CN101454019A - Rapid acting and long acting insulin combination formulations - Google Patents
Rapid acting and long acting insulin combination formulations Download PDFInfo
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- CN101454019A CN101454019A CNA2007800194503A CN200780019450A CN101454019A CN 101454019 A CN101454019 A CN 101454019A CN A2007800194503 A CNA2007800194503 A CN A2007800194503A CN 200780019450 A CN200780019450 A CN 200780019450A CN 101454019 A CN101454019 A CN 101454019A
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Abstract
An injectable formulation containing a combination of rapid acting insulin and long acting insulin has been developed wherein the pH of the rapid acting insulin is adjusted so that the long acting insulin, e.g. insulin glargine, remains soluble when they are mixed together. In the preferred embodiment, this injectable basal bolus insulin is administered before breakfast, provides adequate bolus insulin levels to cover the meal, does not produce hypoglycemia after the meal and provides adequate basal insulin for up to 24 hours. Lunch and dinner can be covered by two bolus injections of a fast acting, or a rapid acting or a very rapid acting insulin. Alternatively, through adjustment of the ratio of rapid acting insulin to long acting insulin, the long acting insulin may be shortened to a 12 hour formulation. This rapid and long acting blend is re-administered to the patient at dinner time, providing a safe and effective basal insulin level until morning. As a result, a patient using intensive insulin therapy should only inject three, rather than four, times a day.
Description
Background technology
Present invention relates in general to unite the preparation that uses Semilente Insulin and protamine zine insulin.
Present patent application requires the priority of following application: the name that Solomon S.Steiner and Roderike Pohl submitted on April 12nd, 2006 is called the application U.S.S.N 60/744 of the combination formulations of protamine zine insulin " quick-acting and ", 687, the name that Solomon S.Steiner and Roderike Pohl submitted in JIUYUE in 2006 on the 29th is called the application U.S.S.N 11/537 of the preparation of protamine zine insulin " quick-acting and ", 335, and the name that Solomon S.Steiner and Roderike Pohl submitted on April 2nd, 2007 is called the application U.S.S.N 11/695,562 of the combination formulations of protamine zine insulin " quick-acting and ".
The insulin strengthening therapy of diabetes relates to provides basal insulin (to it is desirable to, this basal insulin can be present in the blood with uniform level in 24 hours time limit), and bolus insulin or when having meal insulin (insulin during meal) thus reduce the increase of the carbohydrate load that the digestion accompaniment by each feed causes.
1936, Hans Christian Hagedorn and B.Noman Jensen found: the effect that the protamine that is obtained in " roe " by adding the effluent salmon or the seminal fluid can prolong insulin injection.Insulin joined in the protamine and with the pH regulator to 7 of this solution to be used for injection.In nineteen forty-six, Nordisk company can make the crystal of protamine and insulin, and the form listing with NPH (neutral protamine Hagedorn's, Neutral Protamine Hagedorn, " NPH ") insulin the 1950's.The advantage of NPH insulin is that it can mix with the insulin with onset performance faster, thereby reaches longer continuous action.Final all animal insulins are all replaced by the biosynthetic human insulin.
As of late, in current many places, still provide basal insulin usually by using two doses of NPH insulins (12 hours at interval) every day.Every day, edible breakfast, lunch and dinner and use NPH insulin were injected five insulins as patient's daily requirement of basal insulin: all will inject once when each in the breakfast, lunch and dinner is eaten, also will inject twice the NPH insulin in addition, once in the morning, another time is at h.d..In order to reduce the frequency injection that the patient must bear, during administration in morning NPH insulin, unite use with the analog of short-acting insulin (recombinant human insulin) or Semilente Insulin (as, insulin lispro).Associating occupation mode commonly used is the mixture of the Semilente Insulin analog of 70% NPH and 30%.As a result, the patient can reduce to four times a day five times from every day with frequency injection.For example referring to Garber, Drugs 66 (1): 31-49 (2006).
Nearer is insulin Glargine (trade name
) (insulin analog of a kind of " very long-acting ") emerge.About one hour of injection back it begin to make blood glucose to reduce and continuous action 24 hours equably.J.Rosenstock and colleagues thereof find to use the patient of insulin Glargine lower than the risk that the patient who uses the NPH insulin suffers from hypoglycemia (hypoglycemia).
Insulin Glargine can not be fugitive with other or Semilente Insulin mix, reason is that described mixture can cause insulin Glargine to precipitate before injection, sedimentary insulin takes place make and can not use known and reliable dosage in fact and use.The manufacturer of insulin Glargine warns user insulin Glargine not to be mixed with any other insulin.
Therefore the purpose of this invention is to provide a kind of insulin preparation, said preparation can be used for the frequency injection of every day is reduced to three times.
Another object of the present invention provides the insulin preparation of a kind of basis-heavy dose.
A further object of the present invention provides a kind of stable insulin preparation with instant-free characteristic and long-term release characteristics.
Summary of the invention
People have developed the combination formulations of quick or quick-acting-protamine zine insulin, wherein regulate described fast or the pH of Semilente Insulin, make that they can remain soluble state when Semilente Insulin and protamine zine insulin mix.Preferred embodiment be included in low pH down with any in imitate, the long-acting or unusual insulin preparation of any very fast, the rapid or quick acting that uses of long acting insulin combination.In another embodiment, under the condition that chelating agen exists, any very fast, rapid or quick insulin can be under low pH with any in imitate, long-acting or very long acting insulin combination use.In most preferred embodiment, VIAject
TM(a kind of very Semilente Insulin) mixes with insulin Glargine under pH4, thereby makes insulin concentration in the blood produce initial spike rapidly reducing the carbohydrate that is absorbed in the digest by food, and makes that the concentration of basal insulin remains unchanged in the blood.
When early before the meal with injectable heavy dose of basal insulin preparation and quick-acting or when very Semilente Insulin is used jointly, it can provide enough bolus insulin levels so that have meal, and hypoglycemia can not take place after the meal and 24 hours enough basal insulins can be provided.When lunch and dinner, can inject heavy dose of quick acting insulin twice, perhaps once quick-acting the or unusual Semilente Insulin of injection.As a result, the patient who has used insulin strengthening to treat only injects three every day and gets final product, rather than four times.
People are by testing to add the importance of specific acid (as aspartic acid, glutamic acid, maleic acid, fumaric acid or succinic acid) verified in six aggressiveness insulins, it can improve infiltration rate and absorbtivity and can still keep biological activity after it is dissociated into dimer/monomeric form.Can also add chelating agen in addition, preferably add ethylenediaminetetraacetic acid (EDTA).No matter how the source of insulin (comprises natural insulin, Recombulin, protamine zine insulin, Iletin II (Lilly), bovine insulin and their insulin derivates and analog), can select polyprotic acid based on the molecular size and the structure of polyprotic acid, with the association in optimization polyprotic acid and the lip-deep hydrogen bonded of insulin site, thereby shield charged amino acid residue (Fig. 1) effectively.Under the concentration that can obtain optimum electron screening effect, use these acid (as shown in the Examples, preferred acid is aspartic acid, glutamic acid, succinic acid, maleic acid, fumaric acid and citric acid).In insulin preparation, unite the reason of using preferred acid and chelating agen seemingly to cause insulin to absorb rapidly simultaneously.EDTA is not all effective to all acid.When EDTA and adipic acid, oxalic acid or HCl together used, the infiltration rate of insulin did not obviously increase.Acid and chelating agen importance in (rat, pig and people) research in external (human oral cavity epithelial cell) and body have been set up in these researchs.These discoveries have confirmed viewed result in the diabetics that uses unusual Semilente Insulin (unite and use citric acid and EDTA) and basic insulin Glargine to treat.
Brief Description Of Drawings
Fig. 1 is the schematic three dimensional views that demonstrates the insulin of electric charge.
Fig. 2 is the figure that is used to measure the Transwell device of the insulin that absorbs by mouth epithelial cells.
Fig. 3 for have in inoculation average insulin cumulant (μ U) in the following chamber of epithelial Transwell lamina membranacea in time (minute) figure that changes, in the figure, the insulin preparation (◆) that contains EDTA, insulin preparation (■) and the not celliferous contrast liquid (▲) that does not contain EDTA are compared.
Fig. 4 is being for uniting in the sample of use with citric acid and EDTA, with citric acid but do not uniting in the sample of use with EDTA and uniting in the sample of use with aspartic acid and EDTA, accumulation insulin (U) in time (minute) figure that changes.
Fig. 5 for EDTA unite the insulin (solid line) of use and not with EDTA unite use insulin (hacures) the sample that contains citric acid, glutamic acid, adipic acid or oxalic acid the insulin apparent permeability in time (minute) variation figure.
Fig. 6 be glucose from the decline percentage rate of baseline in time (minute) figure that changes, in the figure, to uniting the insulin of use with aspartic acid and EDTA and comparing in the intravital situation of rat with insulin that HCl and EDTA unite use.
Fig. 7 is the time dependent figure of average glucose level of miniature pig, in the figure, and to uniting the insulin of use with EDTA and citric acid and comparing with insulin that EDTA and HCl unite use.
Fig. 8 be from human clinical trial's continuous blood sugar value in time (hour) figure that changes, wherein, insulin Glargine (
) and VIAject used (injecting twice) respectively separately, perhaps co-administered in a shot.
Detailed Description Of The Invention
I. composition
A. insulin
Described composition comprises quick acting, quick-acting or very quick-acting insulin and middle effect or length Effect insulin. Described Semilente Insulin is adjusted to low pH, under this pH, works as quick-acting pancreases The island is plain when mixing with protamine zine insulin, though their ratio in wider scope, Protamine zine insulin can not precipitate yet.
There is the commercially available insulin of number of different types to be applicable to diabetics.The type of these insulins is according to following situation and difference: their need the level that how long just can enter in the blood flow and begin blood sugar lowering (1); (2) insulin can be brought into play effect how long under maximum effect; And (3) insulin can continue to produce effect how long to blood glucose.
The quick acting insulin
The quick acting insulin be intended to in the dining process by the glucose generation effect that digest produced of carbohydrate.The quick acting insulin began to play a role in 1 to 20 minute, reached peak value after about one hour, and continuous action three to five hours.The quick acting insulin requirement could be absorbed in the body circulation in about two hours fully.The quick acting insulin comprises that conventional recombinant human insulin (lists a company as Lilly
, and NovoNordisk lists a company
), it is applied in pH is 7 isosmotic solution.Bovine insulin also is the quick acting insulin with Iletin II (Lilly) (although there is several amino acid different with insulin human, they are biologically active in human body).
Semilente Insulin
Some diabeticss use Semilente Insulin at table, and use protamine zine insulin to continue insulin as " background ".This group insulin comprises the insulin that adorned insulin or amino acid sites have changed for the infiltration rate of improving them.
Three kinds of commercially available Semilente Insulin analog are arranged at present: insulin lispro (Eli Lilly company with
The Lys-Pro insulin that title is sold), rely the paddy insulin (Sanofi-Aventis company with
Title is sold) and insulin aspart (NovoNordisk company with
Title is sold).
Unusual Semilente Insulin
Biodel company has the insulin preparation of Patent right a kind of conventional insulin human, itself in addition than the analog-VIAJECT of Semilente Insulin
TM-quicker.This be a kind of be the preparation of under the condition under 4 conventional insulin human and EDTA and citric acid being united use at pH.
Intermediate-acting insulins
The expected endurance of intermediate-acting insulins is than the intended performance limit for length of short-acting insulin, but the former onset is slow and need the longer time just can reach its maximum effectiveness.Intermediate-acting insulins onset in 2-4 hour after injection usually reached peak efficacy in about 4-14 hour and continuous action reaches 24 hours.The type of intermediate-acting insulins comprises: NPH (neutral protamine Hagedorn's) insulin and LENTE insulin.The protamine that contains the infiltration rate that can slow down in the NPH insulin makes the longer time of this insulin requirement just can enter into blood flow, but it has peak value and the expected endurance of longer time.Intermediate-acting insulins can be united use with Semilente Insulin under neutral pH, thus the total frequency injection that reduces every day.
Protamine zine insulin
LANTUS
TM(insulin Glargine) is a kind of recombinant human insulin's analog, and it can have and reaches 24 hours persistent period.The difference part of it and insulin human is that the former has glycine rather than agedoite on 21, and is combined with two arginine on the carboxyl terminal of β chain.LANTUS
TMForm by the insulin Glargine (85% glycerol of 100IU, 3.6378mg insulin Glargine, 30mg zinc, 2.7mg metacresol, 20mg adds water to 1ml) that is dissolved in the clarifying aqueous fluids.With HCl pH is transferred to 4.
After the injection, the middle bit time between finishing from the start injection to the drug effect is 24 hours to the maximum.For insulin Glargine, after the injection, the middle bit time between finishing from the start injection to the drug effect is 24 hours, and for the NPH insulin human, bit time is 14.5 hours in this.
Different with intermediate-acting insulins with most of Semilente Insulins is, because this insulin produces precipitation when mixing, so indicates not with LANTUS on the package insert
TMMix with the insulin of other any kinds.
Under the situation of insulin Glargine, as the Viaject that with itself and pH also is 4
TMDo not generate precipitation during mixing, so Viaject
TMBe complementary with insulin Glargine.Finally, this unite to use a kind of very Semilente Insulin is provided, thereby make the patient in the dining process, use bolus insulin still less, this be because after meals digestion this very Semilente Insulin can very rapidly be absorbed and elimination speed slower, thereby reduced the generation probability of hypoglycemia, and 24 hours for a long time lasting basal insulin can be provided.This finally can every day is required frequency injection reduce to three times from four times.
B. acid stabilizer and chelating agen
Acid stabilizer
The dissolved effectively acid of crystallinity six aggressiveness insulins can be selected based on their molecular size and pKa, and estimate that these acid can shield the electric charge (Fig. 1) that exposes on it most effectively when insulin molecule is dissociated into monomer or dimeric forms.When six aggressiveness insulins were dissociated into monomeric form, specific acid can keep biological activity, shield electric charge and improve infiltration rate effectively.Embodiment (rat, pig and people) all demonstrates the importance of acid in external embodiment (human oral cavity epithelial cell) and the body.With HCl with conventional insulin human
Dissolving, and under physiological pH, prepare.The pharmacokinetics collection of illustrative plates of this insulin shows that this insulin is not very rapidly absorbed, but just occurs insulin peak concentration after administration in about two hours.
Preferred acid is " polyprotic acid ", promptly contains the acid of a plurality of acidic residues.Preferred polyprotic acid comprises: aspartic acid, glutamic acid, succinic acid, fumaric acid, maleic acid and citric acid.For every milliliter of solution that contains 0.5 to 4mg insulin, the useful concentration range of acid is 0.1 to 3mg/ml.The scope of pH is 3.0 to 4.2, and preferable range is 3.8 to 4.1.These acid can be united use with reduction pH with any Semilente Insulin, and they can be dissolved when mixing with Lantus.
Chelating agen
In preferred embodiments, chelating agen mixes with active substance.Except the main effect in the chelating process, it is believed that chelating agen also with insulin generation hydrogen bonded, thereby shield electric charge and promote the absorption of insulin.It is believed that chelating agen pulls away zinc from insulin, thereby after insulin was injected into subcutaneous tissue (for example, mucosa or fatty tissue), with respect to six aggressiveness forms, this insulin more advantageously remained monomeric form.Promoted the absorption of insulin by remaining monomeric form.In addition, described chelating agen is also sheltered or is shielded and help absorb by being exposed to surface charge on the insulin molecule.
Described chelating agen can be ion-type or nonionic.Suitable chelating agen comprises: ethylenediaminetetraacetic acid (EDTA), citric acid, dimercaptopropanol, BAL (BAL), penicillamine, alginic acid, chlorella, cilantro, alpha-lipoic acid, dimercaptosuccinic acid (DMSA), dimercaptopropane sulphonate salt (DMPS) and oxalic acid.In preferred embodiments, chelating agen is EDTA.Ion can be that a part, the ion of active substance can join in the stabilizing agent, ion can mix with chelating agen and/or ion can be contained in the coating.Representative ion comprises: the ion of zinc ion, calcium ion, iron ion, manganese ion, magnesium ion, aluminium ion, cobalt ion, copper ion or any divalent metal or transition metal.With Ca
+ 2Compare Zn
+ 2Stronger with the binding energy (binding preference) of EDTA.
C. preparation
Reactive compound or its pharmaceutically useful salt can be used with the form of pharmaceutical composition, and wherein this reactive compound is with one or more pharmaceutically useful carriers, excipient or diluent fusion or mix.In preferred embodiments, come administration of insulin by injection.Alternatively, compositions can be used by the mode of oral, oral cavity, Sublingual, vagina, rectum or nasal administration.
Liquid preparation
Liquid preparation can or spray to carry out nasal cavity, Sublingual, vagina or oral administration by injection (subcutaneous injection, intramuscular injection, lumbar injection).Injection preparation is suspended in sterilized water, phosphate buffered saline (PBS), saline or the glycerol usually.Other suitable pharmaceutically acceptable reagent also are known.Usually these reagent are joined in the insulin that is in lyophilizing or dried forms with preceding shortly, but also can add before use.Solubilizing agent comprises: wetting agent (as, polysorbate and poloxamer), nonionic and ionic surfactant material, acid condiment and the agent (for example sodium bicarbonate) of food alkali flavor, alcohols and control pH buffering acid or the salt used.Fig. 8 shows human clinical trial's the data of the injectable mixture of Viaject and insulin Glargine.
Solid preparation
Solid or semi-solid gel can be by preparation to be used for subcutaneous injection (the low viscosity gel of available injector to inject) or to be dried to thin film with the oral cavity that is used for the economic benefits and social benefits insulin, Sublingual, oral, rectum or vaginal application.They can be by sneaking into one or more hydrophilic polymeies in solution, and gelation or solidify forms by ionic bond and/or covalent bond.Suitable material includes, but is not limited to: starch, pre-gelatinized starch, gelatin, saccharide (comprises sucrose, glucose, dextrose, lactose and sorbitol), chitosan (various forms), dextrin, maltodextrin, Polyethylene Glycol, wax, natural and rubber polymer (as, arabic gum, guar gum, tragacanth, alginate, sodium alginate), cellulose (comprises hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, ethyl cellulose, methylcellulose), and modification aluminium-magnesium silicate, hydrogenated vegetable oil, I type aluminium-magnesium silicate, and synthetic polymer (as, acrylic acid and methylpropanoic acid alkene copolymer, carbomer, methacrylic acid copolymer, methylmethacrylate copolymer, the amino alkanol ester copolymer of methacrylic acid, the poly propenoic acid methacrylic, polyvinylpyrrolidone).Mixing method or copolymerization method (this method is enough to give hydrophilic to a certain degree) can be used for improving the wettability and the mucosa-adherent of material.For example, about 5% to about 20% monomer can be used as hydrophilic monomer.Hydrophilic polymer (as, hydroxypropyl cellulose (HPC), hydroxypropyl emthylcellulose (HPMC), carboxymethyl cellulose (CMC)) be generally used for this purpose.Preferably, described polymer is for biological erosion property, and its preferred molecular weight range is 1000 to 15, and 000Da most preferably is 2000 to 5000Da.These polymer also can be non-ionic polyalcohols, for example ethylene glycol monostearate, propylene glycol myristinate, glyceryl monostearate, tristerin, polyglycereol-4-oleate, anhydrous sorbitol acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, Vinlub 73, polysorbate, NONIN HS 240, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether,
401, stearyl monoisopropanolamine and polyethylene glycol hydrogenated Adeps Bovis seu Bubali amide.The example of amophoteric surface active material comprises: N-dodecyl-Beta-alanine sodium, N-lauryl-β-imino-diacetic sodium propionate, myristoyl both sexes guanidine-acetic acid salt, empgen BB and dodecyl sulfobetaines.
In one embodiment, described preparation is for containing the Sublingual solid preparation of excipient (as poly-(vinyl alcohol), glycerol, carboxymethyl cellulose (CMC), chitosan and optional poly-(ethylene glycol) and water).That said composition can be is transparent or opaque, it is flexible to have, the form of thin material.General thickness range is 0.01 to 4mm.This thin film can have any suitable shape, comprises circle, ellipse, rectangle or square.This thin film can be monolayer, bilayer or trilamellar membrane.In preferred embodiments, described thin film is designed to be suitable for the form of sublingual administration.Single thin film contains active substance and one or more excipient.Bilayer film contains one or more excipient, for example contains solubilizing agent and/or metal-chelator in ground floor, contains active substance in the second layer.With (if) situation that contains excipient and active substance in single one deck compares, this structure makes active substance and excipient separate storage can improve active agent stability, and can randomly improve the storage life of compositions.Three-layer thin-film comprises trilamellar membrane.Each tunic can be different, and perhaps two-layer (for example bottom and top layer) in the trilamellar membrane can have identical composition basically.In one embodiment, bottom and top layer clip the sandwich layer that contains active substance.Bottom and top layer can contain one or more excipient (for example, solubilizing agent and metal-chelator).Preferably, bottom has identical composition with top layer.Alternatively, bottom can contain different excipient with top layer, or contains not commensurability identical excipient.Sandwich layer contains insulin usually, and can randomly contain one or more excipient.In one embodiment, this film is such bilayer film: contain EDTA and citric acid in one deck, contain insulin in the second layer.Every layer can contain other excipient (as glycerol, polyvinyl alcohol, carboxymethyl cellulose and optional PEG (as PEG400 or PEG1600)).In one embodiment, the 3rd layer can place insulin layers and contain between the layer of other compositions, thereby further protects active substance can not be subjected to placing the infringement of the degradability composition of other layers in storage process.The suitable material that is used for protective layer comprises: sodium carboxymethyl cellulose, Brazil wax, cellulose acetate phthalate, hexadecanol, the broken sugar of close grain, ethyl cellulose, gelatin, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, liquid glucose, maltodextrin, methylcellulose, microwax, polymethacrylates, polyvinyl alcohol, Lac, sucrose, Talcum, titanium dioxide and zeatin.For absorption feature and the follow-up effect that reaches expectation,, this film can be designed to rapid dissolving (less than 30 seconds) or dissolving (reaching 15 minutes) at a slow speed by changing the composition of excipient.This film can dissolve in the time bar of 3 to 5 minutes, 5 to 8 minutes or 8 to 15 minutes.Preferably, this film dissolves in 2 to 10 minutes time bar.
Many commercially available coloring agent and flavoring agent are arranged.Flavoring agent comprises Herba Menthae, Fructus Citri Limoniae, Fructus Pruni pseudocerasi, bubble gum and other standard flavoring agents.Can add sweeting agent (comprising sugar-free sweetener), this is particularly conducive to using of insulin.It is red, blue, green, yellow, orange that coloring agent can be, or other any Standard Colors of FDC permission.
Stabilizing agent is used to suppress or postpone the decomposition reaction (for example comprising oxidation reaction) of medicine.Can use many stabilizing agents.Suitable stabilizers comprises: polysaccharide (as cellulose and cellulose derivative); Simple alcohol (as glycerol); Antibacterial (as phenol, metacresol and methyl hydroxybenzoate); Isotonic agent (as sodium chloride, glycerol and glucose); Lecithin (for example, natural phosphatidyl choline (for example Ovum Gallus domesticus Flavus lecithin or soybean lecithin) and synthetic or semi-synthetic lecithin (as dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline or distearoyl phosphatidylcholine)); Phosphatidic acid; PHOSPHATIDYL ETHANOLAMINE; Phosphatidylserine (for example, distearyl Phosphatidylserine, two palmityl Phosphatidylserine and two Semen arachidis hypogaeae tetraene acyl Phosphatidylserine); Phosphatidyl glycerol; Phosphatidylinositols; Cuorin; Sphingomyelins; And synthectic detergents (as two caprylyl phosphatidylcholine and polyethylene-polypropylene glycols).Other suitable stabilizers comprise: arabic gum, albumin, alginic acid, bentonite, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, cyclodextrin, glyceryl monostearate, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, aluminium-magnesium silicate, propylene glycol, propylene glycol alginate, sodium alginate, white beeswax, xanthan gum and Cera Flava.In preferred embodiments, active substance is an insulin, and stabilizing agent can be the combination of one or more polysaccharide and glycerol, antibacterial, isotonic agent, lecithin or synthectic detergents.
II. the preparation method of preparation
Can use the last acceptable carrier (it comprises excipient and auxiliary agent) of one or more physiologys to come compounding pharmaceutical compositions, wherein said carrier to help reactive compound is processed in a conventional manner can be by medicinal preparation.For example, the compound method of medicine is at Hoover, John E., Pharmaceutical Sciences that Remington writes (Mack publishing company, Easton, pennsylvania, USA (1975)) and Liberman, H.A. and Lachman, L. discuss to some extent among the Pharmaceutical Dosage Forms that writes (Marcel Decker, New York, New York, United States (1980)).Appropriate formulation depends on selected route of administration.
III. the using method of preparation
Described preparation can be used in many ways, comprise injecting using (preferred subcutaneous injection), or local application (as oral, oral cavity, nasal cavity, Sublingual, rectum, vagina, pulmonary or ocular administration) is to mucomembranous surface.Preferred subcutaneous injection, oral cavity or sublingual administration.After using, dosage form is dissolved fast, thereby discharges medicine or formation contains the medicine granule of (can randomly contain one or more excipient).Described preparation is designed, so that it is by fast Absorption and be delivered in the blood plasma and send to carry out system.
In preferred embodiments, described preparation forms by Powdered active substance is mixed with liquid diluent, and wherein said liquid diluent contains pharmaceutically useful liquid-carrier and one or more solubilizing agents.In the most preferred embodiment, active substance is an insulin, comprises salt or glycerol, EDTA and citric acid in the diluent.Before using powder and mixing diluents are in the same place, thereby form injectable compositions.
Will be further understood that the present invention with reference to following non-limiting instance.
Embodiment 1:EDTA is to the effect by the multiwalled absorption of insulin of epithelial cell
Purpose: confirm in vitro tests to have under the condition of citric acid EDTA to effect by the multiwalled absorption of insulin of epithelial cell.
Material and method:
With two kinds of salt solution mix, thereby obtain to contain the solution (" solution 1 ") of 1mg/ml insulin, 2mg/ml EDTA and 2mg/ml citric acid or contain the solution (" solution 2 ") of 1mg/ml insulin and 2mg/ml citric acid.Contrast liquid (acellular) contains EDTA, citric acid and insulin.The human oral cavity epithelial cell strain culture of infinite multiplication is inoculated in (Fig. 2) on the transwell plate.The cell growth is merged, and utilize the transepithelial electrical resistance method to detect the integrity of film.When the time is zero, replace the liquid in the last chamber of transwell plate with 0.5ml insulin solutions (that is, solution 1 or solution 2).Simultaneously the test contain solution 1 two boards, contain the two boards of solution 2 and contain the contrast liquid (acellular) a plate.Contain the 1.5ml saline solution in the following chamber of every block of plate.From following chamber, take out 100 μ L liquid at each time point, and analyze with insulin enzyme linked immunosorbent assay analysis method (ELISA).Add 100 μ L saline in the chamber so that in whole research process, keep the constancy of volume of 1.5mL downwards.The amount of the insulin that will take out from following chamber at each time point adds the amount of the insulin that time point took out in front, with the cumulative amount of the insulin determining to recover in the infra chamber.Pair cell dyes with the viability of cell before and after the checkout facility.Cell survival on each plate does not have significant difference.
The result:
Fig. 3 for have in inoculation average insulin cumulant (μ U) in the following chamber of epithelial Transwell plate in time (minute) figure that changes, in the figure, the insulin preparation (◆) that contains EDTA, insulin preparation (■) and the not celliferous contrast liquid (▲) that does not contain EDTA are compared.
Compare with the solution 2 that does not contain EDTA, the solution 1 that contains EDTA is more effectively by epithelial multilamellar.Therefore, EDTA and citric acid are united infiltration rate and the absorbtivity that effect that use produces is to promote insulin.
Embodiment 2: aspartic acid and citric acid are to the effect by the multiwalled absorption of insulin of epithelial cell
Purpose: increase shownly as the insulin absorption that sees through cell, confirmed that polyprotic acid is for having different affinitys with insulin that EDTA unites use.
Method and material:
As described in embodiment 1, use the mouth epithelial cells that is inoculated on the transwell plate to determine to see through the multiwalled absorption of insulin speed of cell.Insulin (1mg/ml) is dissolved in aspartic acid (0.2mg/ml) or the citric acid (2mg/ml), and all adds EDTA (2mg/ml) among both.The insulin (no EDTA) that to unite use with citric acid in contrast.The pH of solution is about 3.5 to 4, and there is normal saline (0.85% NaCl, be enough to produce the osmotic pressure of 280-310mOsm, this osmotic pressure value is the Microsmette that adopts the Precision systems company be positioned at Massachusetts, United States Natick city to produce, utilizes cryoscopic method to measure) so that ooze environment for cell provides etc.By taking out in the receiving chamber, and utilize ELISA (Linco company) to detect biosynthetic human insulin (μ U/ml) in sample.
The result:
Shown in embodiment 2, by adding EDTA, the absorption that sees through the insulin/citric acid of cellular layer is improved.Yet, as shown in Figure 4, the transhipment that aspartic acid more effectively improves insulin under the condition that EDTA exists.
Conclusion:
Under the condition that EDTA exists, different polyprotic acid is to the effect difference of absorption of insulin, and this may be because the different cause of electron screening degree.
Embodiment 3: relatively citric acid, glutamic acid, adipic acid and oxalic acid are to the effect by the multiwalled absorption of insulin of epithelial cell
Material and method:
Use inoculation to have the transwell plate of mouth epithelial cells to carry out these tests.Monitor the effect of EDTA according to the amount that sees through the insulin of chamber under the transwell plate.
Mouth epithelial cells was grown for 2 weeks on plug-in type transwell plate, till forming multilamellar (4-5 layer) cellular layer.By joining suitable solution (insulin human that all contains 1mg/ml) in the supply hole (donor well) and after 10 minutes, from receiver hole, taking out sample and transport research.Adopt the ELISA method to analyze the amount of insulin in the receiver hole.Utilize following formula to calculate apparent permeability: apparent permeability=Q/A (C) t, wherein Q is the total infiltration capacity (μ g) in incubation time, A is for inserting the area (cm of plate
2), C is initial concentration (the μ g/cm in the supply hole
3), t is total test period (second).
The concentration of EDTA is 0.45mg/ml in all situations, and the concentration of acid is as follows: citric acid 0.57mg/ml, glutamic acid 0.74mg/ml, adipic acid 0.47mg/ml, oxalic acid 0.32mg/ml.The pH of solution is 3.6 in all situations.
The result:
Fig. 5 shows and exists and do not exist under the condition of EDTA, the variation of the apparent permeability that is obtained by detected different organic multicomponent acid.The result shows that in the situation of citric acid and glutamic acid when joining EDTA in acid/insulin, the cumulant of insulin apparent permeability increases.Be not all to be such for all organic multicomponent acid.Adipic acid and oxalic acid just do not demonstrate such reaction.
Embodiment 4: acid is to the effect of the absorption of the insulin in the polymer gel that is administered to rat by the rectal administration mode
Purpose: observe the effect of acid and EDTA in vivo in the model
Material and method:
Sample
By mixing mutually with insulin/aspartic acid or insulin/HCl, with the insulin enclose in the gel that constitutes by PVA (0.5%), Carbopol (2.7%), CMC (0.005%) and PEG 400 (0.14%), glycerol (0.14%) and EDTA (0.005%).The ultimate density of insulin is 0.7mg/g in insulin/aspartic acid gel, and the ultimate density of insulin is 1.7mg/g in insulin/HCl gel.
The research of rat rectum:
The rat overnight fasting is also cleared up all Excretas with the warm water enema agent.Then gel preparation is inserted rectum, and monitored rat blood sugar 8 hours.
The result:
The result the figure shows and will unite the insulin of use with aspartic acid and EDTA and when comparing with insulin that HCl and EDTA unite use, the percentage rate that glucose reduces from baseline as shown in Figure 6.The result shows with the insulin that contains HCl and compares that the insulin that contains aspartic acid has obviously better glucose reduction rate.
Embodiment 5: relatively HCl and citric acid pair are united the effect of the insulin of use in the intravital absorption of small-sized diabetes pig with EDTA
Purpose: the response time of observing glucose when insulin is injected with polyprotic acid or organic acid and united use with EDTA.
Material and method:
In order further to confirm the importance of the type of acid, in the miniature pig body of suffering from diabetes, citric acid and HCl are compared dissociated insulin quick acting.(0.9mg/ml) makes clarifying isosmotic solution with insulin, and this solution contains citric acid (1.8mg/ml), EDTA (1.8mg/ml) and as the metacresol of antiseptic, the pH of this solution is about 4.Prepare the contrasting fluid in the same way, difference is to replace citric acid with HCl (0.001N), and is about 4 with NaOH adjusting pH.
Do not give the miniature pig that suffers from diabetes feed the same day in research, and gave the HCl preparation that dosage is 0.08U/kg at three time points.As a comparison, give the citric acid preparation of this dosage at two time points, and give the more citric acid preparation of high dose 0.125U/kg at other four time points in addition.Blood drawing is to be determined at insulin and glucose in 8 hours research time limits.
The result:
Fig. 7 shows the result, and this result has compared the time that reaches minimum glucose level (minimum point) after giving the miniature pig administration of insulin of suffering from diabetes.Compare with using the prepared same preparation of HCl, the citric acid preparation always touches the bottom quickly.
Embodiment 6: insulin Glargine and Viaject
TMUse to diabetics separately together or respectively
Material and method:
Stablize 9 patients (5 male 4 woman by glucose clamp technology; Age is 40 ± 10 years old, and Body Mass Index (" BMI ") is 24.0 ± 2.0kg/m
2) blood glucose (" BG ") (target BG is 120mg/dl).Before the administration, stop the infusion glucose.Use the orthogonal design treat order at random, giving the VIAject of same patient's subcutaneous injection given dose before the meal immediately
TMAnd Lantus.In a kind of situation, in once injecting, using above-mentioned two kinds of preparations together.In another kind of situation, each insulin of individual application same dose in double injection respectively.Continuous monitoring blood glucose 8 hours if BG is lower than 60mg/dl, then restarts the infusion glucose.In whole research process, measure the insulin level in the blood plasma.
The result:
Fig. 8 shows the figure that the average blood sugar value changed in first three hours.Both have very similarly curve in first three hours, and this is the quick-acting Viaject in back that has meal
TMTypical case.
Claims (16)
1. compositions, it contains the quick acting that uses with middle effect or long acting insulin combination, quick-acting or very quick-acting insulins, and the pH that wherein regulates described compositions is to dissolve described protamine zine insulin.
2. compositions as claimed in claim 1, it contains insulin Glargine.
3. compositions as claimed in claim 1, it also contains Semilente Insulin.
4. compositions as claimed in claim 1, it also contains intermediate-acting insulins.
5. compositions as claimed in claim 1, the pH of said composition is 3.0-4.2.
6. compositions as claimed in claim 1, it contains the chelating agen that is selected from following group, and described group by ethylenediaminetetraacetic acid (EDTA), dimercaptopropanol, BAL (BAL), penicillamine, alginic acid, chlorella, cilantro, alpha-lipoic acid, dimercaptosuccinic acid (DMSA), dimercaptopropane sulphonate salt (DMPS) and oxalic acid formation.
7. compositions as claimed in claim 6, wherein said chelating agen are ethylenediaminetetraacetic acid (EDTA).
8. compositions as claimed in claim 1, it contains the acid that is selected from following group, and described group is made of aspartic acid, glutamic acid, maleic acid, fumaric acid, succinic acid and citric acid.
9. insulin preparation, it contains: be selected from by the insulin in Semilente Insulin, protamine zine insulin and their group that constitutes, be selected from the acid in the group that constitutes by aspartic acid, glutamic acid, succinic acid, maleic acid, fumaric acid or citric acid, insulin and chelating agen.
10. preparation as claimed in claim 9, it contains EDTA.
11. preparation as claimed in claim 9, it contains citric acid.
12. preparation as claimed in claim 9, it contains the proportional Semilente Insulin of 1:2:2 that is.
13. being the derivant of natural human insulin, recombinant human insulin, Iletin II (Lilly), bovine insulin, insulin human or be fit to, preparation as claimed in claim 9, wherein said insulin be applied to the analog of people's insulin human.
14. a method that makes the insulinize patient, this method comprise any described compositions among the claim 1-13 is applied to the individual.
15. method as claimed in claim 14, wherein said insulin is used by injection.
16. being included in, method as claimed in claim 14, wherein said insulin adopt in the preparation that Sublingual, oral, nasal cavity, oral cavity, rectum or vaginal application mode use.
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| US74468706P | 2006-04-12 | 2006-04-12 | |
| US60/744,687 | 2006-04-12 | ||
| US11/537,335 | 2006-09-29 | ||
| US11/695,562 | 2007-04-02 |
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