first-pass metabolism" that occurs in conventional delivery forms of active ingredients in tablet form. Furthermore, the mucosal adhesive layer or membrane has the advantage of protecting macrolides from degradation by the pH and digestive enzymes of the gastrointestinal tract. Mucosal adhesive layers or membranes also provide rapid onset of action, for example, compared to oral routes. Mucosal adhesive layers or membranes are a simple method of drug administration and are therefore particularly suitable for pediatric and elderly patients. Furthermore, mucosal adhesive layers or membranes avoid the difficulties associated with drug administration via nasogastric tubes and offer flexibility in terms of physical shape, state, size, and surface. Another advantage of mucosal adhesive layers or membranes is that they allow for precise drug delivery. In a preferred embodiment, when referring to "mucosal adhesive layer," it means a mucosal adhesive layer in the form of a mucosal adhesive membrane (particularly a mucosal adhesive membrane comprising the said mucosal adhesive layer and optionally additional layers). In one embodiment, the mucosal adhesive membrane comprises alginate. In one embodiment, the mucosal adhesive membrane is an alginate membrane.

[0203] In one embodiment, the mucosal adhesive membrane further includes an intermediate layer disposed between the mucosal adhesive layer and the backing layer; wherein, preferably, the intermediate layer promotes adhesion between the mucosal adhesive layer and the backing layer; wherein, optionally, the intermediate layer comprises a plasticizer, preferably selected from glycerol, polyethylene glycol (e.g., low molecular weight polyethylene glycol such as PEG 200 or PEG400), propylene glycol, sorbitol, glyceryl triacetate and tributyl citrate, more preferably glycerol; and a polymer, preferably a polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone, more preferably a vinylpyrrolidone-vinyl acetate copolymer.

[0204] In one embodiment, the mucosal adhesive membrane (preferably a mucosal adhesive buccal membrane) includes a mucosal adhesive layer, a backing layer, and an intermediate layer.

[0205] The intermediate layer is disposed between the mucosal adhesive layer and the backing layer, and the mucosal adhesive layer comprises a macrolide, preferably tacrolimus;

[0206] Preferably, the intermediate layer promotes adhesion between the adhesive layer and the backing layer;

[0207] Optionally, the intermediate layer comprises a plasticizer, preferably selected from glycerol, polyethylene glycol (e.g., low molecular weight polyethylene glycol such as PEG 200 or PEG 400), propylene glycol, sorbitol, triacetin, and tributyl citrate, more preferably glycerol;

[0208] Optionally, the intermediate layer comprises a polymer, preferably a polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone, more preferably a vinylpyrrolidone-vinyl acetate copolymer.

[0209] In one embodiment, the mucosal adhesive membrane is a solid preparation comprising a single or multiple layers of suitable material intended for application to a body cavity (preferably the buccal cavity) to achieve a systemic or local effect, preferably a systemic effect; and / or the mucosal adhesive membrane is a flexible, single-dose preparation configured for application to a body cavity (preferably the oral cavity) to achieve a systemic or local effect by delivering a macrolide over a specific time period, thereafter being removed. In one embodiment, the mucosal adhesive membrane is an oral mucosal patch.

[0210] In one embodiment, the mucosal adhesive membrane includes the mucosal adhesive layer and an optional backing layer. In a preferred embodiment, the mucosal adhesive membrane includes the mucosal adhesive layer and a backing layer. In one embodiment, the mucosal adhesive membrane includes the mucosal adhesive layer; a backing layer, preferably an impermeable backing layer; and an optional intermediate layer. In one embodiment, the mucosal adhesive layer (e.g., in a polymer matrix or nanoparticles) contains a macrolide and provides prolonged contact between the macrolide and the buccal mucosa. In one embodiment, the membrane includes at least two layers, for example, two layers laminated together; preferably a backing layer and a mucosal adhesive layer containing an active ingredient. In one embodiment, to prevent the macrolide from being released into the oral cavity, the back side of the mucosal adhesive layer is sealed with a backing layer (preferably a water-insoluble and / or macrolide-impermeable backing layer). In one embodiment, the back side of the mucosal adhesive layer is configured to face the oral cavity. In one embodiment, the two layers are adhered to each other via an intermediate layer (preferably an adhesive layer). In one embodiment, the mucosal adhesive layer is configured to be applied to a patient (e.g., by incorporating the mucosal adhesive layer into a mucosal adhesive membrane, oral mucosal patch, or any other application system).

[0211] In one embodiment, the adhesive properties of the mucosal adhesive layer and / or membrane are sufficient for application for at least 30 minutes, preferably at least 60 minutes, i.e., the layer and / or membrane adheres to the mucosa and remains there for at least 30 minutes, preferably at least 60 minutes. In one embodiment, ethyl cellulose is contained in the mucosal adhesive layer and / or membrane and, due to its low water solubility, allows for an application time of at least 30 minutes, preferably at least 60 minutes. In one embodiment, the backing layer contains ethyl cellulose. In one embodiment, the mucosal adhesive membrane is an insoluble membrane that must be removed from the mucosa (e.g., the buccal mucosa) after drug release. In one embodiment, the mucosal adhesive layer is applied to the patient and left there for at least 30 minutes.

[0212] In one embodiment, the mucosal adhesive layer and / or the mucosal adhesive membrane has a thickness of 0.5 cm. 2 Up to 10cm 2 2cm is preferred 2 Up to 8cm 2 The area. In one embodiment, the area weight of the mucosal adhesive membrane is approximately 20 g / m². 2 Approximately 300g / m 2 Preferred weight is approximately 50g / m³ 2 Approximately 260g / m 2 In one embodiment, the mucosal adhesive membrane has a film thickness of about 20 μm to about 1000 μm, preferably about 50 μm to about 500 μm, more preferably about 50 μm to about 300 μm, for example about 150 μm to about 260 μm.

[0213] In one embodiment, the mucosal adhesive layer has a content of 70 to 180 g / m². 2 Within the range, 100 to 150 g / m³ is preferred. 2 Area weight within the range; and / or

[0214] The backing layer has a strength of 40 to 100 g / m². 2 Within the range, 40 to 60 g / m³ is preferred. 2 Within a range, for example, 50g / m 2 Area weight; and / or

[0215] The intermediate layer (if present) has a content of 40 to 100 g / m 2 Within the range, 40 to 70 g / m² is preferred. 2 Within a range, for example, 60g / m 2 Area and weight.

[0216] In one embodiment, at least one of these layers contains a colorant, for example, the mucosal adhesive layer contains a white pigment and the backing layer contains a blue dye. Advantageously, the colorant in at least one of these layers allows for differentiation between the adhesive layer and the backing layer. In one embodiment, the mucosal adhesive membrane also contains a flavoring agent and / or sweetener, such as an agent selected from citric acid, peppermint oil, sodium saccharin, and citrus flavoring agents. Advantageously, the flavoring agent and / or sweetener enhances the palatability for the patient. In particular, such flavoring agents and / or sweeteners effectively mask the unpleasant taste of macrolides or other MBF components. In one embodiment, at least one layer also contains at least one adjuvant selected from the group consisting of stabilizers such as chelating agents, colorants, flavoring agents, sweeteners, masking agents, emulsifiers, enhancers, pH adjusters, humectants, preservatives, and / or antioxidants. In one embodiment, at least one layer contains a chelating agent, preferably EDTA. In one embodiment, when referring to "layer," it means the mucosal adhesive layer, the intermediate layer, and / or the backing layer. In a preferred embodiment, the mucosal adhesive layer is provided in the form of a mucosal adhesive film.

[0217] In one embodiment, the dose intensity of the membrane is determined by the size and / or area of ​​the membrane, wherein, optionally, the quantitative composition per unit membrane area is constant. In one embodiment, the membrane contains a dose of up to 250 mg of macrolide (e.g., up to 50 mg of macrolide). In one embodiment, the amount of macrolide is measured using HPLC. In one embodiment, HPLC is used to quantify the macrolide. In one embodiment, the mucosal adhesive membrane is applied to and / or configured for application to adult patients or pediatric patients, such as children aged up to about 18 years.

[0218] In one embodiment, the adhesive layer and / or backing layer comprises a colorant. In one embodiment, the adhesive layer and the backing layer each comprise a colorant, wherein the adhesive layer comprises a first colorant such as TiO2, and the backing layer comprises a second colorant such as brilliant blue, wherein the first colorant and the second colorant are different from each other. In one embodiment, the adhesive layer and / or the adhesive film has a water content of <5% by weight, preferably <3% by weight, more preferably <2% by weight.

[0219] As used herein, the term "plasticizer" refers to any plasticizer known to those skilled in the art, preferably applicable to plasticizers applied in vivo. In one embodiment, the plasticizer (e.g., a plasticizer contained in the mucosal adhesive layer, intermediate layer, and / or backing layer) is selected from glycerol, poly(ethylene glycol) (preferably low molecular weight poly(ethylene glycol) such as PEG 200 or PEG 400), propylene glycol, sorbitol, triacetin, and tributyl citrate. In one embodiment, the low molecular weight poly(ethylene glycol) has a molecular weight of ≤600 Daltons, preferably ≤450 Daltons, for example, 420 Daltons. Plasticizers allow the layer to have advantageous mechanical properties.

[0220] As used herein, the term "backing layer" refers to a layer of a mucosal adhesive membrane. In one embodiment, the backing layer covers the back side of the mucosal adhesive layer in the mucosal adhesive membrane. The back side is preferably the side of the mucosal adhesive layer or membrane configured to face the body cavity (preferably the oral cavity), i.e., the side facing away from the mucosa. In one embodiment, the backing layer is impermeable to macrolides and / or impermeable to water. Advantageously, the backing layer prevents macrolides from being released from the mucosal adhesive layer into the body cavity, such as into the oral cavity. In one embodiment, the backing layer covers the back side of the mucosal adhesive layer and optionally further covers the lateral regions of the mucosal adhesive layer. In one embodiment, the backing layer is a sealing layer. In one embodiment, the backing layer (preferably an impermeable backing layer) prevents undesirable release of macrolides into the body cavity, preferably the oral cavity. In one embodiment, the backing layer is configured to ensure unidirectional release of macrolides into the mucosa, preferably the buccal mucosa. In one embodiment, the backing layer prevents macrolides from being released into the buccal cavity. Advantageously, side effects are reduced by preventing release into the cavity. In one embodiment, the backing layer is insoluble in water and / or aqueous liquids such as saliva. In one embodiment, the backing layer is insoluble in water and / or aqueous liquids such as saliva for a period of 30 to 75 minutes, preferably at least 60 minutes. In one embodiment, the backing layer and / or the backing layer polymer mixture comprises a water-insoluble polymer and / or a cellulose derivative (e.g., hydroxyethyl cellulose, preferably a water-insoluble cellulose derivative, more preferably ethyl cellulose), thus preventing the backing layer from dissolving in the oral cavity. In one embodiment, the backing layer and / or the backing layer polymer mixture comprises a water-insoluble polymer and / or a polymer with low water solubility, preferably a water-insoluble polymer such as ethyl cellulose. In one embodiment, the backing layer polymer mixture comprises at least one component of the backing layer, preferably all components. In one embodiment, the backing layer is based on an organic solvent, such as ethanol, and / or the mucosal adhesive layer is water-based. In one embodiment, the backing layer comprises a polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone, preferably polyvinyl acetate. In one embodiment, the backing layer contains a colorant, such as brilliant blue. In another embodiment, the backing layer contains a plasticizer, such as glyceryl triacetate.

[0221] As used herein, the term "water-insoluble polymer" refers to a polymer that is insoluble in water, such as ethyl cellulose and poly(methyl methacrylate). As used herein, the term "polymer with low water solubility" refers to a polymer that has negligible and / or low solubility in water, such as hydroxyethyl cellulose. In one embodiment, "water-insoluble polymer" and "polymer with low water solubility" are polymers that prevent dissolution of the mucosal adhesive membrane during application to a body cavity (preferably the buccal cavity) for at least 30 minutes. In one embodiment, the water-insoluble polymer and / or polymer with low water solubility are selected such that a membrane application time of at least 15 minutes, preferably at least 30 minutes, is provided, preferably with no membrane dissolution. In one embodiment, the water-insoluble polymer is ethyl cellulose and / or poly(methyl methacrylate). In one embodiment, the cellulose derivative contained in the backing layer is hydroxyethyl cellulose and / or ethyl cellulose. In one embodiment, the backing layer is constructed to be insoluble in aqueous liquids for at least 30 minutes, preferably at least 60 minutes. In one embodiment, the backing layer is configured to be impermeable to macrolides for at least 30 minutes, preferably at least 60 minutes; preferably configured to be impermeable to macrolides in aqueous liquids such as saliva for at least 30 minutes, preferably at least 60 minutes. In one embodiment, the backing layer and / or the backing layer polymer mixture comprises a polymer that is insoluble in aqueous liquids for at least 30 minutes. In one embodiment, the backing layer comprises ethyl cellulose, hydroxyethyl cellulose, and / or poly(methyl methacrylate), and optionally also comprises a plasticizer. In one embodiment, the backing layer comprises ethyl cellulose and / or poly(methyl methacrylate), and optionally also comprises a plasticizer.

[0222] As used herein, the term "intermediate layer" refers to a layer of an adhesive membrane, preferably disposed between the adhesive layer and the backing layer. In one embodiment, the intermediate layer is an adhesive layer. In one embodiment, the intermediate layer facilitates adhesion between the adhesive layer and the backing layer. In one embodiment, the intermediate layer prevents macrolides from migrating into the backing layer. In one embodiment, the membrane includes an intermediate layer between the adhesive layer and the backing layer to prevent macrolides from migrating into the backing layer. In one embodiment, the terms "adhesive interlayer" and "intermediate layer" are used interchangeably. In one embodiment, the adhesive layer and the backing layer are joined via the intermediate layer. For example, a membrane including the backing layer and the intermediate layer can be combined with the adhesive layer after these layers have dried to prevent macrolides from migrating into the adhesive interlayer and / or the backing layer. Advantageously, the inclusion of an intermediate layer in the adhesive membrane allows for the prevention of macrolide dissolution in the backing layer during the method of membrane preparation. Advantageously, the intermediate layer prevents a reduction in the amount of macrolides in the mucosal adhesive layer and / or degradation of macrolides during the method of preparing the backing layer on the mucosal adhesive layer. Advantageously, the intermediate layer prevents macrolides from dissolving in the ethanol contained in the backing layer. In one embodiment, the mucosal adhesive membrane includes an intermediate layer, for example, a membrane containing micronized macrolides, preferably in the form of micronized crystalline macrolides, and / or molecularly dissolved non-nanoparticle form of non-nanoparticle macrolides. In one embodiment, the intermediate layer contains a polymer, optionally an adhesive polymer. In one embodiment, the intermediate layer contains a polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone; for example, selected from poly(vinylpyrrolidone), poly[(vinylpyrrolidone)-co-(vinyl acetate)] (e.g., a copolymer of 6 parts polyvinylpyrrolidone and 4 parts polyvinyl acetate), and mixtures of poly(vinyl acetate) and poly(vinylpyrrolidone) (e.g., an 8:2 mixture of poly(vinyl acetate) and poly(vinylpyrrolidone)). In one embodiment, the intermediate layer contains a plasticizer, such as glycerin.

[0223] As used herein, the term "solid solution" refers to a macrolide dissolved in a diluent or matrix at the molecular level, preferably dissolved in a polymer matrix at the molecular level. In one embodiment, the term "solid solution" refers to a macrolide dissolved and optionally embedded in a polymer matrix. In one embodiment, a molecularly dissolved, non-nanoparticle form of a macrolide refers to a solid solution of a macrolide. In one embodiment, the terms "solid solution" and "molecularly dissolved, non-nanoparticle form" are used interchangeably. In one embodiment, a solid solution is a molecularly dissolved, non-nanoparticle macrolide provided in a polymer matrix, preferably comprising at least one polymer soluble in an organic solvent. In one embodiment, a molecularly dissolved, non-nanoparticle macrolide is provided in a polymer matrix, preferably comprising at least one polymer soluble in an organic solvent. In one embodiment, a polymer soluble in an organic solvent (e.g., a copolymer of methyl vinyl ether and maleic anhydride) is used to achieve suitable mucosal adhesion in an anhydrous mucosal adhesive film formulation, for example, for a solid solution. In one embodiment, a molecularly dissolved, non-nanoparticle macrolide is a solid solution form of a macrolide. In one embodiment, the polymer soluble in organic solvents is any polymer selected from the following: a) amphiphilic and hydrophilic polymers, b) poly(methacrylate), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers comprising polyvinyl acetate and / or polyvinylpyrrolidone, f) cellulose derivatives, and combinations thereof. In one embodiment, the polymer soluble in organic solvents is an amphiphilic or hydrophilic polymer, such as... Poly(methacrylate), such as methacrylic acid copolymers; cellulose derivatives, preferably hydroxypropyl cellulose (HPC) or ethyl cellulose (EC), more preferably HPC; crosslinked polyacrylic acid polymers, such as Or polycarboxylic acid; copolymers of methyl vinyl ether and maleic anhydride, such as Gantrez. TM ; and / or polymers containing polyvinyl acetate and / or polyvinylpyrrolidone, for example In one embodiment, the solid solution of the macrolide comprises HPC; a crosslinked polyacrylic acid polymer, such as... Or polycarboxylic acid; copolymers of methyl vinyl ether and maleic anhydride, such as Gantrez. TM ; and / or polymers containing polyvinyl acetate and / or polyvinylpyrrolidone, for example In one embodiment, the solid solution comprises HPC; and a crosslinked polyacrylic acid polymer, such as Or polycarboxylic acid; and / or copolymers of methyl vinyl ether and maleic anhydride, such as Gantrez TMIn one embodiment, the non-nanoparticle macrolide is present in the mucosal adhesive layer as a micronized macrolide, preferably a micronized crystalline macrolide, and / or as a molecularly dissolved non-nanoparticle, preferably a molecularly dissolved macrolide, solid solution. Such a mucosal adhesive layer allows for highly advantageous macrolide blood distribution. As used herein, the term "molecularly dissolved non-nanoparticle form" refers to the macrolide being dissolved at the molecular level, for example, dissolved at the molecular level in a polymer matrix. In one embodiment, the mucosal adhesive layer comprises at least one component selected from the group consisting of, preferably, polymers: a) amphiphilic and hydrophilic polymers, b) poly(methacrylate), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers comprising polyvinyl acetate and / or polyvinylpyrrolidone, f) cellulose derivatives, and combinations thereof; preferably comprising at least one component selected from a)-e), and further comprising cellulose derivatives; wherein, preferably, if the layer comprises molecularly dissolved non-nanoparticle macrolides, the at least one component is a polymer soluble in an organic solvent, preferably ethanol, acetone, and / or isopropanol. In one embodiment, the mucosal adhesive layer comprises a plasticizer. In one embodiment, the mucosal adhesive layer comprises non-nanoparticle micronized crystalline macrolides and / or molecularly dissolved non-nanoparticle macrolides.

[0224] In one embodiment, if the non-nanoparticle macrolide is present in the layer in a molecularly dissolved non-nanoparticle form, then the mucosal adhesion polymer and / or cellulose derivative is a film-forming polymer, preferably a film-forming polymer soluble in an organic solvent such as ethanol. In one embodiment, if the non-nanoparticle macrolide is present in the layer in a molecularly dissolved non-nanoparticle form, then the molecularly dissolved non-nanoparticle form is dissolved in an organic solvent. In one embodiment, if the non-nanoparticle macrolide is present in the layer in a molecularly dissolved non-nanoparticle form, then the cellulose derivative is selected from HPC, EC, and combinations thereof. In one embodiment, if the non-nanoparticle macrolide is present in the layer in a molecularly dissolved non-nanoparticle form, then the mucosal adhesion polymer is selected from: amphiphilic or hydrophilic polymers, such as... Crosslinked polyacrylic acid polymers, such as Or polycarboxylic acid; copolymers of methyl vinyl ether and maleic anhydride, such as Gantrez. TM Polymers comprising polyvinyl acetate and / or polyvinylpyrrolidone, preferably polymers comprising polyvinyl acetate and / or polyvinylpyrrolidone, such as... And cellulose derivatives, such as HPC, EC, and combinations thereof.

[0225] In one embodiment, to dissolve the macrolide at the molecular level, the macrolide is dissolved in an organic solvent at a concentration of about 10 mg / mL to about 500 mg / mL. As used herein, the term "organic solvent" refers to any organic solvent known to those skilled in the art. In one embodiment, the organic solvent is an ICH 3 or ICH 2 solvent. In one embodiment, the organic solvent is non-toxic and / or volatile. In one embodiment, the organic solvent is selected from ethanol, methanol, acetone, tetrahydrofuran, acetic acid, acetonitrile, anisole, 1-butanol, 2-butanol, butyl acetate, chloroform, cyclohexane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 1,2-dimethoxyethane, 1,4-dioxane, 2,2-dimethoxypropane, dichloromethane, diethyl ether, diisopropyl ether, dimethyl sulfoxide, dimethylformamide, 2-ethoxyethanol, ethyl acetate, ethyl formate, ethylene glycol (1,2-ethylene glycol), formic acid, heptane, hexane, isobutyl acetate, isopropyl acetate, 2-methoxyethanol, 2-methyl-1-propanol, 3-methyl-1-butanol, 1-methyl-2-pyrrolidone, methyl acetate, methyl tert-butyl ether, methyl butyl ketone, methyl cyclohexane, methyl ethyl ketone (MEK), methyl Isobutyl ketone, methyl isopropyl ketone, methyltetrahydrofuran, n-methylpyrrolidone, 1-pentanol, 1-propanol, 2-propanol, pentane, petroleum ether, propyl acetate, pyridine, sulfolane, tert-butanol, 2,2,4-trimethylpentane (isooctane), toluene, trichloroacetic acid, trichloroethylene, trifluoroacetic acid, xylene, and combinations thereof; preferably selected from acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, DMSO, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, 2-methyltetrahydrofuran, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, trimethylamine; more preferably selected from ethanol, acetone, and isopropanol. In one embodiment, as used herein, the term "micronized macrolide solution" refers to a solution of micronized macrolides, particularly a solution of micronized macrolides dissolved in an organic solvent. In one embodiment, the terms "micronized macrolide solution" and "macrolide solution" are used interchangeably.

[0226] As used herein, the term "mucosal adhesion polymer" refers to polymers that promote and / or mediate mucosal adhesion. In one embodiment, the mucosal adhesion polymer is selected from: a) amphiphilic and hydrophilic polymers, b) poly(methacrylate), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers comprising poly(vinyl acetate) and / or poly(vinylpyrrolidone), and mucosal adhesion cellulose derivatives. In one embodiment, the mucosal adhesion polymer is selected from poly(acrylic acid), for example... 934 or 971NF; cross-linked poly(acrylic acid), such as polycarboflavone, especially poly(acrylic acid) cross-linked with diethylene glycol, more specifically its calcium salt; amylopectin, such as Prolocene. TM 15; Poly(methacrylic acid), for example L100 or S100; Poly(methacrylate), for example E100 RL or RS; poly[(maleic anhydride)-co-(vinyl methyl ether)] or its salts, such as Gantrez TM AN 119, Gantrez TM AN 139, Gantrez TM AN 149, Gantrez TM AN 169 or Gantrez TM MS-955; gelatin; polysaccharides, such as alginate, chitosan, xanthan gum, hyaluronic acid, pectin, or pullulan; cellulose derivatives, such as sodium carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl methyl cellulose (HEMC), hydroxyethyl cellulose (HEC), or methyl cellulose (MC); poly(vinylpyrrolidone), such as... 30LP or 90F; poly[(vinylpyrrolidone)-co-(vinyl acetate)], for example VA64; a mixture of poly(vinyl acetate) and poly(vinylpyrrolidone), for example SR; poly(vinyl alcohol); and poly(vinyl acetate).

[0227] As used herein, the term "amphiphilic polymer" refers to any amphiphilic polymer known to those skilled in the art, preferably an amphiphilic polymer for mucosal adhesion. Typically, amphiphilic polymers have a hydrophilic (polar) portion and a hydrophobic (non-polar) portion. In one embodiment, the amphiphilic polymer is selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, for example... Polyoxymethylene castor oil and D-α-tocopherol-polyethylene glycol-succinate (TPGS).

[0228] In one embodiment, the hydrophilic polymer is a polymer containing polar or charged groups. In one embodiment, these groups are nonionic, anionic, cationic, and / or zwitterionic. In one embodiment, the hydrophilic polymer is soluble in water. For example, the hydrophilic polymer may be selected from cellulose and cellulose derivatives, such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acid, polyacrylate, polyvinylpyrrolidone, polyethylene glycol / polyvinyl alcohol copolymer, polyvinyl alcohol, polyethylene oxide polymer, polyethylene oxide / polyethylene glycol copolymer, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth gum, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, starch and starch derivatives, dextran, carrageenan, shellac, natural gums and / or copolymers thereof.

[0229] In one embodiment, the poly(methacrylate) is selected from neutral protonable poly(methacrylate) and cationic poly(methacrylate), preferably from copolymers of dialkylaminoethyl methacrylate and methacrylate, and copolymers of trialkylaminoethyl methacrylate and methacrylate, specifically copolymers of dimethylaminoethyl methacrylate and methacrylate, and copolymers of trimethylaminoethyl methacrylate and methacrylate. For example, the poly(methacrylate) can be... L100 S100 E100 RL or RS.

[0230] As used herein, the term "crosslinked polyacrylic polymer" refers to polyacrylic polymers and crosslinked polyacrylic polymers known to those skilled in the art, preferably crosslinked polyacrylic polymers, such as homopolymers, copolymers, and interpolymers, for example, acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol, acrylic acid crosslinked with allyl pentaerythritol, and acrylic acid C. 10 -C 30 Alkyl esters, and carbomer homopolymers or copolymers containing block copolymers of polyethylene glycol and long-chain alkyl esters. For example, crosslinked polyacrylic acid polymers may be... 934 or 971NF or polycarboxyphenidate.

[0231] As used herein, the term "copolymer of methyl vinyl ether and maleic anhydride" refers to any copolymer of methyl vinyl ether and maleic anhydride / maleic acid known to those skilled in the art, such as copolymers of monoalkyl esters of poly(methyl vinyl ether / maleic acid) with different ester groups. In one embodiment, the copolymer of methyl vinyl ether and maleic anhydride is in the form of an anhydride or in a hydrolyzed form, such as a mixed sodium and calcium salt of methyl vinyl ether and maleic anhydride, for example, Gantrez. TM MS-955 polymer. In one embodiment, the copolymer of methyl vinyl ether and maleic anhydride is selected from: poly(methyl vinyl ether-co-maleic anhydride), poly(methyl vinyl ether-co-maleic acid), monoethyl ester of poly(methyl vinyl ether / maleic acid), a mixture of monoethyl ester of poly(methyl vinyl ether / maleic acid) and monobutyl ester of poly(methyl vinyl ether / maleic acid), and mixed sodium / calcium salts of poly(methyl vinyl ether / maleic anhydride). In one embodiment, the copolymer of methyl vinyl ether and maleic anhydride (e.g., Gantrez) TM This is a mixed sodium and calcium salt of a copolymer of methyl vinyl ether and (hydrolyzed) maleic anhydride. In one embodiment, the copolymer of methyl vinyl ether and maleic anhydride is a complexing agent. For example, the copolymer of methyl vinyl ether and maleic anhydride can be Gantrez. TM AN 119, Gantrez TM AN 139, Gantrez TM AN 149, Gantrez TM AN 169, Gantrez TM AN-903, Gantrez TM S-96, Gantrez TM S-97, Gantrez TM ES-225, Gantrez TM ES-425 or Gantrez TM MS-955.

[0232] As used herein, the terms "polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone" and "polymer comprising polyvinyl acetate and polyvinylpyrrolidone" refer to any polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone known to those skilled in the art, such as poly(vinylpyrrolidone), poly(vinyl acetate), poly[(vinylpyrrolidone)-co-(vinyl acetate)], and mixtures of poly(vinyl acetate) and poly(vinylpyrrolidone). In one embodiment, the polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone is selected from poly(vinylpyrrolidone), poly(vinyl acetate), poly[(vinylpyrrolidone)-co-(vinyl acetate)] (e.g., a copolymer of 6 parts polyvinylpyrrolidone and 4 parts polyvinyl acetate), and mixtures of poly(vinyl acetate) and poly(vinylpyrrolidone) (e.g., an 8:2 mixture of poly(vinyl acetate) and poly(vinylpyrrolidone)). In one embodiment, the polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone comprises or is composed of poly(vinylpyrrolidone). In one embodiment, the polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone comprises a vinylpyrrolidone-vinyl acetate copolymer, particularly poly[(vinylpyrrolidone)-co-(vinyl acetate)], or is composed of. In one embodiment, the polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone comprises or is composed of a mixture of poly(vinyl acetate) and poly(vinylpyrrolidone). In one embodiment, the polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone comprises one or more, preferably multiple, vinyl acetate monomers and / or one or more, preferably multiple, vinylpyrrolidone monomers. For example, the polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone may be... 30LP 90F VA64 or SR.

[0233] As used herein, the term "cellulose derivative" refers to cellulose and its derivatives. In one embodiment, the cellulose derivative is preferably a cellulose derivative that swells but does not dissolve upon contact with water and / or saliva. In one embodiment, the cellulose derivative is selected from hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC) (e.g., sodium carboxymethyl cellulose (CMC)), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), hydroxyethyl methyl cellulose (HEMC), ethyl cellulose (EC), and combinations thereof. In one embodiment, the mucosal adhesive layer comprises a cellulose derivative, i.e., a mucosal adhesive cellulose derivative, such as selected from hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), and combinations thereof. In one embodiment, the cellulose derivative soluble in organic solvents is HPC and / or EC. In one embodiment, CMC is soluble in water but insoluble in organic solvents.

[0234] In a preferred embodiment, the mucosal adhesive layer comprises hydroxypropyl cellulose, alone or in combination with another mucosal adhesive polymer selected from: a copolymer of methyl vinyl ether and maleic anhydride; poly(acrylic acid); crosslinked poly(acrylic acid); poly(methacrylic acid); poly[(maleic anhydride)-co-(vinyl methyl ether)] or a salt thereof; gelatin; alginate, chitosan, xanthan gum, hyaluronic acid, pectin or pullulan; carboxymethyl cellulose; hydroxypropyl methyl cellulose; poly(vinylpyrrolidone), poly[(vinylpyrrolidone)-co-(vinyl acetate)]; a mixture of poly(vinyl acetate) and poly(vinylpyrrolidone); poly(vinyl alcohol); and poly(vinyl acetate).

[0235] In a particularly preferred embodiment, the mucosal adhesive layer comprises hydroxypropyl cellulose as the mucosal adhesive polymer in combination with another non-cellulose mucosal adhesive polymer selected from: a copolymer of methyl vinyl ether and maleic anhydride; poly(acrylic acid); crosslinked poly(acrylic acid); poly(methacrylic acid); poly[(maleic anhydride)-co-(vinyl methyl ether)] or a salt thereof; gelatin; alginate, chitosan, xanthan gum, hyaluronic acid, pectin or pullulan; poly(vinylpyrrolidone), poly[(vinylpyrrolidone)-co-(vinyl acetate)]; a mixture of poly(vinyl acetate) and poly(vinylpyrrolidone); poly(vinyl alcohol); and poly(vinyl acetate).

[0236] In a particularly preferred embodiment, which can be combined with any of the other embodiments disclosed herein (particularly with the embodiments in the preceding paragraphs), the mucosal adhesive layer comprises a combination of two different types of hydroxypropyl cellulose, wherein such types of hydroxypropyl cellulose have different molecular weights, wherein, preferably, the first type of hydroxypropyl cellulose has a weight-average molecular weight of about 370,000, and the second type of hydroxypropyl cellulose has a weight-average molecular weight of about 80,000. Preferably, in this combination of two different types of hydroxypropyl cellulose, the first type of hydroxypropyl cellulose with a weight-average molecular weight of about 80,000 is present in an amount ranging from 15 to 43% by weight, more preferably from 30 to 43% by weight, and the second type of hydroxypropyl cellulose with a weight-average molecular weight of about 370,000 is present in an amount ranging from 2 to 28% by weight, more preferably from 8 to 13% by weight, or equally more preferably from 12 to 28% by weight. Within the above ranges, the weight percentages are based on the dry weight of the respective mucosal adhesive layer.

[0237] As used herein, the term "hydroxypropyl cellulose with a viscosity of about 300-600 mPa·s [weight-average molecular weight of about 80,000-Klucel EF]" is intended to refer to hydroxypropyl cellulose with a weight-average molecular weight of about 80,000 or a viscosity of about 300-600 mPa·s, or both a weight-average molecular weight of about 80,000 and a viscosity of about 300-600 mPa·s; this type of hydroxypropyl cellulose can be used, for example, as... Purchased from merchants

[0238] As used herein, the term "hydroxypropyl cellulose with a viscosity of about 150-400 mPa·s [weight-average molecular weight of about 370,000-Klucel GF]" is intended to refer to hydroxypropyl cellulose with a weight-average molecular weight of about 370,000 or a viscosity of about 150-400 mPa·s, or both a weight-average molecular weight of about 370,000 and a viscosity of about 150-400 mPa·s; this type of hydroxypropyl cellulose can be used as... Purchased from merchants

[0239] In embodiments where the mucosal adhesive layer comprises a combination of two different types of hydroxypropyl cellulose, wherein these types of hydroxypropyl cellulose differ in molecular weight, it is particularly preferred that such mucosal adhesive layer further comprises another mucosal adhesive polymer (more preferably a non-cellulose polymer). In a particularly preferred embodiment, such non-cellulose polymer is selected from: copolymers of methyl vinyl ether and maleic anhydride; poly(acrylic acid); crosslinked poly(acrylic acid); poly(methacrylic acid); poly[(maleic anhydride)-co-(vinyl methyl ether)] or its salts; gelatin; alginate, chitosan, xanthan gum, hyaluronic acid, pectin or pullulan; poly(vinylpyrrolidone), poly[(vinylpyrrolidone)-co-(vinyl acetate)]; mixtures of poly(vinyl acetate) and poly(vinylpyrrolidone); poly(vinyl alcohol); and poly(vinyl acetate).

[0240] In other embodiments in which the mucosal adhesive layer comprises a combination of two different types of hydroxypropyl cellulose as described herein, wherein such types of hydroxypropyl cellulose are also different in terms of molecular weight as described herein, and, alternatively preferably, such mucosal adhesive layer does not contain any other mucosal adhesive polymer; and the mucosal adhesive properties of the mucosal adhesive film and / or the corresponding mucosal adhesive layer are caused solely by the presence of hydroxypropyl cellulose.

[0241] When preparing an adhesive membrane, the layers of the membrane can be prepared individually and then joined together (e.g., via an intermediate layer and / or via an adhesive), and or can be prepared, for example, by first preparing an adhesive membrane layer and then subsequently coating it with a backing layer, or optionally by coating the adhesive membrane layer with an intermediate layer and a backing layer and then stacking them together. For example, preparing an adhesive membrane may include preparing an adhesive membrane layer, a backing layer, and optionally an intermediate layer separately, and then joining these layers using lamination (e.g., hot lamination or compression). For example, after casting and subsequently drying the adhesive membrane layer, a second layer (e.g., an intermediate layer or a backing layer) is cast onto the adhesive membrane layer. In one embodiment, the first and second layers (e.g., the adhesive membrane layer and the intermediate or backing layer) are bonded to each other. In one embodiment, the adhesive membrane layer is not completely dry before the intermediate and / or backing layers are applied. In one embodiment, rollers can be used to compress these layers onto each other. In one embodiment, preparing a mucosal adhesive membrane includes preparing a mucosal adhesive layer and a backing layer, and then (e.g., by compression or bonding) joining the mucosal adhesive layer and the backing layer. In another embodiment, preparing a mucosal adhesive membrane includes preparing a mucosal adhesive layer, an intermediate layer, and a backing layer, and then (e.g., by compression or bonding) joining these layers.

[0242] In one embodiment, after the steps of preparing the mucosal adhesive layer and the backing layer, a step of joining the mucosal adhesive layer and the backing layer is performed by compression and / or lamination (e.g., hot lamination). Optionally, the mucosal adhesive layer and / or the backing layer are dried or partially dried before the step of joining the mucosal adhesive layer and the backing layer. In one embodiment, after the steps of preparing the mucosal adhesive layer, the intermediate layer, and the backing layer, a step of joining the mucosal adhesive layer, the intermediate layer, and the backing layer is performed by compression and / or lamination (e.g., hot lamination). Optionally, the mucosal adhesive layer, the intermediate layer, and / or the backing layer are dried or partially dried before the step of joining the mucosal adhesive layer, the intermediate layer, and the backing layer. In one embodiment, the joining is performed by compression and / or lamination (e.g., hot lamination).

[0243] In one embodiment, the backing layer is prepared on the surface of the mucosal adhesive layer (e.g., by coating the surface of the mucosal adhesive layer with the polymer mixture), or the backing layer is prepared separately and subsequently bonded to the mucosal adhesive layer, optionally via an intermediate layer. In one embodiment, if the mucosal adhesive layer and the backing layer, optionally the intermediate layer, are prepared separately, the layers are prepared on a process liner. In one embodiment, if the mucosal adhesive layer contains micronized macrolides, preferably micronized crystalline macrolides, the backing layer is prepared on the surface of the mucosal adhesive layer (e.g., by coating the surface of the mucosal adhesive layer with the polymer mixture). In one embodiment, if the mucosal adhesive layer contains molecularly dissolved macrolides, the backing layer is prepared separately from the mucosal adhesive layer, and the mucosal adhesive layer and the backing layer are subsequently bonded after their preparation, optionally via an intermediate layer. In one embodiment, the mucosal adhesive layer, the backing layer, and the optional intermediate layer are each prepared on a process liner and subsequently bonded after their preparation.

[0244] In one embodiment, preparing the mucosal adhesive film includes the step of bonding an adhesive layer, a backing layer, and an optional intermediate layer (e.g., by compression and / or lamination, such as heat lamination). In one embodiment, the adhesive layer, backing layer, and optional intermediate layer are dried or partially dried prior to the bonding step. In one embodiment, the adhesive layer, backing layer, and optional intermediate layer are prepared separately and then bonded together after their preparation, and / or prepared on top of each other.

[0245] The inventors have discovered that the negative effects of oral application via the gastrointestinal tract can be eliminated using the innovative buccal therapy system presented herein. Another positive finding from human pharmacokinetic studies is the low variability in pharmacokinetic (PK) distributions between the two comparison groups: the average PK distribution variation between the high-dose and low-dose groups was approximately 25%, which is very low inter-patient variability for tacrolimus. The inventors have found that, advantageously, buccal application can positively impact the core deficiencies of oral therapy.

[0246] As used herein, the terms “(this) invention,” “according to the invention,” etc., are intended to refer to all aspects and embodiments of the invention described and / or claimed herein.

[0247] As used herein, the term “comprising” should be interpreted to encompass both “including” and “consisting of”, both meanings being specifically contemplated and therefore specific to the individual disclosed embodiments of the invention. The term “and / or” as used herein should be considered as a specific disclosure of each of two specified features or components with or without the other. For example, “A and / or B” should be considered as a specific disclosure of (i) A, (ii) B, and (iii) A and B, as if each were stated separately herein. In the context of this invention, the terms “about” and “approximately” indicate a range of accuracy of the technical effect of the features in question, which will be understood by those skilled in the art. This term typically indicates a deviation from the indicated numerical value of ±20%, ±15%, ±10%, and, for example, ±5%. As will be understood by those skilled in the art, the specific such deviation for a given numerical value of technical effect will depend on the nature of the technical effect. For example, natural or biotechnological effects can often have a larger such deviation than artificial or engineered effects. When referring to a singular noun, the use of an indefinite or definite article (such as "a," "a kind," or "the") includes the plural form of the noun unless otherwise explicitly stated. Attached Figure Description

[0248] The invention will now be further described with reference to the following figures.

[0249] All methods mentioned in the following figures are performed as described in detail in the embodiments.

[0250] Figure 1 The arithmetic mean whole blood concentration-time curve of tacrolimus is shown (ng / mL; PK set, N=10). Treatment group 1 (T1): two doses of tacrolimus MBF 8.8 mg; Treatment group 2 (T2): two doses of tacrolimus MBF 12.0 mg.

[0251] Figure 2Individual tacrolimus blood levels were shown in 10 healthy volunteers (5 subjects in each group) (bid administration, second dose 4 hours later).

[0252] Figure 3 The mean blood levels of tacrolimus in 10 healthy volunteers (5 subjects in each group) are shown (bid administration, second dose 4 hours later).

[0253] Figure 4 Individual pharmacokinetic (PK) curves are shown within different groups (5 miniature pigs per group) that employed an asymmetric dosing regimen for cheek application, wherein a second dose was administered 3, 4, or 5 hours after the first dose.

[0254] Figure 5 A graph showing the average value curve is provided. The highest blood levels were achieved when the second dose unit was administered 3 hours after the first dose.

[0255] Figure 6 The residual drug levels in the membranes used in the low-dose group (loaded 8.8 mg tacrolimus = 17.6 mg (bid)) and the high-dose group (loaded 12 mg tacrolimus = 24 mg (bid)) are shown. Each subject was treated with a first dose in the form of a first mucosal adhesive membrane at a first time point and with a second dose in the form of a second mucosal adhesive membrane at a second time point approximately 4 hours after the first time point. Each membrane was removed after a duration of approximately 1 hour. The patterned bars show the residual amount of macrolides in the first mucosal adhesive membrane after membrane removal. The black bars show the residual amount of macrolides in the second mucosal adhesive membrane after membrane removal.

[0256] Figure 7 Normalized concentration-time curves for human subjects are shown (tacrolimus blood concentration at each measurement time point as a percentage of maximum concentration).

[0257] Figure 8 The results showed relatively small inter-individual variability (CV) in tacrolimus blood levels in both groups over a 24-hour interval with buccal application. Advantageously, buccal administration reduced blood level variability compared to oral administration.

[0258] The following examples are given for illustrative purposes only and are not intended to limit the invention. Detailed Implementation

[0259] Example

[0260] Example 1: Phase I kinetic study in humans (proof of concept in humans)

[0261] The first human study of a tacrolimus mucosal adhesive buccal mask formulation has been conducted:

[0262] Research Principles

[0263] The primary objective of this first-in-human preliminary study was to investigate the pharmacokinetic (PK) of tacrolimus MBF in healthy male subjects. Additionally, the safety and tolerability of tacrolimus MBF were assessed, and the residual amount of tacrolimus in MBF after use was determined.

[0264] To overcome the PK problems associated with currently available oral tacrolimus formulations, a novel tacrolimus formulation in the form of a mucosal adhesive buccal membrane (MBF) has been developed.

[0265] Research objectives and endpoints

[0266]

[0267] Methodology (research design):

[0268] This study was conducted using a single-center, open-label, non-randomized, multi-dose, parallel-group design, with two consecutive treatment groups.

[0269] To overcome the pharmacokinetic issues associated with currently available oral tacrolimus formulations, a novel tacrolimus formulation in MBF form was developed.

[0270] The aim of this study was to investigate the pharmacokinetics of tacrolimus MBF in healthy male subjects. Additionally, the safety and tolerability of tacrolimus MBF were evaluated, and the residual amount of tacrolimus in MBF after administration was determined.

[0271] The treatment plan is as follows:

[0272]

[0273] MBF-1 = Tacrolimus Mucosal Adhesive Buccal Mask 8.8mg

[0274] MBF-2 = Tacrolimus Mucosal Adhesive Buccal Mask 12.0mg

[0275] The research structure is as follows:

[0276] • Screening visit: 21 days to 2 days before the first administration of the study treatment.

[0277] Day -1: Subjects check into the study ward and are assigned to study treatments.

[0278] Day 1: Study treatment with two single doses administered via the buccal route. In certain subjects, the interval between the two subsequent doses was 4 hours. Each MBF remained adhered to the buccal mucosa for 1 hour.

[0279] Day 2: Subjects are discharged from the study ward after completing all protocol procedures, provided there are no medical objections.

[0280] • Follow-up visit: 1 to 3 days after the last administration of the study treatment.

[0281] Safety and tolerability parameters were collected throughout the study, from screening to follow-up. Blood samples were collected for pharmacokinetic analysis up to 28 hours after the first administration of tacrolimus.

[0282] Number of participants (planning and analysis):

[0283] Administer to two (2) consecutive treatment groups receiving tacrolimus MBF. At least 10 healthy subjects are planned to be assigned to the study treatment, ensuring that at least 5 evaluable subjects in each treatment group complete the study.

[0284] Finally, the 10 subjects were assigned to treatment groups and treated, namely, 5 subjects in treatment group 1 and 5 subjects in treatment group 2.

[0285] Diagnostic and primary inclusion criteria:

[0286] Weight ≥65kg and ≤85kg, Body Mass Index (BMI) between 18.0 and 30.0 kg / m² 2 Healthy male subjects (aged 18 to 40, inclusive) within the specified range are eligible for inclusion.

[0287] Test product, dosage and mode of administration, batch number:

[0288] treat Test Product 1 Test Product 2 Compound Name MBF-1 MBF-2 Active substances Tacrolimus Tacrolimus Dosage formulation Mucosal adhesive buccal membrane Mucosal adhesive buccal membrane Unit dose intensity <![CDATA[8.8mg / 4.4cm 2 ]]> <![CDATA[12.0mg / 6.0cm 2 ]]> dose level 8.8mg, twice daily 12.0 mg, twice daily Application route cheek cheek Drug substance batch number 09166102E 09166102E Drug product batch number (primary packaging) 7009392 7009402 Batch number label D033G D034G

[0289] Treatment duration:

[0290] The study lasted approximately 4 weeks per participant.

[0291] On day 1, subjects were given two single doses of study treatment. In certain subjects, the interval between the two subsequent doses was 4 hours. Each MBF remained adhered to the buccal mucosa for 1 hour.

[0292] Statistical methods:

[0293] Pharmacokinetics: No formal statistical assumptions were defined in this exploratory study. Appropriate summary tables and figures are provided.

[0294] Security: Descriptive assessment of security data.

[0295] Summary and conclusion:

[0296] Pharmacokinetics:

[0297] In treatment group 1 (T1), all subjects had whole blood concentrations below LLOQ until 0.5 hours after the start of the first MBF administration, and all subjects had whole blood concentrations above LLOQ 3 hours after the start of the first MBF administration (equivalent to 2 hours after the end of the first MBF administration). In treatment group 2 (T2), all subjects had whole blood concentrations below LLOQ until 0.25 hours after the start of the first MBF administration, and all subjects had whole blood concentrations above LLOQ 1.5 hours after the start of the first MBF administration.

[0298] The mean whole blood concentration curves for both treatment groups reached their first peak 3 hours after the start of the first MBF administration (equivalent to 2 hours after the end of the first MBF administration), and after a slight decrease, reached their second peak 8 hours after the start of the first MBF administration (equivalent to 4 hours after the start of the second MBF administration and 3 hours after the end of the second MBF administration), showing mean concentrations of 0.9526 ng / mL (T1) and 6.548 ng / mL (T2). Results are shown in... Figure 1 middle.

[0299] Geometric mean AUC of tacrolimus in treatment group 2 (12.0 mg; 6.063 h*ng / mL) 0-4 Significantly higher than treatment group 1 (8.8 mg; 1.044 h*ng / mL). This also applies to the geometric mean AUC. 0-tlast (T1: 13.594 h*ng / mL; T2: 56.021 h*ng / mL) and geometric mean C max (T1: 0.878ng / mL; T2: 3.771ng / mL).

[0300] The median t between the two treatment groups max It is equivalent to (T1: 8.083 hours after the start of the first MBF application; = 3.083 hours after the end of the second MBF application; T2: 8.017 hours after the start of the first MBF application; = 3.017 hours after the end of the second MBF application).

[0301] The geometric mean half-life and elimination rate are also comparable (t1 / 2: T1: 14.475 h and T2: 14.926 h; λz: T1: 0.04789 1 / h and T2: 0.04644 1 / h).

[0302] Particularly in treatment group 2, subjects showed individual differences regarding pharmacokinetic parameters. Subject 015 had the highest C... max Value (17.5 ng / mL), which is the lowest C maxThe measured value (subject 012; 0.703 ng / mL) was 24.9 times higher than that of the measured value. Subject 015 also showed the highest AUC. 0-tlast (224.76 h*ng / mL), which is the lowest AUC. 0-tlast (Subject 012; 11.51 h*ng / mL) 19.5 times.

[0303] Summary of key PK parameters for tacrolimus (PK set, N=10)

[0304]

[0305] Treatment group 1: Two doses of tacrolimus MBF 8.8mg

[0306] Treatment group 2: Two doses of tacrolimus MBF 12.0 mg CV = coefficient of variation; Geom. = geometric; Max = maximum value; Min = minimum value; N = number of subjects in the population under consideration.

[0307] In summary, a significant amount of tacrolimus remained in the MBF. After each administration, the mean percentage of residual tacrolimus in the MBF in treatment group 1 (first administration: 91.076%; second administration: 85.650%) was higher than that in treatment group 2 (first administration: 78.214%; second administration: 74.296%).

[0308] First biomechanical data for tacrolimus—MBF

[0309] Individual tacrolimus blood levels (bid, second dose 4 hours later) in 10 healthy volunteers (5 subjects in each group) as follows Figure 2 As shown.

[0310] The mean blood level curve of tacrolimus in 10 healthy volunteers (5 subjects in each group) (bid administration, second dose 4 hours later) is as follows: Figure 3 As shown.

[0311] in conclusion

[0312] • First-line human pharmacokinetic results indicate that systemic exposure was achieved following administration of the buccal, one-way release MBF formulation.

[0313] This provides a proof of concept in the human body.

[0314] In clinical settings, tacrolimus dosage is typically adjusted based on body weight, whereas in this preliminary pharmacokinetic study, a fixed nominal dose was administered to all subjects in a specific dose group. This likely resulted in observed variability in tacrolimus blood levels.

[0315] Example 2: Dosing regimen for buccal application

[0316] The current recommendation for standard oral tacrolimus therapy (prograf capsules) in adult patients with kidney, liver, or heart transplants is:

[0317] kidney 0.2 mg / kg body weight / day, divided into two doses, administered every 12 hours. liver 0.10-0.15 mg / kg body weight / day, divided into two doses, administered every 12 hours. heart 0.075 mg / kg body weight / day, divided into two doses, administered every 12 hours.

[0318] (bw=weight)

[0319] Tacrolimus drug monitoring (TDM) is recommended for all patients receiving Prograf.

[0320] Monitoring tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an important adjunct to patient management, used to assess rejection, toxicity, dose adjustment, and compliance.

[0321] The novel buccal application route will introduce a new dosing regimen for daily tacrolimus therapy, covering a 24-hour dosing interval.

[0322] Based on kinetic data from preclinical animal studies, a twice-daily (bid) administration with a 4-hour interval between the first and second doses was selected for human kinetic studies.

[0323] Blood level curves in the high-dose group (n=5 healthy subjects) with 12 mg tacrolimus per membrane unit showed that clinically relevant blood levels were achieved using a twice-daily application system with a 4-hour interval between the first and second doses.

[0324] To validate this specific asymmetric dosing regimen for buccal application, further animal studies were conducted under GLP conditions using three different application variants:

[0325] Research Design (GLP - Research):

[0326] • Intra-individual three-way cross

[0327] ·3 sets of comparisons

[0328] • Bid application (5 young miniature pigs per group, GLP)

[0329]

[0330] Results: Individual PK curves within different groups are as follows Figure 4 As shown. Figure 5As shown in the graph of the average values, the highest blood levels were achieved with the bid-and-hold (bid) dosing regimen when the second dose unit was administered 3 hours later. The tested asymmetric dosing regimen was highly advantageous. In particular, the asymmetric 3-hour bid-and-hold system demonstrated excellent results in terms of the achieved blood concentrations.

[0331] Example 3: Dosage Reduction Based on Increased Bioavailability

[0332] The standard daily oral tacrolimus dose (Prograf) for SOT patients is calculated using the following formula:

[0333] tacrolimus mg / kg bw / day

[0334] For a 70kg patient who has already received kidney transplant, the starting dose of oral tacrolimus is therefore calculated as follows:

[0335] 0.2mg × 70kg / day = 14mg daily dose

[0336] Divide into two single doses (morning dose / evening dose).

[0337] This dosage guideline is part of the international registration document for oral Prograf capsules, the current standard of care for oral tacrolimus therapy.

[0338] The situation is different for cheek therapy systems:

[0339] In the human studies presented in this paper, buccal membranes were used at two different dose levels:

[0340] • Low dose: Load 8.8 mg tacrolimus = 17.6 mg (bid).

[0341] • High dose: 12mg tacrolimus = 24mg (bid).

[0342] After application, the membrane remains on the buccal mucosa for 60 minutes; thereafter, the membrane is actively removed from the oral cavity.

[0343] Only the bioavailable portion of the active ingredient that permeates from the membrane matrix into the mucosal tissue within 60 minutes and is subsequently released into the systemic circulation via passive diffusion is associated with achieving therapeutic blood levels.

[0344] This reabsorption process typically occurs in three steps:

[0345] Step 1: Drug release into mucosal tissue

[0346] Step 2: Constructing an API reservoir in the mucosa

[0347] Step 3: Diffusion into the bloodstream

[0348] The residual tacrolimus content in the membrane used after buccal removal was analyzed to determine how much drug permeates into the mucosal tissue, thereby constructing a reservoir for diffusion. Figure 6 The residual drug levels in the membranes used for the two dosage groups are shown.

[0349] result:

[0350] 1. Remaining tacrolimus after application (average value of the membrane)

[0351] • 8.8 mg membrane: 88.4% ± 5.6% (low-dose group)

[0352] • 12mg membrane: 81.8% ± 8.0% (high-dose group)

[0353] More than 80% of the applied tacrolimus remains in the membrane.

[0354] 2. Advantageously, only a lower buccal dose of tacrolimus is required to achieve therapeutic blood levels:

[0355] Dosage example (patient bw = 80 kg):

[0356] Standard oral dose: 16 mg tacrolimus / day

[0357] Cheek application = 3.2 mg tacrolimus / day

[0358] These data confirm that, advantageously, the bioavailability of drugs absorbed into the buccal mucosa is much higher than that of oral applications, since only about 20% of the oral dose is needed to achieve therapeutic levels after buccal application.

[0359] Without being bound by any theory, the inventors believe that these effects can be scientifically explained by the fact that the low bioavailability of tacrolimus (BCS class II) after oral administration, the significant first-pass effect, and the systemic pre-degradation of tacrolimus are unrelated to buccal application.

[0360] Advantageously, the side effects of tacrolimus therapy can also be positively altered because it can potentially reduce the patient's drug load by approximately 80%.

[0361] Example 4: Blood level variability

[0362] One of the most challenging aspects of tacrolimus therapy management is the significant intra- and inter-patient variability in concentration-time curves following oral administration of tacrolimus.

[0363] The reasons for this variability are well known and have been well described in international literature: (1) poor water solubility, resulting in low bioavailability and high variability (4%-90%) of the drug; (2) first-pass effect; (3) pre-systemic degradation; and (4) food effect.

[0364] All these effects are irrelevant in the buccal delivery system due to its better bioavailability and direct entry into the systemic circulation.

[0365] Data from my own human studies also confirms this. Figure 7 ). Figure 7 The figure shown illustrates the normalized concentration-time curves for the two dose groups (the blood concentration of tacrolimus at each measurement time point is a percentage of the maximum concentration).

[0366] Comparing the average normalized concentration-time curves of the two groups shows that the inter-individual variability (CV) in tacrolimus blood levels was relatively small in both groups over a 24-hour interval. Figure 8 Compared to the internationally reported range of blood level fluctuations of tacrolimus following oral administration exceeding 80%, the range of blood level fluctuations following buccal application described herein, at 25%–30%, is classified as low. Therefore, advantageously, buccal administration as described herein reduces blood level fluctuations compared to oral application.

[0367] Without being bound by any theory, the inventors believe that one reason why the variation in blood level distribution is smaller after buccal administration compared to oral administration of tacrolimus is that the bioavailability of the active substance is better after buccal administration (see Example 2).

[0368] The primary goal of individualized dosing titration with tacrolimus is to regulate the distribution of blood levels within a 24-hour therapy interval, maintaining them for at least 24 hours (mean residence time (MRT)) within a therapeutic window of 5–20 ng / mL whole blood. In this context, the blood level fluctuations of tacrolimus—the lowest level—at the end of the 24-hour dosing interval are of particular clinical importance (C0). trough (i.e., the pre-dose level before the next administration).

[0369] In the first year post-transplantation, the time spent within the therapeutic window is directly associated with clinical efficacy. Therefore, dosing regimens (bid) and individual daily doses are preferably designed such that tacrolimus blood levels remain within the therapeutic window at the end of a 24-hour dosing interval.

[0370] In this human pharmacokinetic study, it has been demonstrated that in both dosing groups, using the selected bid-only dosing regimen, C24 hours later was [value missing]. troughBlood levels represent 30%-40% of the Cmax value. This high C level occurs after 24 hours. trough Blood levels are important for the safe and clinically effective management of tacrolimus therapy.

[0371] Furthermore, the lower inter-individual variation in blood levels compared to oral therapy underscores the additional benefits of the innovative cheek therapy system presented in this paper.

[0372] Example 5: Exemplary composition of an adhesive membrane

[0373] The applied tacrolimus mucosal adhesive buccal membrane (8.8 mg / 4.4 cm) 2 An exemplary composition of the following is given by layer: (The percentage values ​​of the components used in the table below are by weight and are expressed with reference to the dry weight of the corresponding layer in which the corresponding component is present.)

[0374]

[0375]

[0376] 1 Weighing tacrolimus H2O: 9.0 mg tacrolimus H2O corresponds to 8.8 mg tacrolimus. 2 For example, EC N50NF

[0377] 3 For example, Klucel EF

[0378] 4 For example, Klucel GF

[0379] 5 Partial removal during the drying process

[0380] The rounded value is actually 0.005.

[0381] The applied tacrolimus mucosal adhesive buccal membrane (12.0 mg / 6.0 cm) 2 An exemplary composition of ) by layer is as follows:

[0382] 1 Weighing tacrolimus H2O: 12.3 mg tacrolimus H2O corresponds to 12.0 mg tacrolimus. 2 For example, EC N50NF 3 For example, Klucel EF

[0383] 4 For example, Klucel GF

[0384] 5Partial removal during the drying process

[0385] The rounded value is actually 0.005.

[0386] The applied tacrolimus mucosal adhesive buccal membrane (16.5 mg / 5 cm) 2 Other exemplary components of ) are as follows, in terms of layers:

[0387] 1 Weigh tacrolimus H2O

[0388] 2 For example, EC N50NF

[0389] 3 For example, Klucel EF

[0390] 4 For example, Klucel GF 5 Partial removal during the drying process

[0391] The rounded value is actually 0.005.

[0392] The applied tacrolimus mucosal adhesive buccal membrane (14.4 mg / 5 cm) 2 Other exemplary components of ) are as follows, in terms of layers:

[0393] 1 Weigh tacrolimus H2O

[0394] 2 For example, EC N50NF

[0395] 3 For example, Klucel EF

[0396] 4 For example, Klucel GF

[0397] 5 Partial removal during the drying process

[0398] 6 For example, Kollidon SR

[0399] 7 For example AA-1 Polycarboxymethyl Fibre USP (Lubrizol)

[0400] The rounded value is actually 0.005.

[0401]

[0402] Example 6: In vivo testing of mucosal adhesive membranes

[0403] Pigs were chosen as the animal model because they closely resemble human functional-anatomical relationships. Animals were fasted (overnight) for at least 16 hours prior to treatment and anesthetized during treatment. A membrane having the composition disclosed in the last table of Example 5 was placed in the animal's mouth, with the mucosal adhesive layer side against the mucosa, and gently pressed until the membrane adhered. The membrane was retained on the buccal mucosa for 30 or 60 minutes, and then removed.

[0404] Blood samples were collected via intravenous catheter. To determine tacrolimus blood levels, 2 mL of blood was collected from all animals and placed in K2EDTA-coated tubes. After collection, the blood collection tubes were chilled on ice and stored in a refrigerator (temperature range -30°C to -15°C) until analysis. Tacrolimus concentrations were determined using a reliable LC-MS / MS method. Pharmacokinetic parameters were calculated based on the time course of blood concentrations. The calculated AUC was normalized relative to the applied dose and set relative to the individual body weight of the animal (AUC_24h / dose).

[0405] MBF administration over 30 minutes in two non-juvenile female Göttingen miniature pigs: individual tacrolimus blood levels and pharmacokinetic parameters.

[0406]

[0407] MBF administration over 60 minutes in three non-juvenile female Göttingen miniature pigs: individual tacrolimus blood levels and pharmacokinetic parameters.

[0408]

[0409]

[0410] Tacrolimus was successfully detected in the blood of all pigs after buccal administration; peak concentrations (t_max) were reached at 2 and 4 hours, respectively. The membrane did not cause local irritation to the buccal mucosa. There were no treatment-related deaths, clinical signs, or changes in body weight.

[0411] The features of the invention disclosed in the specification, claims and / or drawings may be used individually or in any combination thereof as material for implementing the invention in its various forms.

Claims

1. A macrolide in a method for preventing or treating immune diseases or conditions (preferably transplant rejection), said method comprising administering said macrolide at least twice daily. The application of at least twice a day includes administering a first dose at a first time point and administering a second dose at a second time point, wherein the second time point is within the range of about 1 hour to about 7 hours after the first time point, preferably about 2 hours to about 5 hours, more preferably about 2.5 hours to about 3.5 hours, or even more preferably about 3 hours after the first time point. in, Preferably, the macrolide is administered via buccal administration.

2. The macrolide of claim 1, wherein the macrolide is applied in the form of a mucosal adhesive layer, preferably a mucosal adhesive buccal layer; in, Preferably, the application includes adhering the mucosal adhesive layer to the patient's body cavity, preferably to the patient's buccal cavity and / or the patient's mucosa.

3. The macrolide for use according to claim 1 or 2, wherein the application comprises applying each of the first dose and the second dose, preferably each in the form of a mucosal adhesive layer, for a duration ranging from about 1 minute to about 7 hours, preferably from about 10 minutes to about 3 hours, more preferably from about 20 minutes to about 2 hours, even more preferably from about 30 minutes to about 90 minutes, even more preferably from about 60 minutes.

4. The macrolide for use according to any one of the preceding claims, wherein the administration comprises administering the first dose for a period of about 30 minutes to about 90 minutes, preferably about 60 minutes; and administering the second dose at a time point about 2.5 hours to about 3.5 hours, preferably about 3 hours after the first time point, for a period of about 30 minutes to about 90 minutes, preferably about 60 minutes.

5. A macrolide for use according to any one of the preceding claims, wherein the first dose and the second dose, preferably prior to their administration, each comprise an amount in the range of about 0.001 mg to about 250 mg, preferably in the range of about 0.01 mg to about 50 mg, more preferably in the range of about 0.05 mg to about 25 mg, even more preferably in the range of about 0.1 mg to about 15 mg, even more preferably in the range of about 0.5 mg to about 13 mg, optionally in the range of about 8 mg to about 12 mg; and / or The macrolide is administered via buccal administration, and the administration of the macrolide at least twice daily comprises administering the macrolide at about ≤40%, preferably about ≤30%, more preferably about ≤25%, and even more preferably about ≤20% of the total daily dose administered orally.

6. The macrolide for use according to any one of claims 2 to 5, wherein, prior to the application, the macrolide is in a solution relative to 1 cm 2 The amount of the mucosal adhesive layer is in the range of about 0.01 mg to about 10 mg, preferably in a quantity relative to 1 cm. 2 The mucosal adhesive layer is in the range of about 0.1 mg to about 5 mg, more preferably relative to 1 cm. 2 The mucosal adhesive layer is in the range of approximately 1.5 mg to approximately 3.5 mg, or even more preferably relative to 1 cm. 2 The amount of the mucosal adhesive layer is in the range of about 1.8 mg to about 2.5 mg.

7. The macrolide of any of the preceding claims, wherein the macrolide is applied in the form of a mucosal adhesive layer, the mucosal adhesive layer comprising: - Mucosal adhesive polymers, preferably selected from the following polymers: a) amphiphilic polymers and hydrophilic polymers, b) poly(methacrylate), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers comprising polyvinyl acetate and / or polyvinylpyrrolidone, and combinations thereof; in, Preferably, The amphiphilic polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyoxyethylene castor oil, and D-α-tocopherol-polyethylene glycol-succinate (TPGS), and / or The poly(methacrylate) is selected from neutral protonable poly(methacrylate) and cationic poly(methacrylate), preferably selected from copolymers of dialkylaminoethyl methacrylate and methacrylate and copolymers of trialkylaminoethyl methacrylate and methacrylate, especially copolymers of dimethylaminoethyl methacrylate and methacrylate and copolymers of trimethylaminoethyl methacrylate and methacrylate. Optionally, the mucosal adhesive layer further comprises: - Cellulose derivatives, preferably selected from hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), hydroxyethyl methyl cellulose (HEMC), ethyl cellulose (EC), and combinations thereof; - A plasticizer, preferably selected from glycerol, polyethylene glycol (e.g., low molecular weight polyethylene glycols such as PEG 200 or PEG 400), propylene glycol, sorbitol, triacetin, and tributyl citrate; more preferably glycerol; and / or - Colorant, preferably TiO2; Optionally, the macrolide exists in the layer in the form of micronized macrolide, preferably micronized crystalline macrolide, and / or in the form of molecularly dissolved non-nanoparticles.

8. The macrolide for use according to any one of the preceding claims, wherein the at least twice daily administration at a time point within the range of about 2 to about 4 hours after the first time point, preferably about 2.5 to about 3.5 hours, more preferably about 3 hours, provides a first peak in whole blood concentration of the macrolide, and at a time point within the range of about 7 to about 9 hours after the first time point, preferably about 7.5 to about 8.5 hours, more preferably about 8 hours, provides a second peak in whole blood concentration of the macrolide; in, Optionally, the administration of the macrolide at least twice daily at a time point approximately 3 to 5 hours after the second time point, preferably approximately 3.5 to 4.5 hours, and more preferably approximately 4 hours after the second time point, provides the second peak concentration of the macrolide in whole blood.

9. The macrolide for use according to any one of the preceding claims, wherein the administration at least twice daily provides a whole blood concentration of the macrolide in the range of about 0.01 ng / mL to about 50 ng / mL, preferably in the range of about 3 ng / mL to about 20 ng / mL, more preferably in the range of about 5 ng / mL to about 20 ng / mL, for a duration of about 24 hours.

10. A macrolide for use according to any one of the preceding claims, wherein the at least twice daily application provides less than 40%, preferably less than 35%, more preferably less than 32%, even more preferably 30% or less, such as a coefficient of variation in the range of 20% to 30% or in the range of 25% to 30%.

11. The macrolide for use according to any one of the preceding claims, wherein the at least twice-daily administration provides: - Within approximately 3 to 10 hours after the first time point, preferably within approximately 7 to 9 hours after the first time point, more preferably within approximately 7.5 to 8.5 hours after the first time point. max ; and / or - Within approximately 1 hour to approximately 6 hours after the second time point, preferably within approximately 2 hours to approximately 5 hours after the second time point, more preferably within approximately 3.5 hours to approximately 4.5 hours after the second time point, for example, within approximately 4 hours after the second time point. max .

12. The macrolide for use according to any one of the preceding claims, wherein the at least twice-daily administration provides: -In the range of about 0.05 ng / mL to about 50 ng / mL, preferably in the range of about 0.1 ng / mL to about 30 ng / mL, More preferably, the C content is in the range of about 0.7 ng / mL to about 20 ng / mL, and even more preferably in the range of about 5.5 ng / mL to about 20 ng / mL. max ; and / or -In the range of about 0.01 ng / mL to about 18 ng / mL, preferably in the range of about 0.5 ng / mL to about 16 ng / mL, More preferably, in the range of about 3 ng / mL to about 15 ng / mL, such as in the range of about 3 ng / mL to about 7 ng / mL or in the range of about 5 ng / mL to about 7 ng / mL, C trough .

13. The macrolide for use according to any one of the preceding claims, wherein the application is performed at least twice daily for at least 2 days, preferably at least 1 week, more preferably at least 1 month, and even more preferably at least 1 year; in, Optionally, if the macrolide is used to prevent or treat transplant rejection, the at least twice-daily administration shall be performed on the patient for life.

14. The macrolide of any of the preceding claims, wherein the macrolide is administered to a human patient; wherein, Preferably, the patient is not a fasting patient.

15. The macrolide for use according to any one of the preceding claims, wherein the macrolide is selected from macrolide immunosuppressants, macrolide antibiotics, and macrolide antifungal agents; in, Preferably, -The macrolide immunosuppressants are selected from tacrolimus, sirolimus, everolimus, and pimecrolimus; - The macrolide antibiotics are selected from erythromycin, clarithromycin, azithromycin, roxithromycin, josamycin, spiramycin, telithromycin, tylosin, and fedamycin; and / or - The macrolide antifungal agent is selected from polyenes, particularly nystatin, natamycin and amphotericin B, wherein, more preferably, the macrolide is tacrolimus or sirolimus, even more preferably tacrolimus.

16. A tacrolimus mucosal adhesive membrane suitable for buccal administration, the tacrolimus mucosal adhesive membrane comprising an adhesive layer and a backing layer, wherein: A) The adhesive membrane layer comprises: Tacrolimus, approximately 12 to approximately 25 percent by weight; Ethyl cellulose, approximately 27 to approximately 31 percent by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 300-600 mPa·s, approximately 28 to about 36% by weight; About 6 to about 10% by weight of hydroxypropyl cellulose [weight-average molecular weight about 370,000-Klucel GF] having a viscosity of about 150-400 mPa·s; and About 2 to about 5% by weight of a calcium / sodium copolymer of methyl vinyl ether and maleic anhydride; and The weight percentages are based on the dry weight of the adhesive membrane layer; Or one of them: B) The adhesive membrane layer comprises: Tacrolimus, approximately 18 to approximately 25 percent by weight; Ethyl cellulose, approximately 3 to approximately 13 percent by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 300-600 mPa·s, approximately 29 to about 42% by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 370,000-Klucel GF] with a viscosity of about 1 to about 28% by weight and a viscosity of about 150-400 mPa·s; and About 2 to about 10% by weight of crosslinked poly(acrylic acid); and The weight percentages are based on the dry weight of the adhesive layer.

17. The tacrolimus adhesive membrane of claim 16, wherein the backing layer comprises ethyl cellulose.

18. The tacrolimus adhesive membrane of claim 17, wherein the backing layer comprises ethyl cellulose in the range of about 50 to about 62 percent by weight based on the dry weight of the backing layer, or wherein the backing layer comprises ethyl cellulose in the range of about 25 to about 27 percent by weight based on the dry weight of the backing layer.

19. The tacrolimus mucosal adhesive membrane according to claim 16, 17 or 18, wherein the tacrolimus membrane contains 8 mg to 17 mg of tacrolimus.

20. The tacrolimus mucosal adhesive membrane of claim 19, wherein the tacrolimus membrane comprises 8.8 mg, 12 mg, 14.4 mg, or 16.5 mg of tacrolimus.

21. The tacrolimus mucosal adhesive membrane according to any one of claims 16 to 20, wherein the tacrolimus mucosal adhesive membrane further comprises an adhesive layer disposed between the mucosal adhesive layer and the backing layer.

22. The tacrolimus adhesive membrane according to any one of claims 16 to 20, wherein the adhesive membrane layer and the backing layer are in direct contact with each other, and no layer is provided between the adhesive membrane layer and the backing layer.

23. A tacrolimus mucosal adhesive membrane suitable for buccal administration, the tacrolimus mucosal adhesive membrane comprising an adhesive layer and a backing layer, wherein: The adhesive membrane layer comprises: About 12 to about 13 percent by weight of tacrolimus, or about 19 to about 23 percent by weight of tacrolimus; Ethyl cellulose, approximately 27 to approximately 30 percent by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 30-600 mPa·s, approximately 30-35% by weight; About 7 to 8% by weight of hydroxypropyl cellulose [weight-average molecular weight about 370,000-Klucel GF] having a viscosity of about 150-400 mPa·s; and A calcium / sodium copolymer of methyl vinyl ether and maleic anhydride, comprising approximately 3 to 4% by weight; and The weight percentages are based on the dry weight of the adhesive layer.

24. A tacrolimus mucosal adhesive membrane suitable for buccal administration, the tacrolimus mucosal adhesive membrane comprising an adhesive layer and a backing layer, wherein: The adhesive membrane layer comprises: Tacrolimus: approximately 19 to approximately 22 percent by weight; Ethyl cellulose, approximately 3 to approximately 13 percent by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 300-600 mPa·s, approximately 29 to about 42% by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 370,000-Klucel GF] with a viscosity of about 1 to about 28% by weight and a viscosity of about 150-400 mPa·s; and About 2 to about 10% by weight of crosslinked poly(acrylic acid); and The weight percentages are based on the dry weight of the adhesive layer.

25. A tacrolimus mucosal adhesive membrane suitable for buccal administration, the tacrolimus mucosal adhesive membrane comprising an adhesive layer and a backing layer, wherein: The adhesive membrane layer comprises: Tacrolimus, approximately 5 to approximately 14 percent by weight; Ethyl cellulose, approximately 29 to approximately 33 percent by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 34 to about 41% by weight; About 7 to about 10% by weight of hydroxypropyl cellulose [weight-average molecular weight about 370,000-Klucel GF] having a viscosity of about 150-400 mPa·s; and A copolymer of about 2 to about 4 weight percent methyl vinyl ether and maleic anhydride; and The weight percentages are based on the dry weight of the adhesive layer.

26. A tacrolimus mucosal adhesive membrane suitable for buccal administration, the tacrolimus mucosal adhesive membrane comprising an adhesive layer and a backing layer, wherein: The adhesive membrane layer comprises: Tacrolimus, approximately 18 to 20 percent by weight; Ethyl cellulose, approximately 11 to approximately 13 percent by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 30-600 mPa·s, comprising about 30 to about 32% by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 370,000-Klucel GF] with a viscosity of about 11 to about 13% by weight; The weight percentages are based on the dry weight of the adhesive layer; and Such mucosal adhesive layers do not contain any polymer selected from the following mucosal adhesive polymers: copolymers of methyl vinyl ether and maleic anhydride; poly(acrylic acid); crosslinked poly(acrylic acid); poly(methacrylic acid); poly[(maleic anhydride)-co-(vinyl methyl ether)] or its salts; gelatin; polysaccharides, especially alginate, chitosan, xanthan gum, hyaluronic acid, pectin or pullulan; carboxymethyl cellulose; hydroxypropyl methyl cellulose; poly(vinylpyrrolidone), poly[(vinylpyrrolidone)-co-(vinyl acetate)]; mixtures of poly(vinyl acetate) and poly(vinylpyrrolidone); poly(vinyl alcohol); and poly(vinyl acetate).

27. A tacrolimus mucosal adhesive membrane suitable for buccal administration, the tacrolimus mucosal adhesive membrane comprising an adhesive layer and a backing layer, wherein: The adhesive membrane layer comprises: Tacrolimus: approximately 9 to approximately 23 percent by weight; Ethyl cellulose, approximately 10 to approximately 13 percent by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 300-600 mPa·s, about 15 to about 32% by weight; About 5 to about 12% by weight of hydroxypropyl cellulose [weight-average molecular weight about 370,000-Klucel GF] having a viscosity of about 150-400 mPa·s; and About 6 to about 28 percent by weight of poly(methacrylate); and The weight percentages are based on the dry weight of the adhesive layer.

28. A tacrolimus mucosal adhesive membrane suitable for buccal administration, the tacrolimus mucosal adhesive membrane comprising an adhesive layer and a backing layer, wherein: The adhesive membrane layer comprises: Tacrolimus, approximately 18 to 20 percent by weight; Ethyl cellulose, approximately 4 to 6 percent by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 31 to about 32% by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 370,000-Klucel GF] with a viscosity of about 27 to about 28% by weight; The weight percentages are based on the dry weight of the adhesive layer; and Such mucosal adhesive layers do not contain any polymer selected from the following mucosal adhesive polymers: copolymers of methyl vinyl ether and maleic anhydride; poly(acrylic acid); crosslinked poly(acrylic acid); poly(methacrylic acid); poly[(maleic anhydride)-co-(vinyl methyl ether)] or its salts; gelatin; polysaccharides, especially alginate, chitosan, xanthan gum, hyaluronic acid, pectin or pullulan; carboxymethyl cellulose; hydroxypropyl methyl cellulose; poly(vinylpyrrolidone), poly[(vinylpyrrolidone)-co-(vinyl acetate)]; mixtures of poly(vinyl acetate) and poly(vinylpyrrolidone); poly(vinyl alcohol); and poly(vinyl acetate).

29. A tacrolimus mucosal adhesive membrane suitable for buccal administration, the tacrolimus mucosal adhesive membrane comprising an adhesive layer and a backing layer, wherein: The adhesive membrane layer comprises: Tacrolimus, approximately 18 to 20 percent by weight; Ethyl cellulose, approximately 4 to approximately 12 percent by weight; Hydroxypropyl cellulose [weight-average molecular weight of about 80,000-Klucel EF] with a viscosity of about 31 to about 42% by weight; About 2 to about 23% by weight of hydroxypropyl cellulose [weight-average molecular weight about 370,000-Klucel GF] having a viscosity of about 150-400 mPa·s; and About 2 to about 6 weights of crosslinked poly(acrylic acid); and The weight percentages are based on the dry weight of the adhesive layer.

30. A method for treating a human patient with an allogeneic solid organ transplant, wherein the patient requires protection against transplant rejection, the method comprising: Apply the mucosal adhesive film according to any one of claims 16 to 29 to the patient's cheek twice daily.

31. The method of claim 30, wherein the buccal application consists of applying a first mucosal adhesive membrane according to any one of claims 16 to 29 for about 30 to 60 minutes, preferably 60 minutes, or equally preferably 30 minutes, followed by a period of no application for about 3 to 5 hours, after which a second mucosal adhesive membrane according to any one of claims 16 to 29 is applied buccally to the patient for about 30 to 60 minutes, preferably 60 minutes, or equally preferably 30 minutes.

32. The method according to claim 30 or 31, wherein 24 hours after the twice-daily cheek application, the human patient's C trough Blood levels of the tacrolimus C max The value is approximately 30-40%.

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