KR101193228B1 - Crystalline polymorphine forms of monosodium n-[8-2-hydroxybenzoylamino]caprylate - Google Patents

Abstract

The present invention relates to a crystalline polymorphic form of SNAC, including two hydrates of monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate ("SNAC"), methanol solvate and ethanol solvate . More particularly, the present invention provides six polymorphic forms of SNAC (called Form I-VI). The present invention also provides amorphous SNAC.

Monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate, SNAC

Description

Crystalline polymorphic form of monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate {CRYSTALLINE POLYMORPHINE FORMS OF MONOSODIUM N- [8- (2-HYDROXYBENZOYL) AMINO] CAPRYLATE}

This application claims priority to US Provisional Patent Application No. 60 / 569,476 on May 6, 2004 and US Provisional Patent Application No. 60 / 619,418 on October 15, 2004, both of which are incorporated herein by reference. It is integrated into.

Field of invention

The present invention relates to crystalline polymorphs of monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate, amorphous monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate, containing these Pharmaceutical compositions, methods for their preparation, and methods for facilitating delivery of the active agent together.

U.S. Patent 5,650,386 discloses N- [8- (2-hydroxybenzoyl) amino] caprylic acid and its salts, their use to facilitate the delivery of various active agents.

[Summary of invention]

The present invention includes monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate ("SNAC) including two hydrates of SNAC, namely methanol / water co-solvate, and ethanol / water co-solvate. ") Polymorphic form. More specifically, the present invention provides six polymorphic forms of SNAC (hereinafter referred to as Form I-VI). The present invention also provides amorphous SNAC.

One embodiment of the invention is a pharmaceutical composition comprising an active agent such as (A) (i) at least one type I-VI SNAC and / or (ii) amorphous SNAC and (B) such as heparin. According to a preferred embodiment, the pharmaceutical composition comprises at least one type I-VI SNAC or amorphous SNAC based on 100% total weight of SNAC in about 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9%. According to another preferred embodiment, the pharmaceutical composition of the present invention comprises at least about 20, 30, 40, 50, 60, 70, at least one type I-VI type SNAC based on 100% total weight of crystalline SNAC in the composition 80, 90, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9%.

Another embodiment of the invention is a method for administering or facilitating delivery of an active agent to an animal (eg a human) by the pharmaceutical composition of the present invention.

Another embodiment is a method of treating thrombosis in an animal (eg, a human) in need thereof by orally administering a pharmaceutical composition of the present invention comprising heparin in an effective amount for an antithrombotic effect.

Another embodiment provides the preparation of Type I SNAC, which comprises heating Type III, V, or VI SNAC or mixtures thereof to at least 50 ° C. (but preferably less than 110 ° C.) for a time sufficient to form Form I SNAC. It is a way.

Another embodiment is a method of making type I SNAC by heating the amorphous SNAC between about 30 ° C. and about 90 ° C., and preferably between about 40 ° C. and about 80 ° C. for a time sufficient to form Form I SNAC.

Another embodiment is a method of producing type I SNAC comprising the step of producing a type I by lyophilizing all the non-type type SNAC. For example, a method of producing Type I by lyophilizing one or more Type II-VI SNACs and / or amorphous SNACs may also be included.

Another embodiment includes, for example, a ground (eg, ball milled) mixture or a direct compacted mixture of type I SNAC and at least one active agent and / or pharmaceutically acceptable additives (such as those described below). Pharmaceutical compositions such as tablets. Pharmaceutical compositions may be prepared by grinding (eg, ball milling) or pressing (eg, direct pressing) a mixture of type I SNAC and at least one active agent and / or pharmaceutically acceptable additive.

Another embodiment is to dry (eg, tumble dry) the solvate (eg, ethanol solvate or methanol solvate) of SNAC without stirring and to expose the dried SNAC to moisture for a time sufficient to produce type II SNAC. It is a method of producing a type II SNAC comprising the step. Preferably, the drying and exposing steps are carried out in a closed container. Dried SNAC can be stored in a humid environment, converting all other SNACs to type II, not just type II SNACs.

Another embodiment is a pharmaceutical composition, such as a tablet, comprising a directly compressed mixture of type II SNAC and at least one active agent and / or pharmaceutically acceptable additives (such as described below). The pharmaceutical composition may be prepared by pressing (eg, direct pressing) a mixture of type II SNAC and at least one active agent and / or pharmaceutically acceptable additive.

Another embodiment provides a method of exposing I, II, IV, V or VI SNAC or a mixture thereof to an environment having a relative humidity of 75%, 80%, 85%, 90% or more for a time sufficient to produce Form III. It is a method of manufacturing a type III SNAC comprising a.

Another embodiment includes exposing the amorphous SNAC to moisture (ie, an environment with relative humidity above 0% and preferably above 5 or 10%) for a time sufficient to produce Form III. It is a manufacturing method.

Another embodiment provides a type III, II, IV, V or VI SNAC or amorphous SNAC or mixtures thereof (with or without one or more active agents and / or pharmaceutically acceptable additives (as described below)). It is a method of producing a type III SNAC comprising the step of wet granulation for a time sufficient to produce. According to one embodiment, Type I SNACs are wet granulated.

Another embodiment comprises exposing the V or VI SNAC or a mixture thereof to an environment having a relative humidity of 30%, 35%, 40%, 50% or more for a time sufficient to produce Form III. Type SNAC is a method of manufacturing.

Another embodiment is a method of making type III SNAC comprising exposing type VI SNAC to an environment having a relative humidity of 10%, 20%, 30% or more for a time sufficient to produce type III. to be.

Another embodiment is a method of making type III SNAC, which comprises crystallizing SNAC from water.

Another embodiment is a method of making type III SNAC comprising wet granulating the type I SNAC for a time sufficient to produce type III.

Another embodiment is a pharmaceutical composition, such as a tablet, comprising a direct compressed mixture of type III SNAC and at least one active agent and / or pharmaceutically acceptable additives (such as described below). The pharmaceutical composition may be prepared by pressing (eg, direct pressing) a mixture of type III SNAC and at least one active agent and / or pharmaceutically acceptable additive.

Another embodiment is directed to producing type IV of Type I, II, III, V, or VI SNAC or mixtures thereof up to a temperature between about 110 or 150 ° C. and to a melting point of SNAC (eg, at 150 or 170 ° C.). It is a method of producing a type IV SNAC comprising the step of heating for a sufficient time.

Yet another embodiment is a method of making a V-type SNAC comprising crystallizing SNAC from methanol solution at a relative humidity of 30, 40 or 50%. Preferably, the methanol is preferably substantially or completely free of water. Without being bound by a particular theory, it is believed that methanol solvates produce V-type methanol-water solvates over time by the exchange of methanol with moisture in the atmosphere. For example, Form V produces a SNAC saturated solution of methanol (e.g., I-IV or VI SNAC or a mixture thereof) at a relative humidity of about 30, 40 or 50% and cools the solution to, for example, room temperature or below. By (eg in an ice bath). The precipitate produced can be filtered and dried.

Another embodiment is a method of making a V-type SNAC comprising equilibrating an I-IV or VI-type SNAC with methanol. Preferably, the methanol solution is substantially or completely free of water. For example, Form V may slurry form I-IV or VI or a mixture thereof in methanol at a relative humidity of 30, 40 or 50% (e.g., precipitation of SNAC from solution) and the slurry mixture at ambient temperature. It can be prepared by holding for a sufficient time (e.g., several days) to form V.

Another embodiment is a method of making type VI SNAC, comprising crystallizing SNAC from ethanol solution at a relative humidity of about 30, 40, or 50%. Preferably, the ethanol solution is substantially or completely free of water. For example, Form VI can be prepared by preparing a saturated SNAC solution of ethanol (eg, Form I-V SNAC or a mixture thereof) at a relative humidity of about 30, 40 or 50% and cooling the solution to room temperature or below.

Another embodiment is a method of making type VI SNAC comprising slurrying any of Form I-V in ethanol at a relative humidity of about 10, 20 or 30%. Preferably, ethanol is preferably substantially or completely free of water. For example, Form VI can be prepared by adding any of Forms I-V to ethanol to form a precipitate and keeping the slurry mixture at ambient temperature for a sufficient time to form Form VI.

Another embodiment is a method of making amorphous SNAC by dehydrating (eg, in vacuum) Type III SNAC for a time sufficient to form amorphous SNAC.

Justice

The term "polymorph" refers to discrete forms in which a substance is crystallographically distinct.

The term "hydrate" as used herein refers to (i) a substance containing water bound in molecular form, (ii) a crystalline substance comprising at least one molecule of crystallized water or containing free water. Including but not limited to crystalline materials.

The term "SNAC" as used herein refers to monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate. Unless otherwise stated, the term "SNAC" as used herein refers to all polymorphic forms of SNAC.

As used herein, the term "SNAC 1/3 hydrate" refers to the crystalline form of SNAC in which one water molecule binds three SNAC molecules.

As used herein, the term "SNAC trihydrate" refers to the crystalline form of SNAC in which three water molecules bind to each SNAC molecule.

The term "solvate" as used herein includes, but is not limited to, molecules or ionic complexes of molecules or ions of a solvent with molecules or ions of a SNAC. As used herein, "cosolvate" includes, but is not limited to, molecules or ionic complexes of molecules or ions of two or more solvents with molecules or ions of SNAC.

As used herein, the term "delivery agent" refers to SNAC, including its polymorphic crystals.

"Effective amount of drug" means an amount of active agent (eg, heparin) that is effective to treat or prevent a disease when administered to a living organism over a period of time that provides a therapeutic effect for a desired dosing interval. Effective dosages vary as is well known to those of skill in the art, depending on the route of administration, the use of additives, and the possibility of use with other agents for the treatment of the disease.

The terms “treat”, “treatment”, or “treat” are used to cure, heal, or alleviate a disease (eg, a disease), a symptom of a disease, or a disease-prone property ( administration of an active agent to alleviate, relieve, alter, remedy, ameliorate, improve, or affect .

An “effective amount of a delivery agent” includes but is not limited to any route of administration (eg, as discussed herein in the oral cavity (eg, via a biofilm in the gastrointestinal tract), nasal cavity, lung, skin, vagina, and / or eye). Means the amount of the delivery agent that promotes the active agent to absorb the desired amount.

As used herein, the term "heparin" refers to unfractionated heparin, heparinoids, dermatan, chondroitin, low molecular weight heparin (eg, tinzaparin (including tinzaparin sodium)), very low molecular weight heparin and ultra low Means all forms of heparin, including but not limited to molecular weight heparin. Preferred types of heparin are unfractionated heparin such as, for example, heparin sodium (eg, heparin sodium USP). The term “low molecular weight heparin” generally refers to heparin wherein at least 80% (by weight) of heparin has a molecular weight between about 3000 and about 9000 daltons. Non-limiting examples of low molecular weight heparin include tinzaparin, enoxaphrine, and dalfalfarin. Tinzaparin has been approved by the FDA for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered with warfarin sodium. The sodium salt of tinzaparin is commercially available from Pharmion Corporation of Boulder, CO under the trademark Innohep ™. The term “very low molecular weight heparin” generally refers to heparin wherein at least 80% (by weight) of heparin has a molecular weight between about 1500 and about 5000 Daltons. Non-limiting examples of very low molecular weight heparin include bemiparin. The term “ultra low molecular heparin” generally refers to heparin wherein at least 80% (by weight) of heparin has a molecular weight between about 1000 and about 2000 Daltons. Non-limiting examples of ultra low molecular weight heparin include fondiparinux.

The term “insulin” refers to all forms of insulin, including but not limited to naturally derived insulins and synthesized forms of insulin, which are described in US Pat. Nos. 4,421,685, 5,474,978 and 5,534,488, respectively. Is incorporated herein by reference in its entirety.

As used herein, the term "AUC" refers to the area under the plasma concentration-time curve calculated by the trapezoidal rule at complete dosing intervals, such as 24 hour intervals.

The term “average”, when preceded by a pharmacokinetic value (eg, mean peak), refers to the arithmetic mean value of that pharmacokinetic value unless otherwise indicated.

As used herein, the term "about" means within 10%, preferably within 5%, and more preferably within 1% of a given value. Alternatively, the term “about” means that the value may fall within the scientifically acceptable margin of error for that type of value, depending on how qualitative measurements are available as tools.

Type I SNAC  anhydride

Crystalline polymorph I type SNAC is an anhydride. Form I is stable at room temperature and does not change the crystalline form when crushing (eg, ball milling) or pressing (eg, direct pressing) is applied. However, Form I converts to Form III when wet granulated with sufficient amount of water for a sufficient time. According to differential scanning calorimetry (DSC), Form I has a melting start temperature at about 198 ° C. (see FIG. 2). Type I SNAC has an XRPD pattern substantially the same as that shown in FIG. 1. Characteristic XRPD peak positions (expressed in 2θ ± 0.2, 0.1, 0.05 or 0.01 ° 2θ degrees) and de-spacing for Form I are shown in Table 1 below. The XRPD peak positions marked "(U)" in Table 1 are unique of type I. For example, the peak at 2.98 ° 2θ ± 0.2, 0.1, 0.05, or 0.01 ° 2θ is unique to Form I.

Type I SNAC Characteristic of XRPD  Peak (expressed in 2θ)  2θ ± 0.2 ° 2θ degree d (Å) 2.98 (U) 29.59 5.85 15.09 8.66 10.20 11.56 7.65 14.53 (U) 6.09 15.72 (U) 5.63 18.88 4.69 22.12 4.02 26.36 (U) 3.38 30.88 2.89

Form I can be prepared by the method described in Example 1 below.

Form I can also be prepared by heating Form III, V or VI or mixtures thereof to a temperature of at least 50 ° C. (but preferably less than 110 ° C.).

Furthermore, Form I can be prepared by heating the amorphous SNAC between about 30 to about 90 ° C., and preferably between about 40 to about 80 ° C. for a time sufficient to form Form I SNAC.

Another type I manufacturing method is the production of type I by freeze-drying all non-type I SNACs. For example, one or more type II-VI SNACs and / or amorphous SNACs can be lyophilized to produce type I.

The present invention also provides pharmaceutical compositions containing type I SNAC, wherein less than 90, 80, 70 or 60% of SNAC is crystalline (based on 100% total weight of SNAC).

The invention also relates to tablets comprising a ground (eg, ball ground) or direct compressed mixture of type I SNAC and at least one active agent and / or pharmaceutically acceptable additives (such as described below). It provides a pharmaceutical composition. Preferably, the pharmaceutical composition (or the milled or directly compacted mixture) is at least 50, 60, 70, of the weight of type I based on the total weight of SNAC in the pharmaceutical composition (or the milled or direct compacted mixture) 80, 90, 95, 96, 97, 98 or 99%.

Type II SNAC  Luggage

Crystalline polymorph II is a hydrate of SNAC. Without being bound to any particular theory, we theorize that Form II is 1/3 hydrate (ie, it has approximately 1 mole of water per 3 moles of SNAC (also called SNAC 1/3 hydrate). ). Form II is stable at room temperature. According to DSC, the initiation temperature of Form II is about 199 ° C. (see FIG. 7). Type II SNAC has an XRPD pattern substantially the same as that shown in FIG. 6. Characteristic XRPD peak positions (expressed in 2θ ± 0.2, 0.1, 0.05 or 0.01 ° 2θ degrees) and de-sparing for Form II are shown in Table 2 below. The XRPD peak positions marked "(U)" in Table 2 are unique of type II. For example, the peaks at 3.29, 11.96 and 17.76 ° 2θ ± 0.2, 0.1, 0.05 or 0.01 ° 2θ are unique of Form II.

II brother SNAC Characteristic of XRPD  Peak (expressed in 2θ degrees) 2θ ± 0.2 ° 2θ degree
d (Å) 2θ ± 0.2 ° 2θ degree
d (Å) 2θ ± 0.2 ° 2θ degree
d (Å) 3.29 (U) 26.83 19.44 4.56 26.20 (U) 3.40 5.78 (U) 15.27 20.16 4.40 26.48 (U) 3.36 6.56 (U) 13.46 20.72 (U) 4.28 26.88 (U) 3.31 8.76 10.08 21.12 (U) 4.20 27.73 (U) 3.21 11.53 7.67 21.84 4.07 28.95 3.08 11.96 (U) 7.39 22.48 3.95 30.12 (U) 2.96 14.47 (U) 6.11 23.44 (U) 3.79 30.69 (U) 2.91 17.12 (U) 5.17 23.96 (U) 3.71 31.57 (U) 2.83 17.76 (U) 4.99 24.56 (U) 3.62 32.76 (U) 2.73 18.08 (U) 4.90 25.16 (U) 3.54 34.99 (U) 2.56 18.76 (U) 4.72 25.40 (U) 3.50 37.98 (U) 2.37

Type II SNACs are prepared by drying the solvate (eg, ethanol solvate or methanol solvate) of the SNAC (eg, tumble dry) without stirring and exposing the dried SNAC to moisture for a time sufficient to produce type II SNAC. can do. Preferably, the drying and exposing steps are carried out in a closed container. The exposing step can be performed following the drying step. The dried SNAC can be selectively stored in a humid environment (eg, in ambient conditions or in a humid environment (eg, relative humidity above 10 or 20%)) to convert any other SNAC to type II, but not the type II SNAC. Ethanol solvates of SNAC can be prepared according to the method described in Example 2.

Type III SNAC  Luggage

Crystalline polymorph III is a hydrate of SNAC. Without being bound to any particular theory, we theorize that Type III is trihydrate (ie it has approximately 3 moles of water per 3 moles of SNAC (also called SNAC trihydrate)). Form III is stable at room temperature and does not change the crystalline form upon compression (eg, direct compression). According to the differential scanning calorimeter (DSC), the melting start temperature of type III is about 198 ° C (see FIG. 12). Type III SNAC has an XRPD pattern substantially the same as that shown in FIG. 11. Characteristic XRPD peak positions (expressed in 2θ ± 0.2, 0.1, 0.05 or 0.01 ° 2θ degrees) and de-sparing for Form III are shown in Table 3 below. The XRPD peak positions marked "(U)" in Table 3 are unique to type III. For example, the peaks at 6.69, 13.58 and 16.80 ° 2θ ± 0.2, 0.1, 0.05, or 0.01 ° 2θ are unique of type III.

III brother SNAC Characteristic of XRPD  Peak (expressed in 2θ degrees) 2θ ± 0.2 ° 2θ degree d (Å) 2θ ± 0.2 ° 2θ degree d (Å) 6.69 (U) 13.20 20.56 (U) 4.32 11.31 (U) 7.78 21.32 (U) 4.16 13.58 (U) 6.51 21.60 (U) 4.11 16.41 (U) 5.40 23.56 (U) 3.77 16.80 (U) 5.27 24.84 (U) 3.58 17.91 (U) 4.95 26.13 3.41 19.40 4.57 28.80 3.10 19.92 (U) 4.45 30.01 (U) 2.97 20.16 4.40

Type III is a period of time (eg, 7 days or more) sufficient to produce Form I, II, IV, V, or VI or mixtures thereof in an environment with a relative humidity of 75%, 85%, 90%, or higher. ) Can be produced by exposure. For example, Form III may have a moisture content of at least about 15% w / w for at least 7 days (eg, at least about 15% w / w) in an environment with a relative humidity of 75% or higher, in any of I, II, or IV-VI. Until the exposure). If the moisture content of the material is significantly greater than 15% w / w, the material is preferably dried at ambient conditions until the moisture content is about 15% w / w.

Form III may also be prepared by exposing amorphous SNAC to moisture (ie, an environment with relative humidity above 0% and preferably above 5 or 10%) for a time sufficient to produce Form III.

Form III can also be prepared through wet granulation of Form I, II, IV, V, or IV SNAC or amorphous SNAC or mixtures thereof. According to one embodiment, Form I is wet granulated. The resulting Form III can then be used to obtain Form I SNAC (eg 50 ° C.).

Another way to make type III is to expose V or VI SNAC or mixtures thereof for a time sufficient to produce type III in an environment with a relative humidity of 30%, 35%, 40%, 50%, or higher. . Another method of making Form III is to expose Form VI SNAC or mixtures thereof for a time sufficient to produce Form III in an environment with a relative humidity of 10%, 20%, 30%, or higher.

Form III can also be prepared by crystallizing SNAC from water. The crystals formed can be separated, for example, by filtering and drying at ambient conditions. Preferably, drying is carried out below 40 or 35 ° C.

The present invention also provides pharmaceutical compositions such as tablets comprising a direct compressed mixture of type III SNAC and at least one active agent and / or pharmaceutically acceptable additives (such as described below). Preferably, the pharmaceutical composition (or directly compressed mixture) has a type III of at least 50, 60, 70, 80, 90, 95, 96 based on the total weight of SNAC in the pharmaceutical composition (or directly compressed mixture). , 97, 98, or 99% by weight.

Type IV SNAC  anhydride

Crystalline polymorph IV type SNAC is anhydride. Form IV is stable at room temperature. In addition, Form IV is less soluble in acetonitrile and is thermodynamically more stable than Form I at ambient conditions. According to a differential scanning calorimeter (DSC), the initiation temperature of Form IV is about 199 ° C (see Figure 17). Type IV SNACs have an XRPD pattern substantially the same as that shown in FIG. 16. Characteristic XRPD peak positions (expressed in 2θ ± 0.2, 0.1, 0.05 or 0.01 ° 2θ degrees) and de-sparing for Form IV are shown in Table 4 below. The XRPD peak positions marked “(U)” in Table 4 are unique to Form IV. For example, the peaks at 8.61, 17.04, and 23.28 ° 2θ ± 0.2, 0.1, 0.05, or 0.01 ° 2θ are unique to Form IV.

IV brother SNAC Characteristic of XRPD  Peak (expressed in 2θ degrees) 2θ ± 0.2 ° 2θ degree d (Å) 2θ ± 0.2 ° 2θ degree d (Å) 3.16 U 27.91 18.92 4.68 5.89 14.98 20.80 4.27 6.32 U 13.97 21.16 4.19 8.61 U 10.26 22.36 U 3.97 11.55 U 7.65 23.28 U 3.82 14.45 U 6.13 23.76 U 3.74 17.04 U 5.20

Form IV may be prepared by heating Form I, II, III, V or VI SNAC or mixtures thereof for a time sufficient to produce Form IV until a temperature between about 110 or 150 ° C. and the melting point of SNAC. For example, type II SNAC may be present at a temperature above the transition temperature of the desolvated material or below the melting point of the SNAC (eg, dehydration of about 130-140 ° C.) until type IV is formed (eg, for several hours). Heating at 10 ° C./min of the starting temperature) can be carried out (eg in a drying oven). After production, Form IV can be cooled and recovered.

The present invention also provides pharmaceutical compositions containing Form IV SNAC, wherein at least 50, 60, 70, 80 or 90% of SNAC is crystalline (based on 100% weight of SNAC).

Methanol-Water Cosolvent of V-Type SNAC

Crystalline polymorph V-type SNAC is a methanol-water cosolvate (approximately 0.8 moles of methanol and 2 moles of water per mole of SNAC). According to a differential scanning calorimeter (DSC), the initiation temperature of V-type is about 197 ° C (see FIG. 22). V-type SNAC has an XRPD pattern substantially the same as that shown in FIG. Characteristic XRPD peak positions (expressed in 2θ ± 0.2, 0.1, 0.05 or 0.01 ° 2θ degrees) and de-sparing for Form V are shown in Table 5 below. The XRPD peak positions marked "(U)" in Table 5 are unique to V-type. For example, the peaks at 6.59, 9.96, 10.86, 13.87, 17.29, and 19.92 ° 2θ ± 0.2, 0.1, 0.05, or 0.01 ° 2θ are unique to V-type.

V type SNAC Characteristic of XRPD  Peak (expressed in 2θ degrees) 2θ ± 0.2 ° 2θ degree
d (Å) 2θ ± 0.2 ° 2θ degree
d (Å) 2θ ± 0.2 ° 2θ degree
d (Å) 6.24 U 14.15 21.35 U 4.16 32.13 U 2.78 6.59 U 13.39 22.68 U 3.92 33.03 U 2.71 9.96 U 8.87 22.92 U 3.88 34.04 U 2.63 10.86 U 8.14 24.16 U 3.68 35.44 U 2.53 13.87 U 6.38 24.64 U 3.61 35.64 U 2.52 16.35 5.42 25.04 U 3.55 35.92 U 2.50 17.29 U 5.12 26.13 3.41 36.49 U 2.46 18.99 U 4.67 30.20 U 2.96 37.50 U 2.40 19.92 U 4.45 30.48 U 2.93 39.03 U 2.31 20.44 U 4.34 31.52 U 2.84

Form V can be prepared by crystallizing SNAC (eg, I-IV or VI SNAC or mixtures thereof (eg, mixtures of Forms I and III)) from methanol solution at a relative humidity of about 30, 40 or 50%. Preferably, the methanol solution is substantially or completely free of water. For example, Form V produces a SNAC saturated solution of methanol (e.g., I-IV or VI SNAC or a mixture thereof) at a relative humidity of about 30, 40 or 50% and cools the solution to, for example, room temperature or below. By (eg in an ice bath). The precipitate produced can be filtered and dried.

Form V can also be prepared by equilibrating form I-IV or VI SNAC with methanol. Preferably, the methanol is preferably substantially or completely free of water. For example, Form V may slurry form I-IV or VI or a mixture thereof in methanol at a relative humidity of 30, 40 or 50% (e.g., precipitation of SNAC from solution) and the slurry mixture at ambient temperature. It can be prepared by holding for a sufficient time (e.g., several days) to form V. Preferably, excess methanol is used (ie the molar ratio of methanol to SNAC is greater than 1). The solid produced can be recovered, for example, by vacuum filtering and air drying.

Ethanol-Water Cosolvent of Type VI SNAC

Crystalline polymorph VI-type SNAC is an ethanol-water cosolvate (approximately 0.6 moles of methanol and 2 moles of water per mole of SNAC). According to a differential scanning calorimeter (DSC), the initiation temperature of Form VI is about 197 ° C (see Figure 27). Type VI SNAC has an XRPD pattern substantially the same as that shown in FIG. Characteristic XRPD peak positions (expressed in 2θ ± 0.2, 0.1, 0.05 or 0.01 ° 2θ degrees) and de-sparing for Form VI are shown in Table 6 below. The XRPD peak positions marked "(U)" in Table 6 are unique to Form VI. For example, the peaks at 9.60, 10.43, 12.68, and 16.58 ° 2θ ± 0.2, 0.1, 0.05, or 0.01 ° 2θ are unique to Form VI.

VI brother SNAC Characteristic of XRPD  Peak (expressed in 2θ degrees) 2θ ± 0.2 ° 2θ degree
d (Å) 2θ ± 0.2 ° 2θ degree
d (Å) 2θ ± 0.2 ° 2θ degree
d (Å) 5.68 U 15.55 18.96 U 4.68 25.56 U 3.48 6.35 U 13.91 19.37 4.58 26.98 U 3.30 6.72 13.13 19.88 U 4.46 27.36 U 3.26 9.60 U 9.20 20.95 U 4.24 28.68 U 3.11 10.43 U 8.47 21.54 U 4.12 29.35 U 3.04 11.31 7.82 22.08 U 4.02 30.48 U 2.93 12.68 U 6.97 22.36 U 3.97 30.84 U 2.89 14.95 U 5.92 22.95 3.87 31.91 2.80 16.58 U 5.34 23.76 3.74 34.00 U 2.63 17.46 U 5.08 24.24 U 3.67 36.16 U 2.48 18.12 U 4.89 25.08 U 3.55 38.32 U 2.34

Form V can be prepared by crystallizing SNAC (eg, Form I-V or a mixture thereof (such as mixture of Form I and III)) from ethanol solution at a relative humidity of about 30, 40 or 50%. For example, Form VI produces a saturated SNAC solution of ethanol (eg, Form I-IV or Form SNAC or a mixture thereof) when the relative humidity is at least about 30, 40, or 50% and the solution is, for example, room temperature or below. By cooling with (for example in an ice bath). The precipitate produced can be filtered and dried.

Form VI may also be prepared by slurrying any of Form I-V in ethanol at a relative humidity of about 10, 20 or 30%. For example, Form VI can be prepared by adding any of Forms I-V to ethanol to form a precipitate and keeping the slurry mixture at ambient temperature for a sufficient time (eg several days) to form Form VI. The solid produced can be recovered, for example, by vacuum filtering and air drying.

Amorphous SNAC

Amorphous SNAC is unstable at ambient conditions and converts to type III when exposed to moisture. Amorphous SNAC can be prepared by dehydrating Type III SNAC for a time sufficient to form amorphous SNAC (eg, in vacuum). Amorphous SNACs can be prepared by dehydrating (eg, in vacuo) a V or VI SNAC for a time sufficient to form an amorphous SNAC.

Crystals prepared by any of the above methods can be recovered by methods well known to those skilled in the art.

Active agent

Active agents suitable for use in the present invention include, but are not limited to, biological and chemical actives, including insecticides, pharmacological agents, and therapeutic agents.

Suitable biological and chemical active agents include proteins; Polypeptides; Peptides; hormone; Specific mixtures of polysaccharides, mucopolysaccharides and mucopolysaccharides; carbohydrate; Lipid; Small polar organic molecules (ie, polar organic molecules having a molecular weight of 500 Daltons or less); Other organic compounds; And certain compounds that do not pass by themselves through the gastrointestinal mucosa (or pass only a portion of the dose) and / or are prone to chemical cleavage by acids and enzymes in the gastrointestinal tract; Or all combinations thereof, including but not limited to.

Still other non-limiting examples of suitable biologically active agents include synthetic, natural or recombinants thereof including: human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth (hGH), bovine growth hormone, and swine Growth hormones, including growth hormones; Growth hormone-secreting hormone; Growth hormone secretion factors (eg, GRF analogs); interferons, including α, β, and γ; Interleukin-1; Interleukin-2; Insulins, such as porcine, bovine, human, and human recombination, optionally with counter ions including zinc, sodium, calcium and ammonium; Insulin-like growth factors, including IGF-1; Heparin, including unfractionated heparin, heparinoids, dermatan, chondroitin, low molecular weight heparin, very low molecular weight heparin and ultra low molecular weight heparin; Calcitonin such as salmon, eel, pig and human; Erythropoietin; Atrial sodium diuretic factor; antigen; Monoclonal antibodies; Growth inhibitory hormones; Protease inhibitors; Adrenal cortical stimulating hormone, gonadotropin-releasing hormone; Oxytocin; Luteinizing hormone-secreting hormone; Follicle stimulating hormone; Glucocerebrosidase; Platelet growth factor; Granulocyte colony stimulating factor; Prostaglandins; Cyclosporin; Vasopressin; Chromoline sodium (sodium or disodium chromoglycate); Vancomycin; Desperioxamine (DFO); Ibandronate, Alendronate, Tilideronate, Ethidronate, Clodronate, Pamideronate, Olpadronate, and Incandronate, and pharmaceutically acceptable salts thereof (e.g. sodium ibandronate) Bisphosphonates, including; Gallium salts (such as gallium nitrate, gallium nitrate nonahydrate, and gallium maltolate); Acyclovir and pharmaceutically acceptable salts thereof (eg, acyclovir sodium); Parathyroid hormone (PTH), including sections thereof; Migraine drugs such as BIBN-4096BS and other calcitonin gene associated protein antagonists; Antibiotics including gram positive activity including daptomycin, bactericidal, lipopeptide based and cyclic peptide based antibiotics, antibacterial and antifungal agents; vitamin; Analogs, fragments, mimetics or polyethylene glycol (PEG) -modified derivatives of these compounds; Or all combinations thereof.

According to one embodiment, the active agent is ibandronate or a pharmaceutically acceptable salt thereof (eg, ibandronate sodium). According to another embodiment, the active agent is a gallium salt such as gallium nitrate or gallium nitrate hydrate. According to another embodiment, the active agent is acyclovir or a pharmaceutically acceptable salt thereof (eg, acyclovir sodium). According to another embodiment, the active agent is heparin. According to another embodiment, the active agent is insulin.

Pharmaceutical composition

The pharmaceutical composition is preferably in solid form and may be made in solid dosage form. Solid dosage forms can be capsules, tablets or particles such as powders or sachets. The powder may be in the form of a sachet mixed with the liquid and administered. Solid dosage forms may also be topical delivery systems such as ointments, creams or semisolids. Solid dosage forms contemplated may include sustained release or controlled release systems. Preferably, the solid dosage form is oral administration.

The powder may be packaged in capsules, compressed into tablets, used in powder form, or mixed into ointments, creams or semisolids. Methods of preparing solid dosage forms are well known to those skilled in the art.

The amount of the delivery agent in the solid dosage form is an amount effective for delivery, and can be determined by methods known to those skilled in the art for any particular compound or biological or chemical active agent.

After administration, the active agent in the unit dosage form is absorbed into the circulation. Bioavailability of the active agent can be readily assessed by measuring known pharmacological activity in the blood, such as an increase in blood clotting time by heparin or a decrease in blood calcium levels by calcitonin. Alternatively, the blood level itself of the active agent may be measured directly.

Solid dosage forms can include pharmaceutically acceptable additives, such as additives, carriers, diluents, stabilizers, plasticizers, binders, glidants, disintegrants, extendibles, lubricants, plasticizers, colorants, film formers, flavors Agents, preservatives, agents of administration, surfactants, and any combination of the foregoing. Preferably, such additives are pharmaceutically acceptable additives, such as Remington's, The Science and Practice of Pharmacy , (Gennaro, AR, ed., 19th Edition, 1995, Mack Pub. Co.) , incorporated herein by this reference. Are described in.

Suitable binders include starch, gelatin, sugars (eg sucrose, molasses and lactose), dibasic calcium phosphate dihydrate, natural gums and synthetic gums (eg acacia), sodium alginate, carboxymethyl cellulose, methyl cellulose, polyvinylpyrroli Don, polyethylene glycol, ethylcellulose, and waxes include, but are not limited to.

Suitable fluidizing agents include, but are not limited to talc, and silicon dioxide (silica) (eg, fumed silica and colloidal silicon dioxide).

Suitable disintegrants include starch, sodium starch glycolate, croscarmellose sodium, crospovidone, clay, cellulose (such as purified cellulose, methylcellulose, sodium carboxymethyl cellulose), alginic acid, pregelatinized corn starch and gums (such as agar, Guar, locust bean, karaya, pectin and tragacanth gum). Preferred disintegrants include, but are not limited to, sodium starch glycolate.

Suitable extendible drugs include starch (such as rice starch), microcrystalline cellulose, lactose (such as lactose monohydrate), sucrose, dextrose, mannitol, calcium sulfate, dicalcium sulfate, and tricalcium sulfate. This includes, but is not limited to.

Suitable lubricants include, but are not limited to, stearic acid, stearates (such as calcium stearate and magnesium stearate), talc, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, polyethylene glycol, hardened cottonseed, and castor oil .

Suitable surfactants include, but are not limited to, sodium lauryl sulfate, soybean hydroxide lecithin, polysorbates and block copolymers of propylene oxide and ethylene oxide.

Delivery system

The amount of active agent used in the pharmaceutical composition of the present invention is an amount effective for the specific active agent to achieve the purpose for the purpose indication. The amount of active agent in the composition is generally an pharmacologically, biologically, therapeutically or chemically effective amount. However, the amount may be less than that when the composition is used in unit dosage form, wherein the unit dosage form contains a plurality of species of delivery agent compound / activator composition or is pharmacologically, biologically, therapeutically or chemically effective. It is because it can contain dividingly. The total effective amount can then be administered in total, in cumulative units containing the effective amount of the active agent.

The total amount of active agent to be used can be determined by methods known to those skilled in the art. However, since the compositions of the present invention can deliver the active agent more efficiently than other compositions or compositions containing only the active agent, the biological or chemical active agent is still administered to the subject in an amount less than that used in the unit dosage form or delivery system. The same blood level and / or therapeutic effect.

In general, the weight ratio of delivery agent to active agent ranges from about 0.1: 1 to about 1000: 1 and preferably from about 1: 1 to about 300: 1. The weight ratio depends on the active agent and the particular indication to which the active agent is administered.

The presently disclosed delivery agents facilitate the delivery of biological and chemical active agents, particularly in the oral cavity, sublingual, cheek, duodenum, intracolon, rectal, vaginal, mucosal, lung, nasal and ocular system.

The compounds and compositions of the present invention can be used in biological or chemical actives such as birds, such as chickens; Mammals such as rodents, cattle, pigs, dogs, cats, primates and especially humans; And to all animals, including but not limited to insects.

The compounds and compositions provide for delivery of a chemical or biologically active agent that will be destroyed or less effective by conditions encountered in the body of the animal to which they are administered before the active agent reaches its destination (ie, where the active agent of the delivery composition is expected to be released). Especially useful for In particular, the compounds and compositions of the present invention are useful in oral dosage actives, especially those that are normally undeliverable to the oral cavity or in need of enhanced delivery.

Compositions comprising a compound and an active agent are useful for delivering the active agent to a selected biological system and for increased or enhanced bioavailability of the active agent as compared to administration of the active agent without a delivery agent. Delivery can be enhanced by delivering more active agent over a certain time period or by delivering the active agent in a particular time period (eg to result in faster or delayed delivery) or over a time period (eg sustained release delivery).

Another embodiment of the invention is a method for the treatment or prevention of a disease in an animal administered the composition of the invention or for achieving the desired physiological effect as listed in the table below. Specific indicators for active agents can be found in the Physicians' Desk Reference (54th Edition, 2000, Medical Economics Company, Inc., Montvale, NJ), which is incorporated herein by reference. The active agents in the table below include analogs, fragments, mimetics, and polyethylene glycol-modified derivatives thereof.

Active agent Disease and Physiological Effects Growth hormones including human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth hormone, and porcine growth hormone; Growth hormone-secreting hormone. Growth disorder interferon, including α, β and γ. Viral infections including chronic cancer and multiple sclerosis Interleukin-1; Interleukin-2. Viral infections; cancer Insulins, such as pig, bovine, human, and human recombination, optionally with counter ions including zinc, sodium, calcium and ammonium; Insulin-like growth factor, including IGF-1. diabetes Heparin, including unfractionated heparin, heparinoids, dermatan, chondroitin, low molecular weight heparin, very low molecular weight heparin, and ultra low molecular weight heparin. thrombosis; Prevention of blood clotting Calcitonin, including salmon, eel, pig and human. osteoporosis; Bone disease Erythropoietin anemia Atrial sodium diuretic factor Vasodilation antigen infection Monoclonal antibodies Prevent graft rejection; cancer Growth inhibitory hormones Hemorrhagic ulcers; Erosive gastritis Protease inhibitors AIDS Adrenal Cortical Stimulating Hormones High cholesterol (to low cholesterol) Gonadotropin-releasing hormone Ovulation dysfunction (promotes ovulation) Growth hormone secretion factor (GRF) Promotes the secretion of growth hormone Oxytocin Childbirth Disorders (Promoting Contractions) Luteinizing hormone secretion hormone; Follicle stimulating hormone Regulates reproductive function. Glucocerebrosides Goche disease (metabolism of lipid proteins) Thrombocytopenia Hypoplatelet Granulocyte colony stimulating factor Reduces infection in chemotherapy patients. Prostaglandins High blood pressure Cyclosporin Transplant rejection Vasopressin Microurea Antidiuresis Chromoline sodium (sodium or disodium chromoglycate); Vancomycin asthma; allergy Desferrioxamine (DFO) Iron excess Parathyroid hormone (PTH) with section osteoporosis; Bone disease Antibacterial agents, including antibiotics, antibacterial and antifungal agents; Gram positive activity, bactericidal, lipopeptide and cyclic peptide based antibiotics including daptomycin and analogs thereof Infections, including Gram-positive bacterial infections


vitamin deficiency disease Bisphosphates, including ibandronate, alendronate, tiludronate, ethidronate, clauderonate, pamideronate, olpadronate and incandronate Osteoporosis and Paget's disease; Inhibits osteoclasts. Gallium salts such as gallium nitrate Treat or prevent hypercalcemia By administering to a mammal an effective amount of a pharmaceutical composition of the invention, the disorder associated with excessive (or accelerated) lack of calcium in the bone of the mammal is treated or prevented. Such disorders include, but are not limited to, hypercalcemia, osteopenia, osteoporosis, bone destruction due to metastases from malignancy, parathyroid hyperplasia, kidney disease, righteous diseases (including drug-induced diseases), and periodontal disease do. Inhibits reabsorption or release of calcium from bone. Acyclovir Viral infections, especially herpes infections such as the first and second herpes simplex viruses (HSV 1, HSV 2), varicella zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) and other herpes virus infections (Such as feline herpes virus infection). By administering an effective amount of a composition or unit dosage form of the invention, herpes keratitis, herpes encephalitis, herpes simplex and genital infections (by simple herpes), especially in immunocompromised patients, including renal and bone marrow transplant patients and AIDS patients ), The clinical disease or condition caused by the viruses listed above, including chickenpox and shingles (caused by varicella zoster) and CMV-pneumonia and retinitis. Epstein-Barr virus (EVB) causes infectious mononucleosis and is also shown as a pathogen of nasopharyngeal cancer, immunoblast lymphoma, Burkitt's lymphoma, and vitiligo.

The following examples illustrate the invention without limitation. All percentages are by weight unless otherwise noted.

DSC

The melting point mentioned was determined by differential scanning calorimetry (DSC). The quoted values were obtained with Perkin Elmer Pyris 1, software for Windows. The instrument was temperature calibrated using the melting points of indium and zinc and enthalpy calibrated using the dissolution enthalpy of indium. Calibration checks were performed on a general basis using an indium standard. Samples were sealed in aluminum pans with pleated lids with small holes in them. The sample was then heated to 30-250 ° C. at 10 ° C./min in a nitrogen atmosphere. To enhance thermal contact with the surface of the sample pan, the uncrushed sample was ground lightly with a mortar and pestle before analysis.

XRPD

Powder X-ray diffraction analysis was performed using a Shimadzu XRD-6000 powder diffractometer commercially available from Shimadzu Scientific Instruments, Inc. of Columbia, Maryland. The instrument was measured using silicon powder, which was found to be correct when tested with the NIST # 675 low angle diffraction standard. Cu Kα radiation (λ = 1.54056 kV) was irradiated to the sample. The uncrushed sample was lightly ground with a mortar and pestle so that the sample was smooth, smooth and flat for analysis. Diffraction patterns between 2 and 40 ° 2θ were used as fingerprint range to identify the crystal structure present in the lot.

Thermal weight  analysis( TGA )

Thermogravimetric analysis of sodium 4-CNAB was performed using a Perkin-Elmer TGA7 thermogravimetric analyzer equipped with Windows software Pyris 1. The machine was calibrated using the Curie temperatures of Alumel and Nickel. The sample was heated to 30-300 ° C. in a nitrogen atmosphere and the percent change in weight was recorded as a function of temperature. In order to reduce the effect of particle size and to enhance contact with the inner surface of the platinum sample holder, the ungrounded lot was ground lightly with a mortar and pestle prior to analysis.

Moisture Adsorption-Desorption Behavior

Adsorption analysis was performed using an SGA-100 Symmetric Vapor Sorption Analyzer (VTI Corporation of Hialeah, Florida). The instrument was calibrated with PVP and NaCl. Samples (other than solvates) were dried to constant weight at 60 ° C. prior to analysis. Samples of solvates were not dried prior to testing. The equilibrium moisture content of the sample dropped from 5% relative humidity (RH) to 95% RH and again to 5% RH was determined at 25 ° C.

FTIR

FTIR was performed on spectral BX FT-IR from Perkin Elmer using KBr disk. 1 mg of sample was dispersed at 150 mg KBr. Resolution is 4 cm^-One And 32 scans were average.

1, 6, 11, 16, 21, 26, and 43 are X-ray powders of type I-VI SNAC and amorphous SNAC (containing approximately 10% Type III SNAC) as prepared in Examples 1-6 and 14, respectively. Diffraction (XRPD).

2, 7, 12, 17, 22, 27, and 44 show differential scanning calorimetry of type I-VI SNAC and amorphous SNAC (containing approximately 10% Type III SNAC) as prepared in Examples 1-6 and 14, respectively. (DSC) analysis.

3, 8, 13, 18, 23, 28, and 45 are thermogravimetric analyzes of type I-VI SNAC and amorphous SNAC (containing approximately 10% Type III SNAC) as prepared in Examples 1-6 and 14, respectively. (TGAs).

4, 9, 14, 19, 24, 29, and 46 are FTIR spectra of type I-VI SNAC and amorphous SNAC (containing approximately 10% Type III SNAC), such as those prepared in Examples 1-6 and 14, respectively. .

5, 10, 15, 20, 25, 30, and 47 show water adsorption of I-VI type SNAC and amorphous SNAC (containing approximately 10% type III SNAC) as prepared in Examples 1-6 and 14, respectively. Desorption spectrum.

31 and 32 are graphs of plasma heparin concentrations in Cynomolgus monkeys versus time after oral administration of type I or III SNAC and heparin capsules as prepared in Example 7.

FIG. 33 is a graph of plasma heparin concentration in cynomolgus monkeys versus time after oral administration of type I or III SNAC and heparin capsules as prepared in Example 7.

34 and 35 are graphs of plasma heparin concentration in cynomolgus monkeys versus time after oral administration of type I or III SNAC and heparin capsules as prepared in Example 8.

36 is a graph of plasma heparin concentration in cynomolgus monkeys versus time after oral administration of type I or III SNAC and heparin capsules as prepared in Example 8.

FIG. 37 is a graph of the amount of weight of precipitate of type I or III SNAC dissolved in deionized water at 37 ° C. for at least 15 minutes (Example 9).

FIG. 38 is a graph of the amount of weight of precipitates of Form I, II, III, or IV SNAC dissolved in deionized water at 37 ° C. for at least 15 minutes (Example 9).

Fig. 39 shows the XRPD of type I SNAC before and after ball milling (Example 11).

40 shows XRPD of type I SNAC before and after wet granulation (Example 12).

Fig. 41 shows the XRPD of type I SNAC before and after crimping (Example 13).

42 shows XRPD of type III SNAC before and after compression (Example 13).

Example  One

Type I SNAC Manufacturing

Type I SNAC was prepared as follows. In the method described in Example 1 of WO 00/59863, which is hereby incorporated by reference in its entirety, an SNAC (i.e., N- (8- [2-hydroxybenzoyl] amino) car may be employed using a suitable starting material. Free acid) was prepared.

Form I SNAC was also prepared from the free acid of SNAC using the following method described in Example 12 of WO 00/59863.

A clean 300 gallon reactor was charged with 321 L of ethanol modified with 0.5% toluene. While stirring, 109 kg (dry) of free acid of SNAC were added. The reactor was heated to 28 ° C. and maintained at a temperature of 25 ° C. or higher. 34 L of purified water, USP and 15.78 kg sodium hydroxide solution were prepared, cooled to 24 ° C., placed in a stirred reactor and kept at a reaction temperature of 25-35 ° C. for at least 15 minutes. The mixture was stirred for an additional 15 minutes.

Adjacent reactors were charged with 321 L of ethanol modified with 0.5% toluene. The reactor was heated to 28 ° C. using a circulator. The solution of the first reactor was added to the second reactor and maintained at a temperature of 25 ° C. for at least 30 minutes. The contents were stirred and 418 L of heptane was added. The reaction mixture was cooled to 10 ° C., centrifuged and washed with 60 L of heptane. The product was collected and dried in a Stokes oven at 82 ° C. under 26 "Hg vacuum for about 65 hours (all weekend). 107.5 kg monosodium SNAC (ie N- (8- [2-hydroxybenzoyl] -amino) Monosodium salt of caprylic acid) was recovered.

XRPD, DSC, TGA, FTIR and adsorption / desorption spectra of Form I are shown in FIGS. 1-5, respectively.

Example  2

Type II SNAC : ≪

Type II SNAC was prepared as follows. The method of Example 1 was repeated except for the last drying step. The SNAC ethanol solvate obtained was then dried in a tumble dryer and aggregated (forming a ball). The dryer did not have an internal stirring device. The SNAC was removed in a rotary dryer, milled with a Comil ^® milling machine (Quadro Engineering Inc. of Waterloo, Ontario, Canada) and tray dried. SNAC was stored in a double-ply polyethylene bag and stored for at least 3 years in a stainless steel drum.

XRPD, DSC, TGA, FTIR and adsorption / desorption spectra for Form II are shown in FIGS. 6-10, respectively.

Example  3

Type III SNAC : ≪

Type III was prepared by exposure to 90% relative humidity environment until not detected by XRPD. The material was then dried under the hood until the moisture content was about 15% w / w.

XRPD, DSC, TGA, FTIR and adsorption / desorption spectra for Form III are shown in FIGS. 11-15, respectively.

Example  4

Type IV SNAC : ≪

Form IV was prepared by heating Form II at 170 ° C. for 3 hours in a dry air oven. According to DSC, the prepared IV had a melting start temperature of about 198 ° C., and XRPD, DSC, TGA, FTIR, and adsorption / desorption spectra are shown in FIGS. 16-20.

Example  5

V type SNAC : ≪

Type I SNAC was slurried in methanol for 1 week to prepare V type SNAC. The precipitate produced was vacuum filtered and air dried for 1 hour. The prepared Form V had a melting start temperature of about 197 ° C. according to DSC, and XRPD, DSC, TGA, FTIR, and adsorption / desorption spectra are shown in FIGS. 21-25.

Example  6

Type VI SNAC Manufacturing method:

Form I was slurried in ethanol for 1 week to prepare Form VI SNAC. The precipitate produced was vacuum filtered and air dried for 1 hour. Form VI of the prepared melting temperature was about 197 ℃ according to DSC, XRPD, DSC, TGA, FTIR and adsorption / desorption spectrum is shown in Figure 26-30.

Example  7

Type I or III Preparation of Capsules Containing SNAC and Heparin USP

As shown in Table 7, a capsule (Size 1, Capsugel of Morris Plains, NJ) containing SNAC (type I or III) and heparin USP (30,000 IU) was prepared as follows. SNAC (forms I or III as prepared in Examples 1 and 3) and heparin were screened through mesh # 35. Heparin and SNAC were weighed in a specific amount and transferred to a clean dry glass 8 oz mortar. A volume of SNAC equal to the volume of heparin was added to the mortar and mixed for 2 minutes with a pestle. The residue of SNAC was added to the mixture and mixed again for 2 minutes. Fill the capsule in the appropriate amount.

ingredient SNAC per capsule (type I)
Capsule amount (mg) SNAC per capsule (type III)
Capsule amount (mg) SNAC 153.33 181.72 ¹ Heparin USP 56.82 56.82

^It is assumed that type ¹ -III SNAC is a trihydrate, about 15.62% (28.39 mg) of type III is water and the remaining 84.38% (153.33 mg) is SNAC (anhydrous base).

Cynomolgus  Administration to monkey

Cynomolgus monkeys (mean body weight 4.1 kg male and 3.0 kg female) were fasted for at least 24 hours prior to administration. 3 SNAC / heparin capsules were injected at the end of the tube and air cleaned to place the capsules on top. It was fed 2 hours after administration. Water can be drunk at any time. Approximately 1.3 ml of total blood was collected in the citric acid tube before and 10, 20, 30 and 50 minutes and 1, 1.5, 2, 3, 4 and 6 hours after administration. Blood samples were centrifuged at 2500 RPM for 10 minutes and 250 μl of plasma produced was used with Xa factor analysis using an Organon Teknika COAG-A-MATE MTX / MTX II machine. The standard range of analysis was 0-2 IU / mL of heparin.

Results for type I and III SNACs used with heparin are shown in FIGS. 31 and 32, respectively. The results were averaged over the sex and weight of the monkeys. In other words, there are data for four monkeys (3.9 kg male, 4.2 kg male, 3.2 kg female and 2.9 kg female). The results for each type of SNAC at each time point for all monkeys are shown in FIG. 33.

Example  8

I or Type III SNAC  And heparin USP Of capsules containing

As shown in Table 7, a capsule (Size 1, Capsugel of Morris Plains, NJ) containing SNAC (type I or III) and heparin USP (30,000 IU) was prepared by the method described in Example 7.

Cynomolgus  Administration to monkey

The method described in Example 7 was repeated for two male monkeys with an average weight of 5.6 kg and two female monkeys with an average weight of 6.9 kg.

Results for Type I and III SNACs with heparin are shown in FIGS. 34 and 35, respectively. The results were averaged over the sex and weight of the monkeys. In other words, data are available for four monkeys (5.7 kg male, 5.6 kg male, 7.6 kg female and 6.3 kg female). Results for each type of SNAC at each time point for all monkeys are shown in FIG. 36.

Example  9

The intrinsic dissolution rate for the type I-IV SNAC prepared in Examples 1-4 was measured as follows.

The intrinsic dissolution rate of Form I-IV precipitates was determined by the Wood's apparatus. 300 mg of a precipitate of Form I, II, III or IV SNAC was prepared in a die. The surface area of the precipitate possible in the dissolution medium was 0.484 cm ² . The precipitate was pressed at 1200-1400 lbs on a Carver press to form a disc. The die was then attached to the shaft of the dissolution apparatus. The die was spun at 50 rpm and then immersed in 900 mL of degassing medium maintained at 37 ° C. (pH 6.3). Dissolution experiments were performed three times in water. Samples were analyzed at 297.5 nm with an on-line UV-spectrum. The intrinsic dissolution rate was determined from the initial linear portion of the dissolution profile under immersion conditions.

The results are shown in FIGS. 37 and 38. The calculated dissolution rates of Form I-IV are shown in Table 8 below.

Crystalline Form of SNAC Calculated Dissolution Rate
(mg / minm ² ) I 18.84 ± 0.65 II 6.84 ± 0.08 III 12.17 ± 0.63 IV 16.24 ± 1.17

Example  10

The solubility of each I-IV SNAC in acetonitrile was determined at ambient humidity and 25 ° C. Acetonitrile was chosen because it is one of the few solvents in which SNAC is relatively insoluble and the solution can be diluted almost completely. Solubility data is shown in Table 9 below.

Crystalline Form of SNAC Solubility (mg / mL)
(± standard deviation) I 0.11 ± 0.01 II 0.08 ± 0.01 III 0.31 ± 0.02 IV 0.04 ± 0.01

Example  11

The effect of the grinding of type I SNAC was determined as follows. Grinding was carried out in ball milling. After 20 hours the samples were taken out and analyzed by XRPD.

The XRPD patterns of the SNAC samples before and after ball milling were substantially the same as shown in FIG. 39.

Example  12

The effect of wet granulation on type I SNAC was determined as follows. Type I SNAC was wet granulated by hand using a mortar while adding 20% w / w of water in a glass mortar. Wet granules were analyzed by XRPD.

40 shows XRPD patterns of SNAC samples before and after the wet granulation method. The sample after wet granulation shows an XRPD pattern that is substantially the same as type III.

Example  13

The effect of compression of type I and III SNAC was measured as follows. Approximately 300 mg of each sample was pressed in a Carver press with 4500 lb of force and 1 minute dwell time. The compression cycle was repeated 20 times. Crystalline SNAC of the composition was analyzed by XRPD.

Results for Forms I and III are shown in FIGS. 41 and 42, respectively. As in this figure, the crystal form of both samples did not change substantially.

Example  14

Amorphous SNAC Manufacturing

An amorphous was prepared by drying Form III for 4 days at 25 ° C. and 0.3 g of Hg in a vacuum oven. The dry material was a mixture of amorphous and initial Type III SNAC approximately 10%. Longer drying and higher vacuums may produce substantially pure amorphous forms.

XRPD, DSC, TGA, FTIR and adsorption / desorption spectra for amorphous SNAC containing approximately 10% of Form III are shown in FIGS. 43-47, respectively.

All patents, applications, articles, publications and test methods mentioned above are incorporated herein by reference.

Claims (59)

Monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate 1/3 hydrate. Monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate showing an X-ray powder diffraction pattern including peaks at 3.29, 11.96, and 17.76 at 2θ ± 0.2 ° 2θ degrees as shown in FIG. 6. Crystalline polymorph of hydrates. Crystalline polymorph of monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate hydrate showing an X-ray powder diffraction pattern having peaks at 3.29, 11.96, and 17.76 at 2θ ± 0.2 ° 2θ degrees. The crystal polymorph according to claim 3, wherein the crystal polymorph has a melting start temperature of 199 ° C as measured by a differential scanning calorimeter. Monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate trihydrate. Monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate showing an X-ray powder diffraction pattern including peaks at 6.69, 13.58, and 16.80 at 2θ ± 0.2 ° 2θ degrees as shown in FIG. 11. Crystalline polymorph of hydrates. Crystalline polymorph of monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate hydrate showing an X-ray powder diffraction pattern with peaks at 6.69, 13.58, and 16.80 at 2θ ± 0.2 ° 2θ degrees. The crystal polymorph according to claim 7, wherein the crystal polymorph has a melt initiation temperature of 198 ° C as measured by a differential scanning calorimeter. Anhydrous monosodium N- [8- (2-hydroxybenzoyl) amino] capryl showing an X-ray powder diffraction pattern including peaks at 8.61, 17.04, and 23.28 at 2θ ± 0.2 ° 2θ degrees as shown in FIG. 16. Crystalline polymorph of rate. Crystalline polymorph of anhydrous monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate showing an X-ray powder diffraction pattern with peaks at 8.61, 17.04, and 23.28 at 2θ ± 0.2 ° 2θ degrees. The crystalline polymorph of claim 10, wherein the crystalline polymorph has a melt initiation temperature of 198 ° C. as measured by a differential scanning calorimeter. Methanol-water cosolvate of monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate. Monosodium N- [8- (2-hydroxybenzoyl) amino] capryl with a ratio of methanol to water to monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate 0.8: 2: 1 Methanol-Water Cosolvents of Rate. Monosodium N- [8- (2-hydroxy), showing an X-ray powder diffraction pattern comprising peaks at 6.59, 9.96, 10.86, 13.87, 17.29, and 19.92 at 2θ ± 0.2 ° 2θ degrees as shown in FIG. 21. Crystalline Polymorph of Methanol-Water Cosolvate of Benzoyl) Amino] Caprylate. Monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate, showing an X-ray powder diffraction pattern with peaks at 6.59, 9.96, 10.86, 13.87, 17.29, and 19.92 at 2θ ± 0.2 ° 2θ degrees. Crystalline Polymorph of the Methanol-Water Cosolvent of. The crystal polymorph of claim 15, wherein the crystal polymorph has a melting start temperature of 197 ° C. as measured by a differential scanning calorimeter. Ethanol-water cosolvate of monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate. Monosodium N- [8- (2-hydroxybenzoyl) amino] capryl with a ratio of ethanol to water to monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate 0.6: 2: 1 Ethanol-water co-solvate. Monosodium N- [8- (2-hydroxybenzoyl) amino], showing an X-ray powder diffraction pattern comprising peaks at 9.60, 10.43, 12.68, and 16.58 at 2θ ± 0.2 ° 2θ degrees as shown in FIG. 26. Crystalline Polymorph of Ethanol-Water Cosolvate of Caprylate. Ethanol-water of monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate, showing an X-ray powder diffraction pattern with peaks at 9.60, 10.43, 12.68, and 16.58 at 2θ ± 0.2 ° 2θ degrees. Crystalline Polymorphs of Cosolvents. The crystal polymorph of claim 20, wherein the crystal polymorph has a melting start temperature of 197 ° C. as measured by a differential scanning calorimeter. Amorphous monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate. (A) (i) the crystalline polymorph according to any one of claims 1 to 21 or (ii) amorphous monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate and (B) a biologically active agent Pharmaceutical composition for delivery of a biologically active agent comprising a. The pharmaceutical composition of claim 23, wherein the biologically active agent is heparin. The pharmaceutical composition of claim 24, wherein the biologically active agent is low molecular weight heparin. delete delete Type III, V, or VI monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate or mixtures thereof is heated to at least 50 ° C. to form type I monosodium N- [8- (2-hydroxy A process for producing type I monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate comprising producing benzoyl) amino] caprylate. The method of claim 28, wherein the monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate is heated to 50 to 110 ° C. 29. Form I monosodium N- [8- (2-hydroxybenzoyl) amino, which comprises heating amorphous monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate to 30 to 90 ° C. ] Method for producing caprylate. 31. The process of claim 30, wherein the amorphous monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate is heated to 40-80 ° C. Form I monosodium N- [8- comprising lyophilizing all forms of monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate other than Form I Process for the preparation of (2-hydroxybenzoyl) amino] caprylate. 33. The method of claim 32, wherein the at least one type II-VI monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate and / or amorphous monosodium N- [8- (2-hydroxybenzoyl) Lyophilizing amino] caprylate to produce Form I. The solvate of monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate is dried without stirring and then dried monosodium N- [8- (2-hydroxybenzoyl) amino] capryl Type II monosodium N- [8- (2-hydroxybenzoyl), comprising exposing the rate to moisture to produce type II monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate ) Amino] caprylate production method. The method of claim 34, wherein the solvate is ethanol solvate or methanol solvate. Monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate or amorphous monosodium N- [8- (2-hydroxybenzoyl) amino] capryl type I, II, IV, V, or VI A method for producing type III monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate, comprising exposing the rate or mixture thereof to an environment having a relative humidity of at least 75% to produce Form III. Type III monosodium N- [8- (2-hydroxy) comprising wet granulating Type I monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate to produce Form III Method for preparing benzoyl) amino] caprylate. Form III mono, comprising exposing type V or VI monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate or mixtures thereof in an environment with a relative humidity of at least 30% to produce Form III. Method for preparing sodium N- [8- (2-hydroxybenzoyl) amino] caprylate. Type III monosodium N-, comprising producing type III by exposing type VI monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate in an environment with a relative humidity of 10% or more. Process for the preparation of [8- (2-hydroxybenzoyl) amino] caprylate. Type III monosodium N- [8- (2-hydroxybenzoyl) comprising the step of exposing amorphous monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate to moisture to produce Form III. ) Amino] caprylate production method. Type III monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate comprising crystallizing monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate from water Method of preparation. Type I, II, III, V, or VI monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate or mixtures thereof from 110 ° C. to monosodium N- [8- (2-hydroxybenzoyl A method for producing type IV monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate comprising the step of producing Form IV by heating to the temperature of the melting point of the amino] caprylate. 43. The method of claim 42 wherein the type II monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate is from 150 ° C. to monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate. Method of producing type IV by heating to the temperature of the melting point of. Form V monosodium N- [8- (2-hydride) comprising crystallizing monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate from methanol solution at at least 30% relative humidity Process for the preparation of oxybenzoyl) amino] caprylate. 45. The method of claim 44, wherein the methanol solution is free of water. Form V monosodium N- [8- (2-hydroxybenzoyl) comprising equilibrating an I-IV or VI monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate with methanol ) Amino] caprylate production method. 47. The process of claim 46, wherein equilibration is performed in the absence of water. At a relative humidity of at least 30%, slurrying one of Form I-IV or VI or a mixture thereof in methanol and maintaining the slurry mixture at ambient temperature to form V-type monosodium N- [8- (2-hydroxy A method for producing V-type monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate comprising producing benzoyl) amino] caprylate. Form VI monosodium N- [8- (2-hydride) comprising crystallizing monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate from an ethanol solution at at least 30% relative humidity. Process for the preparation of oxybenzoyl) amino] caprylate. The method of claim 49, wherein the ethanol solution is free of water. Form VI mono, comprising preparing a saturated ethanol solution of monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate at a relative humidity of at least 30% and cooling the resulting solution to room temperature or below Method for preparing sodium N- [8- (2-hydroxybenzoyl) amino] caprylate. The method of claim 51, wherein the method is performed in the absence of water. A process for producing type VI monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate comprising slurrying any one of Form I-IV in ethanol at a relative humidity of at least 30%. Biologically active agent delivery comprising type I monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate, a ground mixture of at least one biologically active agent and at least one pharmaceutically acceptable additive Pharmaceutical composition for. Biologically active agents comprising type I monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate, a direct compressed mixture of at least one biologically active agent, and at least one pharmaceutically acceptable additive Pharmaceutical compositions for delivery. Biologically active agent comprising a direct compressed mixture of type III monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate and at least one biologically active agent and at least one pharmaceutically acceptable additive Pharmaceutical compositions for delivery. Dehydrated III, V, or VI monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate to form amorphous monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate A method for producing amorphous monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate comprising the step of forming. 58. The process of claim 57, wherein the type III, V, or VI monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate is dehydrated in vacuo. 58. The process of claim 57, wherein Form III is dehydrated to form amorphous monosodium N- [8- (2-hydroxybenzoyl) amino] caprylate.

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