CN100588422C - Oral insulin composition and methods of making and using thereof - Google Patents
Oral insulin composition and methods of making and using thereof Download PDFInfo
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- CN100588422C CN100588422C CN200480009195A CN200480009195A CN100588422C CN 100588422 C CN100588422 C CN 100588422C CN 200480009195 A CN200480009195 A CN 200480009195A CN 200480009195 A CN200480009195 A CN 200480009195A CN 100588422 C CN100588422 C CN 100588422C
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Abstract
A method of lowering blood glucose in a mammal includes orally administering a therapeutically effective amount of crystallized dextran microparticles and insulin to the mammal to lower blood glucoseof the mammal. The composition may be a one phase or a structured multi-phase composition for controlled release of insulin.
Description
Technical field
The application requires the rights and interests of following U.S. Provisional Application: the serial number of submitting on March 4th, 2003 is 60/451,245 U.S. Provisional Application; The serial number of submitting on May 5th, 2003 is 60/467,601 U.S. Provisional Application; The serial number of submitting on May 9th, 2003 is that 60/469,017 U.S. Provisional Application and the serial number submitted on August 15th, 2003 are 60/495,097 U.S. Provisional Application, and its all the elements are incorporated herein by reference.
The present invention relates generally to analgesic composition, especially, the present invention relates to contain the oral insulin composition of insulin and crystallized dextran microparticles.
Background technology
Glucosan is by some microorganisms or the synthetic high molecular weight polysaccharide of biochemical method.The glucosan that mean molecule quantity is about 75kDa has and the similar colloid osmotic pressure of blood plasma, so its aqueous solution uses as plasma expander in clinical.The cross-linking dextran of pearl form is to use among the proteic GPC (gel permeation chromatography)
The basis and as by Pharmacia research and development
The basis, should
In order to satisfy the special requirement of microcarrier cell culture.For example, the patent No. be 6,395,302 and the patent No. be that 6,303,148 United States Patent (USP) (Hennink etc.) has disclosed various biomaterials are attached on the crosslinked dextran microparticles.But, owing to used cross-linking agent, make pearl have potential toxicity based on cross-linking dextran, so this pearl can not be used for manufacturing (the Blain J.F. of implant usually, Maghni K., Pelletier S. and Sirois P. inflammation research (Inflamm.Res.), 48 (1999): 386～392).
The patent No. is the production method that 4,713,249 United States Patent (USP) (Schroder) has been described the depot matrix that is used for bioactive substance.According to this patent, described depot matrix allegedly is made up of carbohydrate microparticles, makes it stable by crystallization, this means and has used non-covalent bond.It below is the method for the so-called crystalline carbohydrate microparticles of production of Schroder description.In one or more hydrophilic solvent, form the solution of carbohydrate polymer and bioactive substance, then in the liquid hydrophobic medium with the emulsifying mixture of described carbohydrate and bioactive substance, to form spherical droplet.Then this Emulsion is imported in the crystallization medium that contains acetone, ethanol or methanol, have the spheroid of the crosslinked crystalline carbohydrate polymeric matrix of non-covalent bond with formation.Described substrate is mixed with the bioactive substance of 0.001 weight %～50 weight %.Thereby, before making this spheroid crystallization, in described solution, add bioactive substance.Schroder does not describe the micro structure by the microgranule of described multistep processes preparation.The multistep processes of Schroder is complicated, and has used the organic solvent that pair cell has genotoxic potential and needs to remove.And the compositions of Schroder designs at injection, is to use inconvenience and is the method for compositions of using that causes pain.
Summary of the invention
The method of blood sugar lowering in mammal, this method comprise to the crystallized dextran microparticles of the Orally administered treatment effective dose of mammal and insulin to reduce this mammiferous blood glucose.Said composition can be to be used for the single-phase or structurized heterogeneous compositions that the insulin controlled release discharges.
Description of drawings
Fig. 1 is that molecular weight is the photo of glucosan crystallized dextran microparticles of spontaneous formation in the aqueous solution of 55.0 weight % of 70.0kDa.
Fig. 2 A is the cross-sectional picture of the crystallized dextran microparticles that shows in Fig. 1.
Fig. 2 B is the cross-sectional picture of the microgranule that shows in Fig. 2 A, can see the microcellular structure of this microgranule in this photo.
Fig. 3 is the photo of the aggregation of crystallized dextran microparticles.
Fig. 4 is that the 14th day fluorescent labeling macromole in injection back slowly is discharged into photo the mouse muscle tissue from the implant that comprises crystallized dextran microparticles between muscle.
Fig. 5 is the photo of the Emulsion of PEG (Polyethylene Glycol) aqueous solution in glucosan (molecular weight is 500kDa) aqueous solution, and described glucan aqueous solution contains the crystallized dextran microparticles that shows among Fig. 1.
Fig. 6 is the photo of the Emulsion of glucosan (molecular weight the is 500kDa) aqueous solution in the PEG aqueous solution, and described glucan aqueous solution contains the crystallized dextran microparticles that shows among Fig. 1.
Fig. 7 is the intramuscular injection photo of the Emulsion of the PEG aqueous solution in glucosan (molecular weight the is 500kDa) aqueous solution, and described glucan aqueous solution contains the crystallized dextran microparticles that shows among Fig. 1.
Fig. 8 is the subcutaneous injection photo of the Emulsion of the PEG aqueous solution in glucosan (molecular weight the is 500kDa) aqueous solution, and described glucan aqueous solution contains the crystallized dextran microparticles that shows among Fig. 1.
Fig. 9 A schematically illustrates dissimilar granules and each distribution behavior mutually in aqueous two phase system with Fig. 9 C.
Fig. 9 B is based on the cross-sectional picture of the implant structure of two-phase system.
Figure 10 schematically illustrates the therapeutic agent delivery method of one embodiment of the invention.
The specific embodiment
The inventor finds, the carrier that the compositions of porous (being micropore) microgranule (for example crystallized dextran microparticles) can be sent as oral insulin.Said composition can be single-phase composite or the heterogeneous compositions that forms structurized implant in mammal.
Preferred crystallized dextran microparticles is described by following first, second portion is described the formation from the structurized implant of heterogeneous compositions, and part is subsequently described the specific embodiment of the preparation method of Orally administered and this oral insulin composition of said composition in mammal.
A. crystallized dextran microparticles
The inventor found through experiments, in 20 ℃～90 ℃ temperature range, be that spontaneous formation average diameter is 0.5 micron～3.5 microns a crystallized dextran microparticles in the concentrated aqueous solution (40 weight %～65 weight %) of the glucosan of 1.0kDa～200.0kDa at molecular weight.Form microgranule in room temperature if desired, can use the dextran solution of 2kDa～18kDa.Certainly, if desired, also can form this microgranule in the temperature that is higher than room temperature by the dextran solution of 2kDa～18kDa.This microgranule can be higher than solution (for example solution of 20kDa～75kDa) spontaneous form of the temperature of room temperature (for example about 40 ℃～about 70 ℃) by the glucosan of higher molecular weight.This microgranule can have such as rule or suitable Any shape such as irregular, but is preferably spherically, and preferred diameter is 10 microns, and is perhaps littler, for example 0.5 micron～5 microns.
The microcellular structure of the dextran microparticles of transmission electron microscopy revealed (seeing Fig. 2 A and Fig. 2 B).Preferably, the porosity of by volume calculating this microgranule is at least 10%, and for example about 10%～about 50%, more preferably about 20%～about 40%.Thereby this structure comprises the microporosity microgranule in the macroporosity zone that has between granule.
To the waterborne suspension of crystallized dextran microparticles carry out spray drying proved can the production crystallized dextran microparticles aggregation, described aggregation is essentially spherical, diameter is 10.0 microns～150.0 microns (see figure 3)s.
It below is the non-restrictive example that forms the method for dextran microparticles.Add the Dextran T 40 (molecular weight be 40kDa) of 50.0g in the 50.0g sterile distilled water in 500ml experiment beaker, under laminar flow, to obtain the solution of 50 weight % from the gloomy bioscience of peace (AmershamBiosciences).With this mixture in 60 ℃ (water-baths) on magnetic stirring apparatus with 50rpm (rev/min) rotating speed stir, dissolve fully up to glucosan, and obtain clear solutions.Can remove the gas that is comprised in this solution by evacuation.Cover the tyvek lid
After this clear solutions is placed in 60 ℃ the experiment baking oven.After 3.5 hours, the result as crystallized dextran microparticles forms has formed muddy viscous suspension.
In order to remove amorphous glucosan, with the sterile distilled water of 3 * 250ml by centrifugal (for example 3,000g, 30 minutes) this microgranule is washed, perhaps for example 1 part microgranule and 10 parts water (sterile distilled water of 3 * 250ml passes through germ tight filter) filter to the suspension of the microgranule of dilution.Described centrifugal/washing under laminar flow, carry out.This microgranule is being put into the experiment beaker of 500ml and covered tyvek lid, and in 60 ℃ experiment baking oven dry 8 hours, make its moisture reach about 5%.The dry powder that is obtained is about 2 microns granulometric composition by average diameter.
In experiment, verified macromole slowly discharges from implant, and in this experiment, macromole dissolves in the waterborne suspension of crystallized dextran microparticles or its aggregation before the injection.Fig. 4 shows the slow release during the 14th day this macromole in injection back organized between the implant contain fluorescently-labeled macromole (FITC-glucosan, molecular weight are 500kDa) and muscle from the implant to the mouse muscle.
B. two-phase system
Can form self-assembled structures on the basis of binary system, this self-assembled structures is based on crystallized dextran microparticles and their aggregation.
For example, in oil condition, can form a kind of structure of specific type, wherein, oil nuclear is by by the skin encirclement that is dispersed in water or forms such as the crystallized dextran microparticles in the aqueous solution of polysaccharide (for example glucosan) organic polymer of etc.ing or its aggregation.Described structure can be called capsule.What should be mentioned that is that described skin can comprise formed coarse spherical skin when this capsule is organized encirclement.But when this capsule was positioned near barriers such as substrate, bone or intestinal wall for example, this capsule is included endorsed with between the opposite side of side of one or more microgranule wall and barrier.And, though oil is used as illustrative example, described endorsing to contain other material, for example other polymer, cell etc.
In order to form the capsule structure, can use biphase water-based system.When the aqueous solution of different polymer mixed to be higher than certain concentration, they often formed the two phase liquid of immiscible liquid.Each contains usually mutually and surpasses 90% water, and it can be cushioned and become etc. and ooze.If cell suspending liquid or particle suspension liquid are added in this system, find that through regular meeting this cell or granule distribute in each alternate inequality of carrying out.Because cell or particulate surface characteristic are directly depended in the distribution in these systems, so can utilize this priority allocation behavior as the basis different cell masses or granule to be separated.Cell or granule with different surfaces characteristic demonstrate enough different distribution behaviors.
The competitive adsorption of described two kinds of polymer phases depends on the chemical characteristic of polymer.The two-phase polymer method has been applied to separating of cell, protein, nucleic acid and mineral or distribution (" distribution in aqueous two phase system (Partitioning in Aqueous Two-Phase Systems) ", 1985, H.Walter, D.Brooks and D.Fisher edit, and Academic Press publishes).
Crystallized dextran microparticles from the mixture of for example glucosan/Polyethylene Glycol (PEG) be mutually in the distribution experiment show, as showing among Fig. 5 and Fig. 6, dextran microparticles preferentially be in glucosan mutually in, and other PEG can be dispersed in mutually this glucosan mutually in, to form W/W Emulsion, and, also set up conversely when the volume of PEG phase during greater than the volume of glucosan phase.
Fig. 5 is the photo of the Emulsion of the PEG aqueous solution in glucan aqueous solution, and described glucan aqueous solution contains crystallized dextran microparticles.In the structure of Fig. 5, the volume of PEG phase is less than the volume of glucosan phase.This glucosan contains glucosan and crystallized dextran microparticles mutually.Thereby this PEG forms the one or more globose nucleuses (that is blind bore structure) that surrounded by the dextran/dextran microparticle shell mutually.
Fig. 6 is the photo of the Emulsion of the glucan aqueous solution in the PEG aqueous solution, and described glucan aqueous solution contains crystallized dextran microparticles, and wherein, the volume of PEG phase is greater than the volume of glucosan phase.In this case, glucosan forms one or more globose nucleuses that contain dextran microparticles that surrounded mutually by PEG (promptly when PEG is dissipated in the tissue fluid, the pore structure of the opening of Xing Chenging) in vivo mutually.As shown in Figure 6, the glucosan of smaller size smaller (droplet) forms the nuclear (bottom right of Fig. 6) of big globular dextran/dextran microgranule mutually, and the less spheroid that contains the dextran/dextran microgranule joins on this nuclear, and merges with it.
Thereby, when the volume ratio of first phase (for example PEG mutually and inclusions such as therapeutic agent) and second mutually (for example glucosan mutually and inclusions such as dextran microparticles) less than 1 the time, just self assembly forms the capsule by first phase (nuclear) of second phase (skin) encirclement.If said composition contains the therapeutic agent that insulin isopreference for example is dispensed into the PEG phase, just then this therapeutic agent optionally is dispensed in the PEG nuclear, and granule optionally distributes by self assembly and form and be enclosed in the circumnuclear skin of this PEG.
Can mix mutually with PEG mutually by the glucosan that will separately prepare and prepare Emulsion, both preferentially are in the PEG phase respectively or are in the dissimilar particulate suspension of glucosan in mutually.Its principle is that their surface texture and the interface energy of granule in this polymer solution depended in the distribution of granule in different polymer phases.
The injection of tissues of experimental animals being carried out with the two-phase system of the aqueous that contains crystallized dextran microparticles has shown the formation of the implant with capsule structure as shown in Figure 7 and Figure 8.In this two-phase system, the volume of glucosan phase is greater than the volume of PEG phase.Fig. 7 and Fig. 8 show that all the capsule with PEG nuclear and dextran/dextran microparticle shell forms (after promptly being expelled to mammalian tissues) by self assembly in vivo.This skin contains in big porose area between adjacent microgranule and the micropore district in microgranule itself.
It below is the non-limiting example that forms the method for capsule structure by two-phase system.10g Dextran T 40 (molecular weight is 40kDa) and 2gPGE are dissolved in 88ml contain 1, the 000UI insulin
Solution in, be added with the 25g crystallized dextran microparticles in the described solution.These steps are carried out under laminar flow condition.On magnetic stirring apparatus, this mixture was stirred 30 minutes with 100rpm in room temperature, to form uniform mixture (being suspension).1.0g this suspension in contain the 8UI insulin.
What should be mentioned that is, dextran microparticles can by be provided to two-phase system in the different dextran solution of dextran solution molecular weight prepare.Thereby, form this crystallized dextran microparticles in can be at the dextran solution that molecular weight ratio the provides low dextran solution (for example solution of 2kDa～20kDa) in two-phase system, described dextran solution in two-phase system provides can be the dextran solution of 40kDa～500kDa, for example can be the solution of 40kDa～75kDa.Be favourable like this,, and can under low concentration, form the skin of capsule because the dextran solution of higher molecular weight (for example solution of 40kDa～70kDa) has obtained the approval of regulations widely.Though in fact the solution of lower molecular weight can not provide the dextran solution of lower molecular weight in vivo in order to reduce crystallization time.And the granule of lower molecular weight in vivo can easier dissolving.
The capsule structure that is formed by two-phase system is favourable, because this capsule structure makes therapeutic agent more even, more lasting from the release of release ratio from comprise the monophasic compositions that contains microgranule in examining.And, it is believed that by using the capsule structure, need less microgranule just can obtain than using single_phase system time control identical or better therapeutic agent to discharge.And it is believed that can be by being controlled at the particulate loading in the two-phase system, thereby control the outer field thickness of this microgranule.In two-phase system, particulate loading is big more, and the skin that obtains will be thick more.Thereby, can control amount, persistent period and/or the opportunity that therapeutic agent discharges from capsule nuclear by controlling outer field thickness.Therefore, can be at the release overview of every patient or every group of patient customized therapeutic agent.
What should be mentioned that is, though with PEG and glucosan as the examples of material of two-phase system, can use any other appropriate materials of the following distribution behavior of demonstration to replace.Fig. 9 A is schematically illustrated in dissimilar particulate partition characteristics in the two-phase system of aqueous.For example, in Fig. 9 A, shown the preferred particulates 10,12,14 of three types molecule or molecule aggregate, and mutually 16 with 18 biphase mutually.But, can be two types or granule above three types.These granules can be the microgranules that is made by organic material and/or inorganic material, liposome, living cells, virus or macromole, for example microsphere or nanometer spheroid.The granule 10 of the first kind preferentially segregates into first phase 16.The granule 12 of second type preferentially be separated to first mutually 16 with second 18 the interface mutually.The granule 14 of the 3rd type preferentially segregates in second phase 18.Thereby by simulating former non-limitative example, first granule 10 can comprise therapeutic agent, and second granule 12 and/or the 3rd granule 14 can comprise crystallized dextran microparticles, and first phase 16 can comprise the PEG phase, and second phase 18 can comprise the glucosan phase.
Shown in the zone 20 of Fig. 9 A, if first phase 16 in a small amount is provided in the second relatively large phase 18, just form the capsule type structure that is arranged in second phase 18, this capsule type structure comprises the discrete spheroid of first phase 16, and described first phase 16 contains certain density first kind granule 10.Second type of particle 12 can be positioned at mutually 16 with 18 interface mutually, and play the outer field effect of capsule.Granule 14 is distributed in second phase 18 and/or forms the capsule skin.
On the contrary, shown in the zone 22 of Fig. 9 A, if second phase 18 in a small amount is provided in the first relatively large phase 16, just form the capsule type structure that is arranged in first phase 16, this capsule type structure comprises the discrete spheroid of second phase 18, and described second phase 18 contains the granule 14 of certain density the 3rd type.Second type of particle 12 can be positioned mutually 16 with 18 interface mutually, and play the outer field effect of capsule.Granule 10 is distributed in first phase 16 and/or forms the capsule skin.Can for example it be delivered in the mammal (for example animal or human) with two- phase system 20 and 22 as implant.Thereby this capsule forms structurized three-dimensional implant, and this implant has the nuclear as storage pool or depots, so that therapeutic agent is carried out controlled release through skin.On the contrary, the equally distributed implant of microgranule is not structurized implant.What should be mentioned that is, the formed structure that is used for the two-phase system by oral delivery generally can be described as containing the structurized suspension of PEG decentralized photo and glucosan continuous phase.
And granule 10,12 and 14 can be dispensed into each fluent material (for example oil) or macromole one of mutually by selectivity and replace.For example, the PEG that can be dispensed into PEG/ glucosan two-phase system such as the therapeutic agent of insulin mutually in.Since insulin optionally be assigned to PEG mutually in, so this PEG forms the nuclear that contains insulin of capsule structure mutually.What should be mentioned that is, distribute although specific granule and therapeutic agent carry out selectivity, term " optionally distribute " might not mean this granule of 100% or therapeutic agent all be assigned to wherein one mutually in.But, most selectivity dispensable materials, this dispensable materials of preferred 80%, be assigned to wherein one mutually in.For example, though most insulin to the PEG phase, a part of insulin can be retained in glucosan mutually in.
Fig. 9 B shows the scanning electron microscopy of the cross section of implant structure, and described implant structure is based on the two-phase system that carries out schematic illustrations in Fig. 9 A.The biphase waterborne compositions that will contain glucosan first phase, PEG second phase and crystallized dextran microparticles is expelled in the agarose gel.This gel composition is simulated mammalian tissues by preventing that crystallized dextran microparticles from spreading from injection side.Figure among Fig. 9 B shows the formation of nuclear-outer implant structure.This nuclear comprises by outer 34 districts that surround 30 and district 32.Before the incision gel carried out cross section SEM (scanning electron microscopy) imaging, district 30 was for being filled with the space of PEG phase region.In the process of crosscut, the PEG phase region oozed from gel when gel was cut open.District 32 is the outsides that are arranged in the nuclear that contains the PEG droplet of crystallized dextran microparticles.District 34 is the skins that contain crystallized dextran microparticles, the position that its encirclement contains the nuclear of PEG and keeps the nuclear that contains PEG.
Though do not wish to be subjected to specific theory, the inventor thinks that the nuclear-layer structure shown in Fig. 9 B is by forming as the self assembly that schematically shows at 9C.When first mutually 16 and second when 18 (aqueous solutions of for example different immiscible polymer) are in the suitable hold-up vessel 19 (for example glass beaker or bottle) mutually, mutually 16 be raised to another mutually 18 above.When this two-phase compositions be injected into such as the restriction of mammalian tissues or host material (as the gel of simulated tissue) etc. mutually 16 with 18 free-pouring materials mutually in the time, said composition is self-assembled into described nuclear-layer structure.At first, the less spheroid that forms the almost spherical shown in Fig. 9 C mid portion mutually of volume.Then, shown in Fig. 9 C bottom, the spheroid combination is to form by the nuclear of the almost spherical of a phase of the skin of other phase encirclement.Though shown the example of the two-phase system of heterogeneous system, if desired, heterogeneous system can be more than biphase.
C. the delivery vector of oral insulin
The inventor finds that porous (as microporosity) microgranule can be as the oral delivery vehicle of insulin.This porous microgranule can be any suitable porous microgranule of the remarkable blood sugar lowering of energy behind the Orally administered insulin, and described remarkable blood sugar lowering for example reduced by 5% at least in Orally administered 60 minutes, for example reduce by 30% at least.Preferably, described microgranule is the biological adhesiveness microgranule, for example at least temporarily attached on the mammal intestine walls so that the granule that insulin is sent by intestinal wall.Most preferably, described porous microgranule contains above-mentioned crystallized dextran microparticles.
In Figure 10, shown a preferred embodiment of the present invention, the inventor finds, the waterborne suspension that mammal 53 (for example rabbit) is carried out Orally administered crystallized dextran microparticles 12,14 and insulin 46 blood sugar lowering horizontal aspect with the almost equivalence of the independent insulin injection of intramuscular.Figure 10 has shown that schematically insulin 46 sees through the wall of the intestinal 52 of mammal 53 from the Orally administered compositions 54 that contains microgranule.Because rabbit is the common model of people in the drug test, so the inventor thinks, the compositions 54 such as the liquid or solid of waterborne suspension, solution, tablet or capsule etc. that contains crystallized dextran microparticles and insulin also can reduce human blood sugar level effectively when Orally administered.
Following examples are illustrated sending of the oral insulin that carries out with crystallized dextran microparticles.This research relates to chinchilla (Chinchilla) (2.3 ± 0.2kg) and observe their reactions to the Orally administered waterborne suspension of being made up of crystallized dextran microparticles that makes according to method described here and biosynthetic human insulin.
The glucosan T20 (Pharmacia, Uppsala, Sweden) of dissolving 3.0g in the water of 2.0g, and put into 60 ℃ box.After 3 hours, with the water of 3 * 5.0ml by crystallized dextran microparticles being washed in that 3000g is centrifugal.Then this crystallized dextran microparticles is suspended in the water of 2.0ml, and is dried in room temperature.Contain the suspension of insulin to be used for oral insulin delivery experiment with the dried powder preparation that obtains.The insulin of described microgranule, 0.3ml (12UI) or 0.6ml (24UI) by mixing 250mg (NovoNordisk Actrapid HM Penfill, 40UI/ml) and distilled water so that volume reaches 2.0ml, preparation contains the suspension of insulin.
With the throat of conduit, import the drinking water of 10.0ml then with this suspension (2.0ml) sample importing rabbit.Import at suspension and not allow animal feed in preceding 3 hours.From the ear vein blood-sample withdrawal of rabbit, and be used for the concentration of glucose analysis.Adopt glucose oxidase method " singly touching system's glucose analyser (One-touch System Glucose Analyzer) " (LifescanJohnson ﹠amp by accurately calibrating; Johnson, Milpitas, CA, the U.S.) glucose in the analyzing blood.
In comparative example 1 and comparative example 2 (control experiment # 1 is summarised in the Table I), the biosynthetic human insulin is imported in 2 rabbits by intramuscular (i.m.) with the dosage of every animal 12UI.In comparative example 3 and comparative example 4 (control experiment # 2 is summarised in Table II), rabbit remains intact (promptly these two rabbits not being carried out insulin or other injection).In comparative example 5 and comparative example 6 (control experiment #3 is summarised in the Table III), by the oral suspension that two rabbits is provided the crystallized dextran microparticles that does not have insulin.In comparative example 7 and comparative example 8 (control experiment #4 is summarised in the Table IV), by the oral suspension that two rabbits is provided commercially available Sephadex G-150 microgranule with insulin (24UI).According to peace gloomy bioscience (AmershamBiosciences) website, Sephadex G-150 microgranule be by glucosan and chloropropylene oxide are carried out crosslinked make have a microgel particle that diameter is 20 microns～150 microns Cheng Zhu.In according to the embodiment 9～embodiment 14 of the preferred embodiment of the invention (being summarised in the Table V), provide the have insulin suspension of crystallized dextran microparticles of (24UI) to 5 rabbits by oral.These results are summarised in down among Table I～V.
Table I
| Rabbit/routine # | Insulin dose | 0 minute mg/dl | 30 minutes mg/dl | 60 minutes mg/dl | 90 minutes mg/dl | 120 minutes mg/ |
| # | ||||||
| 1 | 12UI i.m. | 91 | 68 | 58 | 49 | 51 |
| #2 | 12UI i.m. | 87 | 65 | 64 | 57 | 58 |
Table II
| Rabbit/routine # | Insulin dose | 0 minute mg/dl | 30 minutes mg/dl | 60 minutes mg/dl | 90 minutes mg/dl | 120 minutes mg/dl |
| #3 | 0.0 | 98 | 87 | 87 | 89 | 86 |
| #4 | 0.0 | 88 | 90 | 91 | 94 | 87 |
Table III
| Rabbit/routine # | Insulin dose | 0 minute mg/dl | 30 minutes mg/dl | 60 minutes mg/dl | 90 minutes mg/dl | 120 minutes mg/dl |
| #5 | 0.0 | 92 | 99 | 94 | 95 | 92 |
| #6 | 0.0 | 90 | 93 | 93 | 93 | 92 |
Table IV
| Rabbit/routine # | Insulin dose | 0 minute mg/dl | 30 minutes mg/dl | 60 minutes mg/dl | 90 minutes mg/dl | 120 minutes mg/dl |
| #7 | The 24UI per os | 85 | 82 | 86 | 81 | 83 |
| #8 | The 24UI per os | 84 | 75 | 86 | 76 | 77 |
Table V
| Rabbit/routine # | Insulin dose | 0 minute mg/dl | 30 minutes mg/dl | 60 minutes mg/dl | 90 minutes mg/dl | 120 minutes mg/ |
| # | ||||||
| 9 | The 24UI per os | 94 | 68 | 59 | 58 | 57 |
| #10 | The 24UI per os | 93 | 64 | 52 | 54 | 52 |
| #11 | The 24UI per os | 78 | 52 | 51 | 49 | 48 |
| #12 | The 24UI per os | 92 | 64 | 52 | 53 | 47 |
| #13 | The 24UI per os | 89 | 53 | 48 | 38 | 49 |
| #14 | The 24UI per os | 97 | 60 | 38 | 54 | 52 |
Data show among Table I～V, when the insulin of using 12UI by intramuscular injection (embodiment 1～embodiment 2) and when using 24UI insulin and crystallized dextran microparticles (embodiment 9～embodiment 14) by per os (oral), the average reduction of sugar (being glucose) is suitable in mammiferous blood.At Orally administered back 60 minutes, the reduction of the maximum of glucose was about 35%～about 60%.In injected delivery mode and oral delivery mode, the concentration of glucose overview is actually identical.What should be mentioned that is to use the insulin of other amount.For example, can use the insulin of 30UI.Usually, with the amount comparison of insulin injection, oral 2 times～3 times insulin is similar reaching the blood glucose reduction amount that is produced in 3 hours.
Well known fact is, independent insulin is subjected to the degraded of intestinal enzyme, can not be absorbed (Amidon GL, Lee HJ intactly when passing gastrointestinal mucosa, Absorption of peptideand peptidomimetic drugs, Ann.Rev.Pharmacol.Toxicol.1994; 34:321-341).But embodiment 9～embodiment 14 shows that crystallized dextran microparticles can be used as the carrier of the oral delivery of albumen (for example insulin), because the hypoglycaemic effects that obtains is significant.Do not wish to be fettered by specific theory or binding mode; but the inventor thinks; in waterborne suspension, protect insulin to avoid the remarkable degraded of intestinal enzyme as the delivery matrices of insulin porous crystallized dextran microparticles, and made insulin when passing gastrointestinal mucosa, can be absorbed intactly.Insulin can be arranged in the micropore of many micropores microgranule and/or the macropore between microgranule.On the contrary, contain the obvious decline that the use (Table IV, embodiment 7～embodiment 8) of the crosslinked Sephadex G-150 dextran microparticles of insulin does not produce blood sugar concentration.
As embodiment 9～embodiment 14 proves, administration is contained after the compositions of crystallized dextran microparticles and insulin 60 minutes, blood sugar concentration in this mammal reduces at least 5%, preferably at least 30% (promptly used behind the suspension 60 minutes, blood glucose value in the mammal reduces at least 5% than just having used the value that records before this suspension, and preferably at least 30%).Preferably, to after the administration said composition 30 minutes, the blood sugar concentration in this mammal reduced at least 5%, and for example at least 30%, preferred about 35%～about 40%.Preferably, to behind this suspension of administration 60 minutes, that the blood sugar concentration in this mammal reduces was about 35%～about 60%, and for example 35%～45%.More preferably, after the administration said composition, during 30 minutes～240 minutes (for example 30 minutes～120 minutes) whole in, with just use said composition before the value that records compare, the blood sugar concentration in this mammal reduces.For example, after this administration said composition, in 30 minutes～240 minutes time, preferably in 30 minutes～120 minutes time, the blood sugar concentration in the mammal preferably reduces at least 10%, and preferably at least 30%, more preferably at least 35%, for example 35%～45%.
Thereby a preferred embodiment of the present invention provides the method that reduces the blood glucose in the mammal by the compositions that contains crystallized dextran microparticles and insulin of oral administering therapeutic effective dose.Disease that can be by treating, damage or disorderly adverse condition or the amount that prevents or improve to determine " effective in the treatment " of said composition of symptom.Preferably, to contain average diameter be the about 0.5 micron～about 5 microns crystallized dextran microparticles and the waterborne suspension of insulin to said composition.And this microgranule is preferably promptly crystalline porous microgranule before insulin is joined suspension, makes the insulin and the surface of this microgranule contact and/or be arranged in the hole of microgranule like this.
Crystalline microgranule preferably contains the dextran molecule (being polymer molecule) that gathers together by a plurality of hydrogen bonds, Van der Waals force and/or ionic bond and do not have covalent bond basically between dextran molecule.Thereby the molecule in the microgranule does not preferably expressly carry out crosslinked (promptly not carrying out cross-linking step) and this microgranule does not contain covalent bond or is lower than 10% covalent bond in intermolecular containing intermolecular.
Though in Figure 10, shown the single-phase composite that contains insulin and microgranule, also can use the above-mentioned two-phase compositions that in Fig. 7, Fig. 8, Fig. 9 A, Fig. 9 B and Fig. 9 C, shows.For example, can use the two-phase compositions that contains glucosan phase, PEG phase, crystallized dextran microparticles and insulin.In vivo, said composition has the capsule structure of self assembly, and this capsule structure comprises wall or skin that contains crystallized dextran microparticles and the nuclear that contains PEG and insulin.
Preferably, the mammal of accepting oral administration of insulin comprises the people who needs blood sugar lowering, for example suffers from the patient of diabetes.Therefore, preferred version of the present invention provides by the suspension of Orally administered above-mentioned insulin and crystallized dextran microparticles the method for treatment diabetes in the people of needs treatment.
Can be to the insulin of any treatment effective dose of described administration.The amount of insulin is different because of the composition of the type of mammal (for example people or rabbit), mammiferous body weight, suspension, the blood glucose reduction amount and the other factors that need.A non-limitative example of the content of insulin in suspension is to be the biosynthetic human insulin of about 10UI～about 2500UI, for example about 12UI～about 30UI, for example biosynthetic human insulin of 24UI in every gram suspension.But this amount can change as required.
The invention should not be deemed to be limited to above-mentioned preferred embodiment.Can be with other host material, for example organic or inorganic microporous particles is used for sending of oral insulin.Preferably, this granule is the microgranule that promotes insulin to see through gastrointestinal mucosa and/or make composition stable.And though this suspension preferably only contains aqueous solvent, substrate and insulin solutions or suspension, this delivery system can also contain other material.For example, said composition can contain second phase of two-phase system, for example PEG phase.Thereby, the preferred aspect of another one of the present invention comprises the method that reduces mammal blood glucose, this method comprises administration is contained the insulin for the treatment of effective dose and the compositions of host material, made after that this mammiferous blood glucose reduced by 30% at least 60 minutes to the administration suspension.Another preferred aspect of the present invention is the method to the administration suspension, and this method comprises the suspension to the insulin of Orally administered crystallized dextran microparticles of mammal and treatment effective dose.
As mentioned above, be used for insulin or other Orally administered crystallized dextran microparticles as host material based on proteic medicine can be prepared (for example, seeing Fig. 1) by any suitable method.Preferably, this microgranule is prepared by the method for any preferred embodiment described herein.Preferred but nonessential, this microgranule forms in the aqueous solution that does not have with an organic solvent.Thereby, of the present invention one preferred aspect, through after the crystallization, insulin and the combination in water of crystalline this dextran microparticles that will the treatment effective dose be to form the suspension of insulin and crystallized dextran microparticles at described microgranule.Can be before insulin be added entry, simultaneously and/or afterwards, this microgranule is added in the entry.And, can in the solvent that forms it, carry out Orally administered this microgranule to mammal.Selectively, this microgranule can be taken out from the solvent that forms it, and add in the entry or add other Orally administered aqueous solution or dry and provide with solid form is provided, for example be used for Orally administered tablet or capsule.
Preferably with crystallized dextran microparticles and the insulin for the treatment of effective dose (or other the suitable insulin and the suspension of host material, the suspension of insulin and microporosity microgranule for example) waterborne suspension provides as the pharmaceutical composition of customization dosage (dosed), the dosage of described compositions is customized to be suitable for (dosed for) and carry out Orally administered to the people.Of the present invention one preferred aspect, said composition is contained in the container, the amount in the container is customized to the dosage that the people is carried out single oral administration.This container can comprise any utensil that can hold suspension, for example plastic bottle or vial, pipe, dropper, nozzle, sack and/or other suitable container.This container is equipped with the suspension that is enough to be used in single agent oral dose compositions.
Of the present invention another preferred aspect, said composition is contained in any suitable container, the amount of compositions is to be suitable for repeatedly Orally administered dosage.Have in this container and be used for the people is carried out the description that peroral dosage form is used.This description can be imprinted on this container as be printed directly on the container or be imprinted on the label that is attached to this container, perhaps is attached to as is imprinted on a piece of paper that is attached to this container in carton or the medicated bag with this container.Frequency that the every dose of amount of composition that should take, this dosage should take can be described in description, how to estimate the dosage that is used for Orally administered compositions and/or any other at the practitioner of management health care and/or need the patient's of this medicine the guidance that is suitable for oral drugs.Replaceability ground, this description can comprise electronics or sound access about quantitatively and use the guidance of explanation, for example contain this explanation or telephone number website link or the SoundRec of this explanation is provided.
Of the present invention another preferred aspect, provide with the pharmaceutical composition kit form being contained in the crystallized dextran microparticles in the container and the waterborne suspension of insulin of treatment effective dose, this pharmaceutical composition test kit has the description that is used for the people who needs said composition is carried out Orally administered said composition.This test kit can comprise the description on the label that is imprinted on the description on this container or is attached to this container or be imprinted on description on a piece of paper that this container is attached to, for example in the carton or medicated bag that comprise bottle (being container) and described description.
What should be mentioned that is, described to be used for Orally administered compositions can be the waterborne suspension form, but also can use other form to reduce the blood glucose in the mammal.For example, porous crystallized dextran microparticles and insulin can be Orally administered with tablet or capsular form.
For said composition is Orally administered to mammal (for example people) with solid form, the solution of at first dry (for example lyophilizing) crystallized dextran microparticles and insulin is to form powder.Then this powder is pressed into tablet with pharmaceutically acceptable excipient arbitrarily, perhaps this powder is placed in the pharmaceutically acceptable capsule.
D. material
In a preferred version of the present invention, therapeutic agent contains insulin.In other words, insulin and other material be formed or be contained to this therapeutic agent can only by insulin basically.Term " insulin " should be interpreted as comprising the insulin that insulin human, cattle source and/or pig source that the insulin human, recombinant of insulin analog, natural extract produce extracts, pig and the insulin of cattle and the mixture of any of these insulin product that recombinant produces.This term is intended to comprise the polypeptide of the abundant purified form that is generally used for treating diabetes, but uses this term to comprise the medicament forms that it is purchased, and this medicament forms that is purchased comprises other excipient.Described insulin is preferably that reorganization produces and can is (bone dry) of dehydration or in solution.
Term " insulin analog ", " monomer insulin " etc. here use alternately, and be intended to comprise any type of aforesaid " insulin ", wherein, one or more aminoacid in this polypeptide chain have been replaced the aminoacid that aminoacid is replaced and/or wherein one or more aminoacid have lacked or wherein one or more are other and have been added on this polypeptide chain or the aminoacid sequence, and described polypeptide chain or aminoacid sequence work in the blood sugar lowering level as insulin.Usually, term in a preferred embodiment of the invention " insulin analog " comprises that the patent No. is No.5, " Semilente Insulin (insulin lispro) analog " that 547,929 United States Patent (USP) is disclosed is incorporated herein the full content of described patent by reference; Insulin analog comprises LysPro insulin and excellent pleasure (humalog) insulin of secreting, and other " super insulin analog ", wherein, compare with more activated liver selectivity insulin in liver than in fatty tissue with traditional insulin, the ability that described insulin analog influences the glucose level in the serum obtains sizable raising.Preferred analog is a monomeric insulin analog, and it is to be used for the Insulin-Like chemical compound identical with the main purpose of insulin, and for example, insulin lispro is promptly by using the chemical compound with the blood sugar lowering level.
Term " analog " is meant and is considered to the molecule suitable with it and has the molecule that common function is active and have the common structure feature usually.
Term " recombinant " is meant that the clone's who expresses of any kind therapeutic agent or genetic engineering molecule maybe can be processed to be another kind of state to form the combination molecule library of another combinatorial library, especially contain the molecule of the blocking group of physicochemical, the pharmacological and safety clinically that improves this therapeutic agent in prokaryotic cell.
Term " dextran microparticles " comprises the dextran microparticles of unsubstituted dextran microparticles and replacement.For example, the dextran microparticles of replacement comprises the glucosan that replaces with suitable group (for example methyl), and its replacement degree reaches the degree of the crystallization that do not damage this dextran microparticles (for example high to 3.5% or the branch of lower percentage ratio).The average diameter of microgranule is preferably about 0.5 micron～about 5 microns, more preferably about 1 micron～about 2 microns.
And, though preferably use porous noncrosslinking dextran microparticles (for example crystalline microgranule) with therapeutic agent, but also can substituting use other suitable organic or inorganic microgranule, for example other polymer particles comprises polysaccharide, PLA, PLGA, PMMA, polyimides, polyester, acrylate, acrylamide, vinyl acetate or other polymeric material; The biomaterial microgranule is alginate and cell for example; Perhaps for example silicon dioxide, glass or calcium phosphate of inorganic particle.Preferred this microgranule is biodegradable.Preferably, use the porous microgranule.Most preferably, this microgranule has enough porositys, with in the therapeutic agent accommodation hole, and provides the time control of this therapeutic agent from hole to discharge.In other words, this therapeutic agent is along with time course discharges from hole, for example surpasses 5 minutes, preferably surpasses 30 minutes, most preferably surpasses 1 hour, and for example a few hours are to a couple of days, rather than discharge suddenly.Therefore, can granular materials, aperture and pore volume be selected based on the environment and the other factors that persistent period, medicament will be delivered to of sending of used therapeutic agent type, the volume of sending required therapeutic agent, therapeutic agent.
Thereby, of the present invention one preferred aspect, therapeutic agent is arranged in the hole of this porous microgranule at least in part.Preferably, therapeutic agent is not encapsulated in the microgranule (that is, this microgranule does not have as the skin that therapeutic agent core wherein is housed) and is not attached on the surface of this microgranule.But if desired, except the hole that is arranged in this porous microgranule, a part of therapeutic agent also can be encapsulated in the microparticle shell and/or be attached on the surface of microgranule.The location of therapeutic agent in hole provides the optimum time control of this therapeutic agent to discharge.On the contrary, the common release of therapeutic agent that is attached to microparticle surfaces is too fast, and the therapeutic agent that is encapsulated in the microgranule often discharges soon inadequately, and discharges suddenly when this microparticle shell disintegrate.In two-phase system, at least 80% therapeutic agent is preferably placed in the wall or the outer nuclear that surrounds that is contained this microgranule.
E. preparation method
Can prepare described microgranule by any suitable method.Preferably, after this microgranule forms, with this microgranule and therapeutic agent combination.Like this, form microgranule (for example crystallized dextran microparticles), by any suitable method therapeutic agent and this microgranule are made up then by any suitable method.On the contrary, in some art methods, by particle-precursors material and therapeutic agent are provided in solution, then this precursor material (for example monomer or oligomer material) are carried out crystallization or crosslinked so that therapeutic agent core is encapsulated in the microparticle shell, thereby therapeutic agent is encapsulated in the microparticle shell.
Preferably, after microgranule forms, therapeutic agent is provided in the hole of this porous microgranule.Like this, at first form the porous microgranule, then therapeutic agent is provided in the solution that contains this microgranule, so that therapeutic agent infiltrates in the hole of this microgranule.Certainly, in this step, some therapeutic agents also can become the surface attached to this microgranule.
Thereby, the method for preparing noncrosslinking porous crystallized dextran microparticles comprises: preparation dextran solution (for example aqueous dextran solution), carry out crystallisation step to form crystalline porous dextran microparticles, and if desired, from solution, isolate crystalline porous dextran microparticles.By therapeutic agent is provided in the crystallization solution that contains microgranule or by will this isolating microgranule and this therapeutic agent be provided in the other solution in (for example other aqueous solution), thereby this therapeutic agent is infiltrated in the hole of this microgranule.For example, can in the first LMD aqueous solution, (for example dextran solution of 2kDa～20kDa) form crystallized dextran microparticles.Then this microgranule is taken out from first solution, put it in second glucan aqueous solution of the higher glucosan of molecular weight, the solution of 40kDa～500kDa for example, for example, the solution of 40kDa～75kDa.Second solution can contain first phase in the two-phase system, then with described second solution and second (the PEG phase that for example contains therapeutic agent) combination mutually.Similarly method can be used for other porous microgranule, wherein, behind any suitable microgranule formation method (including but not limited to crystallization) formation porous microgranule, this therapeutic agent is infiltrated in the hole of this microgranule.Can be with said composition equate that such as insulin, microgranule and one or more aqueouss composition is by any suitable order or make up simultaneously.
Preferably, described microgranule forms by self assembly in the solution that does not contain organic solvent and organic reaction promoter, and wherein said organic solvent and organic reaction promoter stay organic residual in microgranule.Thereby for example, dextran microparticles is preferably formed by self assembly by glucan aqueous solution.But, if desired, also can be with an organic solvent and/or organic reaction promoter.In this case, can before follow-up use, carry out purification to this microgranule, deleterious organic residual to remove.
As mentioned above, have first mutually nuclear wall or outer field capsule structure can be by two-phase compositions in vivo or external formation mutually with second.Said composition can be exsiccant powder, for example the freeze-dried powder of storing as powder or porous block.When preparation is applied to mammal with said composition, itself and aquation merging through port clothes are applied to mammal.
Preferably, the described compositions that comprises described microgranule and therapeutic agent is mobile gluey system.The example of the gluey system of described flowability comprises Emulsion and suspension.On the contrary, some prior art combinations are included in the glucosan hydrogel or the therapeutic agent in the crosslinked glucosan substrate.If do not carry out specific preparation, glucosan hydrogel and crosslinked glucosan substrate are not mobile compositionss.
Of the present invention another preferred aspect, described microgranule comprises that the mammal mucosa is had adhering microgranule.Preferably, described adhesiveness microgranule is above-mentioned porous microgranule.This has further promoted effectively sending of described therapeutic agent.
Of the present invention another preferred aspect, described microgranule comprise its surface through improved especially microgranule to improve described therapeutic agent to the adhesiveness of this microparticle surfaces and optimize sending of this therapeutic agent.This microparticle surfaces can contain adhering any improvement of suitable this therapeutic agent of raising.
The purpose that foregoing description of the present invention is provided is to carry out illustration and explanation, but not be intended to limit or limit the invention to disclosed precise forms, and under above-mentioned instruction, can make amendment and change, maybe can be obtained from the practice of the present invention modifications and variations.Selecting accompanying drawing and purpose of description is that principle of the present invention and practical application thereof are made an explanation.Scope of the present invention is intended to be limited by claims and its equivalent.
The all publications quoted in this description and patent application and patent all are incorporated herein by reference.
Claims (22)
1. have the porous crystallized dextran microparticles of at least 10 volume % porositys and insulin and be used for reducing application in the combination of oral medication of blood glucose of mammal in preparation, wherein insulin is not encapsulated in the described microgranule, and is arranged in the hole of described dextran microparticles to the small part insulin.
2. application as claimed in claim 1, wherein, it is 0.5 micron～5 microns the crystallized dextran microparticles and the waterborne suspension of insulin that described compositions comprises average diameter.
3. application as claimed in claim 2, wherein, the suspension of described compositions for the human oral that needs blood sugar lowering is used.
4. application as claimed in claim 1, this is applied as the combination of oral medication that preparation is used for the treatment of diabetes.
5. it is 0.5 micron～5 microns the crystallized dextran microparticles and the waterborne suspension of insulin that application as claimed in claim 4, wherein said compositions comprise average diameter.
6. application as claimed in claim 2, wherein, described microgranule makes the described insulin and the surface of this microgranule contact or be arranged in the hole of this microgranule for promptly crystalline porous microgranule before described insulin is joined suspension like this.
7. application as claimed in claim 2, wherein, the amount of described insulin is 10UI～2, the biosynthetic human insulin of 500UI/every gram suspension.
8. application as claimed in claim 1, wherein:
Described compositions comprises two-phase compositions, this two-phase compositions contain glucosan mutually with PEG mutually;
Described insulin optionally be assigned to PEG mutually in, described microgranule optionally be assigned to glucosan mutually in; With
In the time of in said composition is present in described mammalian body, said composition comprises the structure that contains PEG decentralized photo and glucosan continuous phase.
9. have the porous crystallized dextran microparticles of at least 10 volume % porositys and insulin and be used for application the Orally administered waterborne suspension of mammal in preparation, wherein insulin is not encapsulated in the described microgranule, and is arranged in the hole of described dextran microparticles to the small part insulin.
10. pharmaceutical composition that customizes dosage, this pharmaceutical composition comprises porous crystallized dextran microparticles with at least 10 volume % porositys and the insulin for the treatment of effective dose, wherein, insulin is not encapsulated in the described microgranule, and be arranged in the hole of described dextran microparticles to the small part insulin, and wherein, the dosage of described compositions is customized to is suitable for carrying out Orally administered the people.
11. compositions as claimed in claim 10, wherein:
Described crystallized dextran microparticles comprises the dextran molecule that combines by hydrogen bond, Van der Waals force or ionic bond, and does not have covalent bond basically between dextran molecule; With
Described crystallized dextran microparticles is that average diameter is 0.5 micron～5 microns a porous microgranule, and described like this insulin and the surface of this microgranule contact or be arranged in the hole of this microgranule.
12. compositions as claimed in claim 11, said composition comprise the waterborne suspension of the insulin of crystallized dextran microparticles and treatment effective dose.
13. compositions as claimed in claim 11, said composition comprise the tablet of the insulin that contains pharmaceutically acceptable mounting medium, crystallized dextran microparticles and treatment effective dose.
14. compositions as claimed in claim 11, said composition comprise the capsule of the insulin that contains pharmaceutically acceptable skin, crystallized dextran microparticles and treatment effective dose.
15. compositions as claimed in claim 11, wherein:
Described compositions comprises two-phase compositions, this two-phase compositions contain glucosan mutually with PEG mutually;
Described insulin optionally be assigned to PEG mutually in, described microgranule optionally be assigned to glucosan mutually in; With
Said composition is suitable for forming the structurized suspension that comprises PEG decentralized photo and glucosan continuous phase.
16. a pharmaceutical composition test kit, this pharmaceutical composition test kit comprises:
Be arranged in the crystallized dextran microparticles of container and the waterborne suspension of the insulin of treatment effective dose, wherein insulin is not encapsulated in the described microgranule, and is arranged in the hole of described dextran microparticles to the small part insulin; With
Be used for said composition is carried out Orally administered description to the people of needs.
17. a pharmaceutical kit, this pharmaceutical kit comprises:
Pharmaceutical composition, this pharmaceutical composition comprises porous crystallized dextran microparticles with at least 10 volume % porositys and the insulin for the treatment of effective dose, wherein insulin is not encapsulated in the described microgranule, and is arranged in the hole of described dextran microparticles to the small part insulin; With
The hold-up vessel that contains described compositions.
18. tablet, this tablet contains pharmaceutically acceptable mounting medium, has the porous crystallized dextran microparticles of at least 10 volume % porositys and the insulin of treatment effective dose, wherein insulin is not encapsulated in the described microgranule, and is arranged in the hole of described dextran microparticles to the small part insulin.
19. capsule, this capsule contains pharmaceutically acceptable skin, has the porous crystallized dextran microparticles of at least 10 volume % porositys and the insulin of treatment effective dose, wherein insulin is not encapsulated in the described microgranule, and is arranged in the hole of described dextran microparticles to the small part insulin.
20. a method for preparing the pharmaceutical composition that customizes dosage, this method comprises:
Porous crystallized dextran microparticles with at least 10 volume % porositys is provided;
After this dextran microparticles crystallization, insulin and this crystallized dextran microparticles of treatment effective dose are made up in solution, to form the compositions of insulin and crystallized dextran microparticles, wherein insulin is not encapsulated in the described microgranule, and is arranged in the hole of described dextran microparticles to the small part insulin; With
The dosage of said composition is customized to is suitable for carrying out Orally administered mammal.
21. method as claimed in claim 20, wherein:
Described compositions comprises mobile jelly composition; With
It is 0.5 micron～5 microns crystallized dextran microparticles that described microgranule comprises average diameter.
22. method as claimed in claim 21, wherein:
Described compositions comprises two-phase compositions, this two-phase compositions contain glucosan mutually with PEG mutually;
Described insulin optionally be assigned to PEG mutually in, described microgranule optionally be assigned to described glucosan mutually in; With
In the time of in said composition is present in described mammalian body, said composition comprises the structure that contains PEG decentralized photo and glucosan continuous phase.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45124503P | 2003-03-04 | 2003-03-04 | |
| US60/451,245 | 2003-03-04 | ||
| US60/467,601 | 2003-05-05 | ||
| US60/469,017 | 2003-05-09 | ||
| US60/495,097 | 2003-08-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1767850A CN1767850A (en) | 2006-05-03 |
| CN100588422C true CN100588422C (en) | 2010-02-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200480009197XA Expired - Fee Related CN100551439C (en) | 2003-03-04 | 2004-03-04 | Long lasting injectable insulin composition and preparation method thereof and using method |
| CN200480009195A Expired - Fee Related CN100588422C (en) | 2003-03-04 | 2004-03-04 | Oral insulin composition and methods of making and using thereof |
| CN 200480009181 Pending CN1767849A (en) | 2003-03-04 | 2004-03-04 | Delivery system for drug and cell therapy |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200480009197XA Expired - Fee Related CN100551439C (en) | 2003-03-04 | 2004-03-04 | Long lasting injectable insulin composition and preparation method thereof and using method |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480009181 Pending CN1767849A (en) | 2003-03-04 | 2004-03-04 | Delivery system for drug and cell therapy |
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| Country | Link |
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| CN (3) | CN100551439C (en) |
| ES (1) | ES2357719T3 (en) |
| ZA (3) | ZA200508023B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2739303B1 (en) * | 2011-08-07 | 2020-04-01 | Transgene Biotek Ltd. | A novel method for peroral delivery of insulin and its analogues for therapeutic usage |
| JP2021528424A (en) * | 2018-06-18 | 2021-10-21 | バイオコン・リミテッドＢｉｏｃｏｎ Ｌｉｍｉｔｅｄ | Methods and Uses to Control Postprandial Glucose Levels in Subjects |
-
2004
- 2004-03-04 CN CNB200480009197XA patent/CN100551439C/en not_active Expired - Fee Related
- 2004-03-04 ZA ZA200508023A patent/ZA200508023B/en unknown
- 2004-03-04 CN CN200480009195A patent/CN100588422C/en not_active Expired - Fee Related
- 2004-03-04 ZA ZA200508022A patent/ZA200508022B/en unknown
- 2004-03-04 ZA ZA200508021A patent/ZA200508021B/en unknown
- 2004-03-04 CN CN 200480009181 patent/CN1767849A/en active Pending
- 2004-03-04 ES ES04251251T patent/ES2357719T3/en not_active Expired - Lifetime
Non-Patent Citations (4)
| Title |
|---|
| Formation of dextran hydrogels by crystallization. R.J.H.Stenekes et al.Biomaterials,Vol.22 No.13. 2001 |
| Formation of dextran hydrogels by crystallization. R.J.H.Stenekes et al.Biomaterials,Vol.22 No.13. 2001 * |
| Regulated insulin release from biodegradable dextranhydrogels...... Kazuteru M. et al.Journal od Controlled Release,Vol.42 No.3. 1996 |
| Regulated insulin release from biodegradable dextranhydrogels...... Kazuteru M. et al.Journal od Controlled Release,Vol.42 No.3. 1996 * |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200508022B (en) | 2007-03-28 |
| CN1774263A (en) | 2006-05-17 |
| CN1767849A (en) | 2006-05-03 |
| ZA200508021B (en) | 2007-03-28 |
| CN100551439C (en) | 2009-10-21 |
| CN1767850A (en) | 2006-05-03 |
| ES2357719T3 (en) | 2011-04-29 |
| ZA200508023B (en) | 2007-03-28 |
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