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CN1027225C - Composition containing calcitonin and its preparation method - Google Patents

Composition containing calcitonin and its preparation method Download PDF

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Publication number
CN1027225C
CN1027225C CN88107895A CN88107895A CN1027225C CN 1027225 C CN1027225 C CN 1027225C CN 88107895 A CN88107895 A CN 88107895A CN 88107895 A CN88107895 A CN 88107895A CN 1027225 C CN1027225 C CN 1027225C
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calcitonin
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glycyrrhetate
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anguilla japonica
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CN1033568A (en
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瓦莱里奥·阿利韦蒂
卢恰诺·多里戈蒂
泰奥多罗·福尼奥
马利奥·平扎
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

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Abstract

The present invention relates to novel pharmaceutical compositions containing calcitonin and novel methods for increasing absorption of calcitonin across the mucosa. The pharmaceutical composition comprises a calcitonin, an effective amount of an absorption enhancer, a glycyrrhizinate salt and a pharmaceutically acceptable carrier. The method comprises combining calcitonin and a salt of glycyrrhizic acid. The glycyrrhetate is ammonium glycyrrhetate, and its concentration in the composition is at least 0.1% (W/W) of the total composition.

Description

Pharmacentical composition containing calcitonins and process for preparing same
The present invention relates to contain the novel medicament compositions of calcitonin, and increase new method by the mucosa absorption calcitonin.
Calcitonin belongs to can have the natural and synthetic peptide class of pharmacologically active, and it contains 32 aminoacid and the function of regulating calcium amount in the serum is arranged.
Numerous already calcitonins all is commercial on sale as calcitonin that comprises natural human body, salmon and trowel eel and the synthetic class anguilla japonica calcitonin (elcatonin) that is similar to the anguilla japonica calcitonin, and be generally used for treating for example Paget, Sudeck's atrophy disease and osteoporosis.
But for the administration of peptide class, given value must consider a problem be they when oral medication, susceptible is in acid and the quick degraded brought out of enzyme.For this reason, when running into the peptide class of using larger molecular weight such as calcitonin medicine, people extensively adopt parenteral, because this administration is unique significantly effectively form.
People generally believe that injection was both inconvenient to the patient, make us unhappy again, and especially repeating needs the patient of regular intervals of time certain hour all the more so to long-term prescription, for example, treats postclimacteric osteoporosis with calcitonin.Therefore, it is more and more interested that people replace route of administration to the more acceptable non-intruding of peptide class, for example sublingual tablet, powder in the suppository, lung, the intranasal drop, spray, powder, gel, ointment and implant [example is seen EP94157(Takeda), EP173990(Teijin), US4,476,116(Syntex) and GB2,042,888(Teijin)].
Problem deserving of attention be biomembrane such as mucosa to many peptides, especially the peptide to those larger molecular weights absorbs extreme difference, so usually causes the bioavaliability of peptide very low.Therefore seek the research that improves peptide class epithelium transfer absorbed method.A kind of solution is to use adjuvant or absorbs dose, requires patent protection to deliver many documents to having the chemical compound that increases the peptide absorbent properties.
For example; following compounds was once proposed as absorbing dose: cholinester (EP214898); acyl group meat alkali (EP215697); aldose and glycosamine (Japanese patent application No. 61 126034), ascorbic acid and Salicylate (EP37943), alpha-cyclodextrin (EP0094157); pyroglutamic acid ester (EP173990); chelating agen (US4,476,116) and other all cpds (EP183527).
The somebody proposes can improve nasal mucosa to calcitonin with aqueous polyacrylic acid gel alkali recently, the absorption of class anguilla japonica calcitonin (Morimoto etc., international pharmacology's magazine 37 volumes, 134-136 page or leaf, 1985).
Once reported, the glycyrrhetinic acid sodium in the licorice ingredient can increase the snuffing of insulin and receive (people such as Mishima, J.Pharmacobio-Dyn, 10,8-69(1987)).Yet this article author shows that with experiment as the absorption dose of insulin, the effect of glycyrrhetinic acid sodium comes poorly than Capric acid sodium salt equally.
Have numerous about using surfactant to increase the report that polypeptide is absorbed, for example EP115627(Armour), GB2,127,689(Sandoz), US4,548,922(Carey etc.) and Hirai etc., international pharmacology's magazine, the 9th volume, 165-184 page or leaf, 1981.
Yet when using the absorption enhancer of surfactant form, a considerable problem is that they cause inflammation and tissue damage at medicine-feeding part.About intranasal administration, people (Hirai etc. were once arranged, Supra) surfactant to the small part that proposes to increase absorption causes nasal mucosa perturbation and the disorder to structural integrity, that is to say that inflammation and tissue damage that surfactant causes are directly related with its increase absorbability.
When peptide is used in the long-term timing of patient, this inflammation, the problem of tissue damage and patient tolerability difference becomes very serious.
From continuing to explore the high level that improves the peptide absorption process.The fact shows a kind of other route of administration that can produce enough peptide blood content (good bioavaliability is promptly arranged) of needs concerning the compositions of the calcitonin that contains the peptide class, and do not adopt the parenteral administration, the more important thing is to have good toleration to the long-term prescription patient.
Have found that the derivant 3-(2-O-B-D-glucopyranuronosyl-α-D-glucopyronosiduronic acid of glycyrrhetinic acid) be referred to as glycyrrhizic acid and salt thereof, not only has the excellent properties that promotes that mucosa absorbs calcitonin, and, can not produce other numerous absorption enhancer and cause local toxicity problem recited above the patient of long-term prescription.
Therefore the present invention at first provides the method for a kind of increase by the mucosa absorption calcitonin, and this method comprises the common absorption dose of giving calcitonin and effective dose, i.e. glycyrrhetate.
The present invention also provides a kind of pharmaceutical composition, and it comprises calcitonin, absorption dose of effective dose (being glycyrrhetate) and pharmaceutically acceptable carrier.
The present composition not only has physiological tolerance, and it is also advantageous in that further it is that dose is received in more effective snuffing that glycyrrhetate and known agent such as benzalkonium chloride are compared with sodium taurocholate.
Glycyrrhetate used herein is meant glycyrrhizic acid and its carboxylate.Concrete glycyrrhetate is ammonium glycyrrhizinate and alkali metal salt, for example sodium glycyrrhetate and dipotaccium glycyrrhizate, and wherein preferred salt is ammonium glycyrrhizinate.
Calcitonin used herein is that a batch class has the polypeptide class of pharmacological activity, not only comprise the calcitonin that nature exists, the various derivants and the analog that also comprise them, for example one or more amino acid residues that wherein exist naturally or order are saved, replace, reverse or by deutero-, perhaps N-or C-end is through the analog of modification.
Hereinafter used term calcitonin is to comprise whole that exist naturally and synthetic calcitonins.
Naturally the calcitonin example of Cun Zaiing comprises: the human body calcitonin, and its chemical abstracts uses registration number (CAS RN)-21215-62-3 and following array structure is arranged:
Figure 881078956_IMG1
-Met-Leu-Gly-
Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-
-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-
-Ala-Pro-NH 2;
The calcitonin of Mus (CAS RN=1118-25-5), structure is as follows:
-Met-Leu-Gly-
Thr-Tyr-Thr-Gln-Asp-Leu-Asn-Lys-Phe-His-
-Thr-Phe-Pro-Gln-Thr-Ser-Ile-Gly-Val-Gly-
-Ala-Pro-NH 2;
The calcitonin of salmon (CAS RN=47931-85-1), structure is as follows:
Figure 881078956_IMG3
-Val-Leu-Gly-
-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-
-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-
-Thr-Pro-NH 2;
The calcitonin of anguilla japonica (CAS RN=57014-02-5), structure is as follows:
Figure 881078956_IMG4
-Val-Leu-Gly-
-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-
-Thr-Tyr-Pro-Arg-Thr-Asn-Vla-Gly-Ala-Gly-
-Thr-Pro-NH 2;
Jungle fowl calcitonin I (CAS RN=96157-98-1) also, structure is as follows:
Figure 881078956_IMG5
-Val-Leu-Gly-
-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-
-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-
-Thr-Pro-NH 2;
The calcitonin II of chicken (CAS RN=103468-65-1), structure is as follows:
Figure 881078956_IMG6
Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-
Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-
Gly-Thr-Pro-NH 2;
The calcitonin of cattle (CAS RN=26112-29-8), structure is as follows:
Figure 881078956_IMG7
-Val-Leu-Ser-
-Ala-Tyr-Trp-Lys-Asp-Leu-Asn-Asn-Tyr-His-
-Arg-Phe-Ser-Gly-Mer-Gly-Phe-Gly-Pro-Glu-
-Thr-Pro-NH 2;
The calcitonin of pig (CASRN=12321-44-7) structure is as follows:
Figure 881078956_IMG8
-Val-Leu-Ser-
-Ala-Tyr-Trp-Arg-Asn-Leu-Asn-Asn-Phe-His-
-Arg-Phe-Ser-Gly-Met-Gly-Phe-Gly-Pro-Glu-
-Thr-Pro-NH 2;and
The calcitonin of sheep (CAS RN=40988-57-6), structure is as follows:
Figure 881078956_IMG9
-Val-Leu-Ser-
-Ala-Tyr-Trp-Lys-Asp-Leu-Asn-Asn-Tyr-His-
-Arg-Tyr-Ser-Gly-Met-Gly-Phe-Gly-Pro-Glu-
-Thr-Pro-NH 2.
The example that wherein saves one or more amino acid whose calcitonins has US4,597,900 des-[Ser that disclose 2, Tyr 22]-Gly 8-calcitonin and US4,304,692 des-[TYr that describe 22] SIGMA.
Wherein the order that exists naturally comprises 1 through the example of the calcitonin of modification, 7-two carbon-calcitonin, and for example anguilla japonica 1,7-two carbon calcitonins (class anguilla japonica calcitonin CAS RN=60731-46-6), structure is as follows:
Figure 881078956_IMG10
-CO-Val-Leu-Gly-
-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-
-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-
-Thr-Pro-NH 2;
Salmon 1,7-two carbon calcitonins (CAS RN=60864-37-1), structure is as follows:
Figure 881078956_IMG11
-CO-Val-Leu-Gly-
-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-
-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-
-Thr-Pro-NH 2;and
Human body 1,7-two carbon calcitonins (CAS RN=66811-56-1), structure is as follows:
-CO-Mer-Leu-Gly-
-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-
-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-
-Ala-Pro-NH 2.
In content of the present invention, particularly preferred calcitonin is class anguilla japonica calcitonin (CAS RN=60731-46-6).With relevant 1, the preparation of 7-two carbon calcitonins and character is in British Patent No. 1,516 about class anguilla japonica calcitonin, 947(Toyo JOZO) in existing the description.
Another kind of preferable calcitonin is the anguilla japonica calcitonin (CAS RN=57014-02-5) that nature exists.The preparation and the character of anguilla japonica calcitonin are seen US3,988,309) (Matsuda etc.).
The known method of this area can be adopted, the present composition can be used aptly by mucosa transmission pharmaceutically active substance.This compositions can be with following form medication, nose for example, and the Sublingual, cheek, rectum, vagina and mucous membrane of colon, and can make drop, aerosol, tablet, capsule, powder, gel, ointment, implant, suppository, vaginal suppository, the form of speckle and film.Compositions can also be made enteric-coated solid oral composition, as EP127535(Hadassah Medical Organisation) described in.
Concrete compositions is those compositionss that are used for the administration of nose film.
When employing passed to the form of nose film with compositions, concrete dosage form was aerosol, drop, gel and powder.Typical aerosol formulations comprises that active substance can accept solution or the delicate suspensions that forms in moisture or the anhydrous solvent on the physiology, and is placed in the sealed container with single or multiple dose sterile form usually.The sealing container can adopt the cartridge case of using for sprayer unit or refill form, or employing unit or dispersal device form, the nasal inhaler of single dose (seeing french patent application FR2578426) or be furnished with the aerosol dispersion device of measuring valve for example, and be disposable drug container.Wherein dosage form comprises the aerosol dispersion agent, and dispersant contains a kind of propellant, and it can be a kind of Compressed Gas such as compressed air or a kind of organic propellant such as fluoro chlorinated hydrocarbons.This class aerosol dispersion agent is to belong to known technology.In addition, the aerosol dose form also can adopt the pump one thiophene mist form that belongs to known technology.
To be used to disperse the spraying of aerosol spray or dispersal device to be designed to energy discrete particles size greater than 10 microns.In order to guarantee that enough amount of composition contact and are not inhaled into mouth or nasal mucosa, require the about 10-160 micron of particulate suitable dimension.
When compositions adopted the liquid spray form administration, on demand, the viscosity of regulating fluid composition with known method was to sprayable property.
Solvent or liquid-carrier used in this prescription are preferably aqueous solvent, but also can select physiologically acceptable nonaqueous solvent for use.The example of nonaqueous solvent or carrier has alcohol, especially polyhydroxy-alcohol such as propylene glycol and glycerol, vegetable oil and mineral oil.This class nonaqueous solvent or carrier can be added to various concentration and make solution, oil-in-water emulsion and water-in-oil emulsion in the water.But preferred solvent is a water.
Desolventize or carrier outside, liquid formulations of the present invention can also contain excipient such as antioxidant, stabilizing agent, antiseptic is regulated the reagent and the buffer agent of viscosity and infiltration.
When using antiseptic in the prescription, the consumption of antiseptic should be chosen as and can play antisepsis and do not cause nasal mucosa is caused stimulation.This seems even more important being used for long term administration prescription.For example be used for the treatment of postmenopausal osteoporosis disease.Suitable antiseptic is that P-hydroxybenzoic acid alkane ester (parabens) is as methyl parahydroxybenzoate and para hydroxybenzene methyl ester propyl ester.Preferred antiseptic is not comprise containing the chlorination benzalkonium.
The concrete dosage form that is used for cheek and sublingual administration is gel, suspension, tablet, speckle agent, powder, ointment and solution.The concrete dosage form that is used for vagina and rectally comprises vaginal suppository, suppository, solution, foam, suspension, gel, ointment and tablet.
Can make above-mentioned compositions by known pharmaceutical operation, for example referring to " pharmaceutical science " of Remington, the 17th edition, Mack publishing company, 1985.
Enteric coated and when being used for oral administration when compositions, be typically and be made into tablet or the capsule that is surrounded by coating materials, make calcitonin pass through the harmonization of the stomach small intestinal, then discharge at colon.Suitable coating materials comprises the copolymer (for example Eudragit S) of anionic polymer such as acrylic acid/methacrylate.
Compositions can also contain protease inhibitor, better is the protease inhibitor of non-surface-active agent, for example described in the EP127535.
The present composition can be used for the treatment of as Paget; Osteoporosis, the sick and various hypercalcemia diseases (for example referring to Physician ' s Desk Reference, the 42nd edition,, 1796 pages and 1797 pages in 1988) of Sudeck's atrophy.
Contain the calcitonin for the treatment of the disease effective dose that takes a disease in the composition dosage that is used for the patient.
In the present composition of unit dose, the amount of pharmaceutically active substance changes by the effectiveness of calcitonin and the attribute of compositions.But usually for the unit dose that is used for human body, compositions typical case is contained the calcitonin of 5 to 200 international positions (I.U.).The unit dose of class anguilla japonica calcitonin preferably contains 20 to 100I.U..
Term " iu " is with reference to human body, the corresponding International Reference Preparations of calcitonin of salmon or pig or class anguilla japonica calcitonin (International Reference Preparation), this International Reference Preparations (I.R.P.) is by National Institute for Biological Standards and Contral, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, the United Kingdom, set up.
In liquid formulations, especially in sprayer formulation, the volume of unit dose is generally 50-130mcl.
The pH value of the present composition is the chemical physical property according to its contained different components, can change in a wide scope.But as a rule, the pH scope that compositions is suitable is 3 to 8, and especially about pH4.5 is to about pH6.
Can use buffer agent to keep a concrete pH value.
Usually glycyrrhetate to absorb the concentration of dose be 0.1%(W/W at least), that be fit to is 0.5-10%(W/W), be preferably composition total weight 0.5 to 5%(W/W).
In liquid or gel combination, the glycyrrhetate amount that contains 0.5g to 5g in every 100ml compositions is more suitable, preferably contains the glycyrrhetate of the 2g that has an appointment in the 100ml compositions.
For Aquo-composition, final medicament forms for example liquid solution or gel will depend on the pH value of solution, the concentration of ionic strength and glycyrrhetate.As a rule, the pH of compositions is about at 5.5 o'clock, on say that form will be liquid, and the lower compositions of pH value trends towards becoming sticky, and will be gel form when its pH is about 4.5.
Following embodiment is with more detailed description the present invention.
Embodiment 1-9(table 1 is seen the literary composition back)
The prescription of embodiment 1-9 is by being prepared as follows, with glycyrrhetate, and citric acid, Sodium Citrate, usp, Dihydrate Powder, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, distilled water and sodium hydroxide mix in the water-bath that is adjusted to about 60 ℃ of temperature.Cooling gained solution adds class anguilla japonica calcitonin then to room temperature.
Embodiment 8 and 9 prescription are gel
Embodiment 10
Accurate weighing 1415mcg class anguilla japonica calcitonin (6500I.U./mg effectiveness) is added in the 100ml carrier of following component formation:
-absorption dose: 1g Radix Glycyrrhizae salt ammonium;
-buffer components; 200mg acetic acid and 200mg sodium acetate trihydrate;
-antiseptic: 130mg methyl parahydroxybenzoate and 20mg propyl p-hydroxybenzoate;
-distilled water adds to 100ml;
The pH value that-INHCl regulates carrier is 3.5.
In about 60 ℃ water-bath, carry out the preparation of carrier at thermoregulation.Cool off the gained gel then to room temperature, add active component again.
Embodiment 11
Accurate weighing 1670mcg SIGMA (5500I.U./mg effectiveness) is added in the 100ml carrier that is made of following component:
-absorption dose: 2g ammonium glycyrrhizinate;
-buffer components; 37mg citric acid and 463mg Sodium Citrate, usp, Dihydrate Powder;
-antiseptic: 130mg methyl parahydroxybenzoate and 20mg propyl p-hydroxybenzoate;
-distilled water adds to 100ml;
-Jia IN NaOH regulates the pH to 6 of carrier.
Carry out the preparation of carrier to about 60 ℃ water-bath at thermoregulation.Cooling gained solution adds active component then to room temperature.
Embodiment 12
Accurate weighing 1840mcg anguilla japonica calcitonin (5000I.U./mg effectiveness) is dissolved in the 100ml carrier of following component composition:
-absorption dose: ammonium glycyrrhizinate 2g;
-buffer components; 37mg citric acid and 463mg Sodium Citrate, usp, Dihydrate Powder;
-antiseptic: 130mg methyl parahydroxybenzoate and 20mg propyl p-hydroxybenzoate;
-distilled water adds to 100ml;
-use IN NaOH to regulate the pH to 6 of carrier.
To about 60 ℃ water-bath, prepare carrier at thermoregulation.Cooling gained solution adds active component then to room temperature.
Embodiment 13 and 14
Method by embodiment 1 to 9 prepares following compositions.
Table 2
Embodiment number
13 14
Class anguilla japonica calcitonin (mcg) 7,380 3690
(6500I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 22
Citric acid (mg) 37 37
Sodium Citrate, usp, Dihydrate Powder (mg) 463 463
Methyl parahydroxybenzoate (mg) 130 130
Propyl p-hydroxybenzoate (mg) 20 20
Distilled water adds to 100ml
IN NaOH is adjusted to pH6
Embodiment 15
Test A
Contain 2% embodiment 2 preparations that absorb the ammonium glycyrrhizinate of dose and carry out drug activity, promptly reduce the controlled trial of calcium concentration in the serum with following series preparation:
Except that not containing the ammonium glycyrrhizinate prescription (control formulation A) that class anguilla japonica calcitonin concentration is identical with excipient;
The class anguilla japonica calcitonin that contains same concentrations is as the benzalkonium chloride of excipient 0.01% and the prescription of citrate (control formulation B);
The class anguilla japonica calcitonin that contains same concentrations, 1% sodium taurocholate, the prescription of 0.15%parabens and citric acid (control formulation C).
To body weight is the male Mus marshalling of Spragne Dawley of 160 ± 10g, 10 every group, this this Mus with a ductule through intranasal each preparation administration with volume 10mcl.The fasting of full group is before accepting class anguilla japonica calcitonin, with 2% tribromoethanol (TBE) (0.9ml/100g body weight, intraperitoneal administration) fiber crops reward 15 minutes.When after giving product 60 minutes and 120 minutes, collect blood sample from the socket of the eye Dou Chu of each animal and carry out serum calcium cancentration and measure (with atomic absorption spectrophotometer VARIAN30/40 mensuration).
From without treatment, record basic value in the top identical time but go up through the animal of fasting and anesthesia equally.
The results are shown in the following table 3.
Table 3
Compare with basic value, at blood
Calcium during dosage is clear reduces percent
I.U./kg 1h 2h
4 18.1 21.3 of embodiment 2
Preparation of the present invention
Control formulation A 4 12.8 4.5
Control formulation B 4 14.1 5.2
Control formulation C 4 15.5 15.8
Test B
Contain 1% ammonium glycyrrhizinate for embodiment 1 preparation that absorbs dose carries out drug activity with following series preparation, promptly reduce the controlled trial of calcium concentration in the serum:
Except that not containing the ammonium glycyrrhizinate prescription (control formulation A) that class anguilla japonica calcitonin concentration is identical with excipient;
Contain same concentrations class anguilla japonica calcitonin, as 0.01% benzalkonium chloride of excipient and the prescription (control formulation B) of citrate.
Undertaken by test A same procedure.
Gained the results are shown in the following table 4.
Table 4
Compare gained blood with basic value
The calcium that dosage is clear reduces percent
I.U./kg 1h 2h
Embodiment's 1
Preparation 4 15.6 13.3 of the present invention
Control formulation A 4 12.0 3.6
Control formulation B 4 13.5 2.3
Test C
Contain 5% ammonium glycyrrhizinate for embodiment 3 preparations that absorb dose carry out drug activity with following series preparation, promptly reduce the controlled trial of calcium concentration in the serum.
Remove and do not contain ammonium glycyrrhizinate, the prescription (control formulation A) that class anguilla japonica calcitonin concentration is identical with excipient;
Contain same concentrations class anguilla japonica calcitonin, as 0.01% benzalkonium chloride of excipient and the prescription (control formulation B) of citrate;
Contain same concentrations class anguilla japonica calcitonin, 1% sodium taurocholate, 0.15%parabens and citrate (control formulation C).
Remove outside blood sampling time 60,120 and 240 minutes after, operate by the method for test A for treatment.
The results are shown in the following table 5.
Table 5
Compare gained blood with basic value
The calcium that dosage is clear reduces percent
I.U./kg 1h 2h 4h
4 18.4 21.9 9.0 of embodiment 3
Preparation of the present invention
Control formulation A 4 10.4 3.5-0.5
Control formulation B 4 12.1 5.2 0.7
Control formulation C 4 14.2 20.4 2.2
Embodiment 16
Test D
Containing class anguilla japonica calcitonin, to carry out bioavaliability as active constituent and 2% ammonium glycyrrhizinate as embodiment 13 preparations that absorb dose and following series preparation be the dynamic test of class anguilla japonica calcitonin in serum:
Except that not containing the ammonium glycyrrhizinate, contain the class anguilla japonica calcitonin identical prescription identical of concentration (control formulation A) with excipient;
Contain same concentrations class anguilla japonica calcitonin, as 0.01% benzalkonium chloride of excipient and the prescription (control formulation B) of citrate.
The Beagle dog of two heavy 10kg is given above-mentioned preparation (with the former 100mcl volume that gives of metering) through intranasal.Accept once to blow in each nostril of two animals, promptly total amount is 80I.U..
After giving product, collect the blood sample (great saphenous vein sampling) of every animal, with the class anguilla japonica calcitonin concentration in the RIA method mensuration serum every 5 minutes (until 60 minutes).
The results are shown in Table 6 for gained.
Table 6
Class anguilla japonica calcitonin peak concentration and AVC value
Dosage peak concentration appearance time AVC
I.U./kg pg/ml (branch) branch * pg/ml
The invention process 8 515 10 7587
The preparation of example 13
Control formulation A 8 95 10 1270
Control formulation B 8 217 20 2869
Embodiment 17,18 and 19
Method by embodiment 1 to 9 makes following compositions.
Table 7
Embodiment number
17 18 19
Class anguilla japonica calcitonin (mcg) 7,380 3,690 3690
(6500I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 0.5 0.5 1
Citric acid (mg) 37 37 37
Sodium Citrate, usp, Dihydrate Powder (mg) 463 463 463
Methyl parahydroxybenzoate (mg) 130 130 130
Propyl p-hydroxybenzoate (mg) 20 20 20
Distilled water is to 100ml
IN NaOH regulates pH to 6
Embodiment 20-25(table 8 is seen the literary composition back)
At thermoregulation to about 60 ℃ water-bath, with ammonium glycyrrhizinate, citric acid, Sodium Citrate, usp, Dihydrate Powder, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium chloride, Spheron MD 30/70, distilled water and sodium hydroxide mixed the prescription of embodiment 20 to 25.Gained solution is cooled to room temperature, adds class anguilla japonica calcitonin then.
Embodiment 26-31(table 9 is seen the literary composition back)
At thermoregulation to about 60 ℃ water-bath, with ammonium glycyrrhizinate, citric acid, Sodium Citrate, usp, Dihydrate Powder, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium chloride, Spheron MD 30/70, distilled water and sodium hydroxide mixed the prescription of embodiment 26 to 31.Gained solution is cooled to room temperature, adds class anguilla japonica calcitonin then.
Embodiment 32-37(table 10 is seen the literary composition back)
At thermoregulation to about 60 ℃ water-bath, with ammonium glycyrrhizinate, citric acid, Sodium Citrate, usp, Dihydrate Powder, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium chloride, distilled water and sodium hydroxide mixed the prescription of embodiment 32 to 37.Gained solution is cooled to room temperature, adds class anguilla japonica calcitonin then.
Embodiment 38
Test E
Containing class anguilla japonica calcitonin as active constituent (is respectively 40I.U./100mcl and 20I.U./100mcl) and carries out the controlled trial (being the class anguilla japonica calcitonin dynamic test in the serum) of bioavaliability as the embodiment 36 of 2% ammonium glycyrrhizinate that absorbs dose and 37 preparations and following series preparation.
Except that not containing the ammonium glycyrrhizinate, contain prescription (control formulation A) with the class anguilla japonica calcitonin of embodiment 36 same concentrations and identical excipient;
Except that not containing the ammonium glycyrrhizinate, contain with the class anguilla japonica calcitonin of embodiment 37 same concentrations and the prescription (control formulation B) of identical excipient;
Contain the 40I.U./ml class anguilla japonica calcitonin that oozes acetate buffer waiting, its pH is 4.25(control formulation C).
The preparation of embodiment 36 and 37 and control formulation A and B intranasal administration (using dosing pump to provide the 100mcl volume) in 6 male's volunteers.Accept once to blow in each nostril of volunteer, promptly for embodiment 36 preparations with for control formulation A, total amount is 80.I.U., or is 40I.U. for embodiment 37 preparations and comparative examples B preparation.
The control formulation C of 1ml volume (40I.U.) in 6 identical male's volunteers, adopts the exchange design through intramuscular administration.
Behind product, collect blood sample every 5 minutes (from 0 to 60 minute), with the class anguilla japonica calcitonin concentration in radioimmunoassay (RIA) the mensuration serum.
Result and in following table 11.(table 11 is seen the literary composition back)
Embodiment 39 and 40
Table 12
Embodiment number
39 40
SIGMA (mcg) 9,090 18180
(5500I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 22
Citric acid (mg) 37 37
Sodium Citrate, usp, Dihydrate Powder (mg) 463 463
Methyl parahydroxybenzoate (mg) 130 130
Propyl p-hydroxybenzoate (mg) 20 20
Sodium chloride (mg) 600 600
Distilled water adds to 100ml
IN NaOH regulates pH6
At thermoregulation to about 60 ℃ water-bath, with ammonium glycyrrhizinate, citric acid, Sodium Citrate, usp, Dihydrate Powder, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium chloride, distilled water and sodium hydroxide mixed embodiment 39 and 40 prescriptions.Gained solution is cooled to room temperature, adds the calcitonin of salmon then.
Embodiment 41 and 42
Table 13
Embodiment number
41 42
Anguilla japonica calcitonin (mcg) 10,000 20000
(5000I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 22
Citric acid (mg) 37 37
Sodium Citrate, usp, Dihydrate Powder (mg) 463 463
Methyl parahydroxybenzoate (mg) 130 130
Propyl p-hydroxybenzoate (mg) 20 20
Sodium chloride (mg) 600 600
Distilled water adds to 100ml
IN NaOH adds to pH6
At thermoregulation to about 60 ℃ water-bath, with ammonium glycyrrhizinate, citric acid, Sodium Citrate, usp, Dihydrate Powder, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium chloride, distilled water and sodium hydroxide mixed example 41 and 42 prescription.Gained solution is cooled to room temperature, adds the calcitonin of anguilla japonica then.
Embodiment 43 and 44
Table 14
Embodiment number
43 44
Chicken calcitonin II (mcg) 10,000 20000
(5000I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 22
Citric acid (mg) 37 37
Sodium Citrate, usp, Dihydrate Powder (mg) 463 463
Methyl parahydroxybenzoate (mg) 130 130
Propyl p-hydroxybenzoate (mg) 20 20
Sodium chloride (mg) 600 600
Distilled water adds to 100ml
IN NaOH adds to pH6
At thermoregulation to about 60 ℃ water-bath, with ammonium glycyrrhizinate, citric acid, Sodium Citrate, usp, Dihydrate Powder, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium chloride, distilled water and sodium hydroxide mixed the prescription of embodiment 43 to 44.Gained solution is cooled to room temperature, adds chicken calcitonin II then.
Embodiment 45 and 46
Table 15
Embodiment number
45 46
Human body calcitonin (mg) 250 500
(200I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 22
Citric acid (mg) 37 37
Sodium Citrate, usp, Dihydrate Powder (mg) 463 463
Methyl parahydroxybenzoate (mg) 130 130
Propyl p-hydroxybenzoate (mg) 20 20
Sodium chloride (mg) 600 600
Distilled water adds to 100ml
IN NaOH adds to pH6
At thermoregulation to about 60 ℃ water-bath, with ammonium glycyrrhizinate, citric acid, Sodium Citrate, usp, Dihydrate Powder, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium chloride, distilled water and sodium hydroxide mixed embodiment 45 and 46 prescription.Gained solution is cooled to room temperature, adds the human body calcitonin then.
Embodiment 47 and 48
Table 16
Embodiment number
47 48
Pig calcitonin (mg) 834 1668
(60I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 22
Citric acid (mg) 37 37
Sodium Citrate, usp, Dihydrate Powder (mg) 463 463
Methyl parahydroxybenzoate (mg) 130 130
Propyl p-hydroxybenzoate (mg) 20 20
Sodium chloride (mg) 600 600
Distilled water adds to 100ml
IN NaOH adds to pH6
At thermoregulation to about 60 ℃ water-bath, with ammonium glycyrrhizinate, citric acid, Sodium Citrate, usp, Dihydrate Powder, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium chloride, distilled water and sodium hydroxide mixed embodiment 47 and 48 prescription.Gained solution is cooled to room temperature, adds the pig calcitonin then.
The nose powder
Embodiment 49 and 50
Table 17
Embodiment number
49 50
Class anguilla japonica calcitonin (mg) 3.69 7.38
(6500I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 2.0 2.0
Lactose adds to (g) 25.0 25.0
With the moistening lactose of class anguilla japonica calcitonin aqueous solution, then make the prescription of embodiment 49 and 50 through vacuum drying.Dry powder mixes with ammonium glycyrrhizinate, and this final mixture is inserted hard gelatin capsule (every capsules is 25mg).
After capsule punctures, use the nose insufflator to be blown into powder.
Sublingual tablet
Embodiment 51 and 52
Table 18
Embodiment number
51 52
Class anguilla japonica calcitonin (mg) 7.7 15.4
(6500I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 4.0 4.0
Sucrose (g) 35.0 35.0
Mannitol (g) 35.0 35.0
Polyethylene glycol 6000 (g) 10.0 10.0
Lactose adds to (g) 120.0 120.0
With sucrose, mannitol and lactose are mixed together the prescription that makes embodiment 51 and 52.With the moistening gained mixture of class anguilla japonica calcitonin aqueous solution, make granule and vacuum drying by stainless steel sift then.Dried granules is mixed with Polyethylene Glycol and ammonium glycyrrhizinate, is pressed into every then and is the tablet of 120mg.
The cheek tablet
Embodiment 53 and 54
Table 19
Embodiment number
53 54
Class anguilla japonica calcitonin (mg) 7.7 15.4
(6500I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 4.0 4.0
Sucrose (g) 30.0 30.0
Mannitol (g) 35.0 35.0
Polyethylene glycol 6000 (g) 15.0 15.0
Carbopol 934(g) 15.0 15.0
Lactose adds to (g) 150.0 150.0
With sucrose, mannitol and lactose are mixed together the prescription that makes embodiment 53 and 54.With the moistening gained mixture of the aqueous solution of class anguilla japonica calcitonin, make granule and vacuum drying with stainless steel sift then.The same ammonium glycyrrhizinate of dried granules, carbopol and Polyethylene Glycol mix, and are pressed into every then and are the tablet of 150mg.
The oral tablet of colon way
Embodiment 55 and 56
Table 20
Embodiment number
55 56
Class anguilla japonica calcitonin (mg) 15.4 30.8
(6500I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 6.0 6.0
Pregelatinized starch (g) 80.0 80.0
Magnesium stearate (g) 2.0 2.0
Lactose adds to (g) 210.0 210.0
Eudragit S（g） 20.0 20.0
Polyethylene Glycol (g) 2.0 2.0
Pregelatinized starch and lactose are mixed together the prescription that makes embodiment 55 and 56.With the moistening gained mixture of the aqueous solution of class anguilla japonica calcitonin, make granule and vacuum drying through stainless steel sift.Dried granules is mixed with ammonium glycyrrhizinate and magnesium stearate, is pressed into every then and is the tablet of 210mg.
Tablet is coated with the water slurry of Polyethylene Glycol and decil first acrylate-methyl first acrylate copolymer (Eudragit) and wraps to such an extent that every final weight is 232g.
Vaginal tablet
Embodiment 57 and 58
Table 21
Embodiment number
57 58
Class anguilla japonica calcitonin (mg) 15.4 30.8
(6500I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 8.0 8.0
Corn starch (g) 180.0 180.0
Adipic acid (g) 140.0 110.0
Sodium bicarbonate (g) 110.0 110.0
Magnesium stearate (g) 20.0 20.0
Lactose adds to (g) 1600.0 1600.0
With ammonium glycyrrhizinate, corn starch, adipic acid and lactose are mixed together the prescription that makes embodiment 57 and 58, with the moistening gained mixture of aqueous solution of class anguilla japonica calcitonin, make granule and vacuum drying through stainless steel sift.Dried granules is mixed with sodium bicarbonate and magnesium stearate, is pressed into every then and is the tablet of 1.6g.
Table 1
Embodiment number
1 2 3 4 5 6 7 8 9
Class anguilla japonica calcitonin (mcg) 1,415 1,415 1,415 7,380 7,380 1,415 7,380 1,415 7380
(6500I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 1251522 0.5 0.5
Citric acid (mg) 37 37 37 37 37 37 37 37 37
Sodium Citrate, usp, Dihydrate Powder (mg) 463 463 463 463 463 463 463 463 463
Methyl parahydroxybenzoate (mg) 130 130 130 130 130--130 130
Propyl p-hydroxybenzoate (mg) 20 20 20 20 20--20 20
Distilled water adds to 100ml
IN NaOH(adds to pH) 6666666 645 *45 *
* regulate pH to 4.5 with 0.1NNaOH
Table 8
Embodiment number
20 21 22 23 24 25
Class anguilla japonica calcitonin (mcg) 7,380 3,690 7,380 3,690 7,380 3690
(6500I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 0.5 0.5 1122
Citric acid (mg) 37 37 37 37 37 37
Sodium Citrate, usp, Dihydrate Powder (mg) 463 463 463 463 463 463
Methyl parahydroxybenzoate (mg) 130 130 130 130 130 130
Propyl p-hydroxybenzoate (mg) 20 20 20 20 20 20
Sodium chloride (mg) 600 600 600 600 600 600
Spheron MD 30/70 (mg) 555555
Distilled water adds to 100ml
IN NaOH adds to pH6
Table 9
Embodiment number
26 27 28 29 30 31
Class anguilla japonica calcitonin (mcg) 7,380 3,690 7,380 3,690 7,380 3690
(6500I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 0.5 0.5 1122
Citric acid (mg) 37 37 37 37 37 37
Sodium Citrate, usp, Dihydrate Powder (mg) 463 463 463 463 463 463
Methyl parahydroxybenzoate (mg) 130 130 130 130 130 130
Propyl p-hydroxybenzoate (mg) 20 20 20 20 20 20
Sodium chloride (mg) 600 600 600 600 600 600
Spheron MD 30/70 (mg) 10 10 10 10 10 10
Distilled water adds to 100ml
IN NaOH adds to pH6
Table 10
Embodiment number
32 33 34 35 36 37
Class anguilla japonica calcitonin (mcg) 7,380 3,690 7,380 3,690 7,380 3690
(6500I.U./mg effectiveness)
Ammonium glycyrrhizinate (g) 0.5 0.5 1122
Citric acid (mg) 37 37 37 37 37 37
Sodium Citrate, usp, Dihydrate Powder (mg) 463 463 463 463 463 463
Methyl parahydroxybenzoate (mg) 130 130 130 130 130 130
Propyl p-hydroxybenzoate (mg) 20 20 20 20 20 20
Sodium chloride (mg) 600 600 600 600 600 600
Distilled water adds to 100ml
IN NaOH adds to pH6
Table 11
Class anguilla japonica calcitonin average peak is shunk and the AVC value
Dosage peak concentration appearance time AVC(on average marks mistake
I.U. the pg/ml branch is poor) branch * pg/ml
Embodiment 36 compositionss 80 186.3 15.2 3551.2(± 160.1)
Embodiment 37 compositionss 40 92.5 15.1 2301.9(± 170.7)
Control formulation A 80 57.6 15.6 1270.2(± 135.6)
Control formulation B 40 27.9 15.1 551.0(± 85.4)
Control formulation C 40 233.3 20.6 3675.2(± 190.6)

Claims (11)

1, a kind of preparation is applicable to the method for the pharmaceutical composition of striding the mucosa transmission, said composition comprises a kind of calcitonin, at least account for a kind of absorption dose glycyrrhetate and the pharmaceutically acceptable carrier of 0.1% (W/W) of total composition, this method comprises mixes calcitonin and glycyrrhetate with carrier.
2, according to the process of claim 1 wherein that glycyrrhetate is an ammonium glycyrrhizinate.
3, according to the process of claim 1 wherein that the concentration of glycyrrhetate is 0.5 to 5%(W/W).
4, according to arbitrary method of claim 1 to 3, wherein calcitonin is a class anguilla japonica calcitonin.
5, according to arbitrary method of claim 1 to 3, wherein calcitonin is the anguilla japonica calcitonin.
6, according to arbitrary method of claim 1 to 3, wherein compositions is that form with liquid or gel is applicable to that nasal mucosa uses.
7, according to the method for claim 6, wherein the amount of glycyrrhetate is to be about 2g corresponding to the 100ml compositions.
8, according to the method for claim 1 to 3, the pH scope about 4.5 to about 6 of compositions wherein.
9, according to the method for claim 1, wherein compositions comprises the saline solution as a kind of pH of being buffered to about 6 of carrier, and a kind of antiseptic of avirulence effective dose and every 100ml compositions are 20,000-100, the class anguilla japonica calcitonin of 000 iu and the ammonium glycyrrhizinate of about 2g.
10, according to the method for claim 6, comprising: in about 60 ℃ water, with glycyrrhetate and arbitrarily excipient be mixed together, look necessary adjusting pH value, cooling gained solution adds calcitonin then to about room temperature.
11, comprise that according to the process of claim 1 wherein compositions is packaged into spray is used for administration.
CN88107895A 1987-11-13 1988-11-12 Composition containing calcitonin and its preparation method Expired - Fee Related CN1027225C (en)

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EP0432431B1 (en) * 1989-11-16 1993-06-16 PHIDEA S.p.A. Liquid pharmaceutical composition for nasal administration containing a polypeptide as active ingredient
IT1238072B (en) * 1990-01-19 1993-07-03 Sclavo Spa PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS FOR ORAL ADMINISTRATION OF CALCITONIN
IT1248725B (en) * 1990-06-12 1995-01-26 Sclavo Spa PHARMACEUTICAL COMPOSITION POWDER FOR NASAL ADMINISTRATION CONTAINING ESSENTIAL CALCITONIN AND A WATER SOLUBLE EXCIPIENT
CN101721376B (en) * 2009-12-30 2011-06-01 上海交通大学 Calcitonin sustained-release microsphere composition and preparation method thereof

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