CN1861061A

CN1861061A - Medicine for treating or preventing newborn hemorrhagic disease

Info

Publication number: CN1861061A
Application number: CN 200510077343
Authority: CN
Inventors: 王杰华
Original assignee: Individual
Current assignee: Individual
Priority date: 2005-06-22
Filing date: 2005-06-22
Publication date: 2006-11-15

Abstract

A medicine in the form of soft capsule for preventing or treating neonatal hemorrhage is composed of the core prepared from VK1 through dissolving it in vegetative oil and the shell containing light shielding agent for higher stability.

Description

The medicine of treatment or prevention hemorrhagic disease of newborn

Technical field

The present invention relates to treat or prevent the medicine of hemorrhagic disease of newborn; More properly relate to vitamin K ₁Soft capsule belongs to field of pharmaceutical preparations.

Background technology

Vitamin K ₁It is the principal mode of the vitamin K in plant, found.Vitamin K ₁Be fat-soluble.Vitamin K in the human body ₁Be mainly derived from food, contain abundant vitamin K in the green vegetable ₁Vitamin K ₁Mainly absorb at ileum, its absorption depends on the normal condition of bile salt and body fat absorption.Store not abundant in the vitamin K body, the normal person is deficient in vitamin in diet under the K situation, stocking of vitamin K will be consumed in 1 week in the body, but not cause symptom usually, because of the synthetic vitamin K of intestinal flora can guarantee the synthetic of vitamin K dependent protein matter.Vitamin K ₁As coagulant, the clinical vitamin K deficiency hemorrhage that is mainly used in.Vitamin K in addition ₁Alleviate the smooth muscle spasm effect in addition, can be used for treatment of diseases such as biliary colic, gastrointestinal convulsion and children's bronchopneumonia.

1, vitamin K ₁Absorption, distribution, metabolism

Natural vitamin K ₁For fat-soluble, must rely on bile after oral and absorb.Oral vitamin K ₁Promptly had an effect in the back in 6～12 hours; Injection back onset in 1～2 hour, hemostatic effect was obvious in 3～6 hours, and prothrombin time recovers normal after 12～24 hours.Vitamin K absorbs back metabolism rapidly in liver, drains in kidney and biliary tract, unlikely mostly storage in vivo.And different, only gastrointestinal tract just absorbs vitamin K to the mechanism of chemical compound that little intestinal absorption has a vitamin k activity fully when cholate exists with its dissolution characteristics ₁And aphthoquinone.But menadione and soluble derivative thereof then can not absorb when having bile to exist yet.Vitamin K ₁Almost completely absorb through lymph with aphthoquinone, menadione and soluble derivative thereof then directly enter blood flow.Vitamin K ₁At the small intestinal near-end is to absorb by the saturable process that relies on energy; Intramuscular injection natural or synthetic Vitamin K preparation all easily absorb.After the absorption, vitamin K ₁At first concentrate, but concentration descends rapidly in liver.Have only very a spot of vitamin K to accumulate in its hetero-organization.Vitamin K ₁Metabolism is the bigger metabolite of polarity rapidly, discharges with bile and urine.Major metabolite is the carboxylic acid that side chain shortens to 5 or 7 carbon atoms in the urine, combines with glucuronic acid before discharging.Menadione main metabolic pentanediol (hydroquinone) type is discharged with the form of glucuronic acid and sulphuric acid conjugate.

2, vitamin K ₁Clinical behaviour in service

Mainly contain X, IX, VII, II with the closely-related thrombin of vitamin K.Under the physiological condition, the above-mentioned factor glutaminic acid residue that its N holds in the building-up process in liver need add carboxylation reaction.This reaction needs the catalysis of carboxylated enzyme, and vitamin K then is the indispensable coenzyme of this enzymatic reaction, in case vitamin K deficiency then the more synthetic blood coagulation activities of liver are low or the cacoplastic protein of non-activity causes blood coagulation disorders.Mainly show as hemorrhage: skin mucosa is hemorrhage, and visceral hemorrhage is hemorrhage behind the trauma surgery, hemorrhage of newborn etc.The rare muscle of primary disease, joint and the hemorrhage generation of other deep tissues.The common cause of vitamin K deficiency has:

(1) Deficiency of Intake: can not take food for a long time, long-term low fat diet, biliary obstruction, the malabsorption syndrome due to the intestinal fistula, extensive small bowel resection, chronic diarrhea, the life-time service antibiotic causes endogenous synthetic minimizing, and this moment can vitimin supplement K ₁

(2) hepatic disease: hepatitis gravis, lose compensatory liver cirrhosis and advanced liver cancer etc., because liver function damage, vitamin K absorption in addition, absorption, metabolism and utilize obstacle, liver can not synthesize the normal amount coagulation factors vitamin K dependent.Should give vitamin K this moment ₁Can give vitamin K ₁Add in the 250-500ml glucose quiet 20-40mg/ day.Vitamin K in addition ₁Also can prevent intrahepatic cholestasis of pregnancy (ICP) postpartum hemorrhage.

(3) oral vitamin K antagonist: as dicoumarol, they have and vitamin K ₁Similarly structure does not but have its function, and competition suppresses to disturb the synthetic of vitamin K-dependent clotting factor.As it is hemorrhage to use excessive generation, promptly answers drug withdrawal, and uses a large amount of vitamin Ks ₁Antagonism, the major complications of oral anticoagulant therapy (warfarin) is hemorrhage, is most commonly in cerebrovascular disease patient and the high strength anticoagulant therapy case of accepting anticoagulant therapy.For inactivity is hemorrhage but prothrombin time obviously prolongs case, but the intravenous injection vitamin K ₁5-10mg, this can cancel anticoagulation in 6 hours, but may cause the warfarin resistance of a few days by a definite date, and this needs continuous anticoagulant patient unfavorable to those.

(4) poison: diphenadione can suppress the effect of vitamin K, makes the biosynthesis block of thrombinogen and labile factor, VII, X etc., thereby reduces the coagulability of blood.Vitamin K ₁Be special efficacy antidote, in case diagnosis is handled immediately, light disease patient can be with 10-20mg intramuscular injection every day 2-4 time.Critically ill patient is with in the quiet notes of 10-50mg or the adding 5%-10% glucose quiet, and until stopped bleeding, it is normal that prothrombin time recovers.

(5) hemorrhagic disease of newborn: 2-7 days the neonate in birth back, can store because of vitamin K in the body and consume, Deficiency of Intake and in life can not wait, cause vitamin K deficiency and cause bleeding.Vitamin K ₁Preventive administration can prevent hemorrhagic disease of newborn.

Lin Liangming, Liu Yulin etc. (baby's vitamin K deficiency and Research of interference thereof, Chinese department of pediatrics magazine, 2002 the 40th the 12nd phases of volume) pass through baby's vitamin K deficiency and Research of interference thereof, and the result shows:

(1) there is about 40% subclinical vitamin K deficiency in Chinese baby;

(2) baby and wet nurse's oral vitamin K ₁Intervention has obtained remarkable result.The colony of baby oral 2mg * 10 time and the oral 10mg of wet nurse * 10 times intervenes, and its result shows, no matter baby oral 10 times, or oral 10 vitamin Ks of wet nurse ₁Can both significantly reduce the hemorrhage case of baby, late-onset VKDB does not all take place, what do not take place that VKDB causes is dead and disabled.

Committee on Nutrition,American Academy of Pediatrics proposed neonate birth back intramuscular injection vitamin K in 1961 ₁0.5-1mg after the suggestion of prevention hemorrhagic disease of newborn, baby's vitamin K ₁Prevention and treatment VKDB have had application widely in world many countries.Total trend is once to develop into repeatedly by using; Change into oral by intramuscular injection.4 kinds of methods of bibliographical information: (1) birth back neonate intramuscular injection vitamin K ₁1mg or oral 2mg, effectively simple, but limited to late-onset VKDB effect; (2) breast-feeding infant was taken 25 μ g every day, to 3 months; (3) the oral vitamin K in birth back ₁2mg, 5mg during 1 week and 1 month, totally 3 times; Oral vitamin K when (4) being born ₁1 or 2mg, weekly 1 time to 3 months later on.Above prevention method, with the most satisfied effect of 1 instructions of taking weekly, 163000 babies of Denmark accept 1 vitamin K weekly ₁The oral intervention of 1mg, a routine tardy property VKDB does not take place in the result.And the accumulate poisoning (Lin Liangming, Liu Yulin etc., ibid) of vitamin K can not take place in this instructions of taking.

Because oral 10 vitamin Ks ₁Only need tens yuan of expensess for medicine, just can effectively reduce neonate and the hemorrhage incidence rate of baby and the death that causes and disabled thereof.Consider that there is the universality of VKD in China's ewborn infant, widelys popularize oral vitamin K in baby and wet nurse ₁Be very important and necessary.It is more more convenient than the baby to consider that wet nurse takes, and therefore is more prone to wet nurse and takes, and has both kept breastfeeding advantage, overcomes the deficiency of vitamin K in the breast milk again.

3, vitamin K ₁Untoward reaction

Vitamin K ₁Untoward reaction is less, oral except that indivedual cases have slight one cross that property is felt sick or epigastric discomfort, do not have tangible untoward reaction; Neonate is given birth to oral vitamin K in the short time of back ₁Tablet 2.5-5mg is safe, does not find anaphylaxis, does not have tangible digestive system untoward reaction (Liang Youling, Lin Chaoqiong, Feng Juntan; Oral vitamin K ₁In neonatal safety research, department of pediatrics pharmaceutical journal, the 7th the 4th phase of volume of calendar year 2001).The drug administration by injection idol has anaphylaxis, and parageusia, flush, perspiration, uncomfortable in chest, blood pressure drops are then arranged when intravenous injection especially, paroxysmal supraventricular tachycardia, even the report that causes severe allergic reaction is arranged.The drug administration by injection anaphylaxis mainly contains: (Chen Zihui, Yang Zhiqiang, Li Chengjian such as allergic rash, contact dermatitis, anaphylactic shock, allergic asthma; Vitamin K ₁Untoward reaction, China mistake rash magazine was rolled up for the 5th phase in 2004 the 4th).

4, vitamin K ₁Existing dosage form situation

With vitamin K ₁Be the preparation of primary raw material, domestic have only vitamin K at present ₁Injection and vitamin K ₁Sheet.Injection is used for clinical acute disease more, and oral tablet then also is used to prevent the shortage of vitamin K.Compound preparation contains vitamin K ₁Dosage form then also have soft capsule etc.External vitamin K ₁Dosage form has injectable emulsion, tablet etc., vitamin K ₁Soft capsule is not seen listing kind and relevant report.

Summary of the invention

Vitamin K ₁As the medicine of blood coagulation disorders due to the treatment vitamin K deficiency, clinical safe in utilization, determined curative effect, untoward reaction is few.This product raw material vitamin K ₁See that light easily decomposes, easily molten in vegetable oil, insoluble in water, therefore the human bioavailability of existing tablet is lower, has influenced the onset of medicine.And the clinical use of injection is convenient not as peroral dosage form.Especially lack hemorrhagic disease of newborn as prevention and treatment vitamin k, injection and tablet are not very ideal dosage forms, and soft capsule is a kind of novel form that grows up behind tablet, injection, can and be encapsulated in the glued membrane the quantitative pressure injection of oily medicine, drug solution or drug suspension, pastel even drug powder, form big or small, different seal capsule.Compare with other dosage forms, possess bioavailability height, content accurately, characteristics such as good uniformity, good looking appearance; If the oily medicine also can save technical finesses such as absorption, curing, can effectively avoid the oily medicine from absorb adjuvant, to ooze out, so soft capsule is the optimum dosage form of oiliness medicine.In addition, the medicine of the hydrophobic drug of low melting point substance, bioavailability difference, bad bitterness and stink, trace active medicine and the medicine of meeting light, wet, thermally labile and easy oxidation also are fit to make soft capsule.Therefore we are with vitamin K ₁Be developed into soft capsule.

Vitamin K ₁Be the clarifying thick liquid of Yellow-to-orange; Odorless or odorless almost; Meeting light easily decomposes; Easily molten in vegetable oil, insoluble in water.Therefore according to this product Material Characteristics, with vitamin K ₁Make soft capsule, in softgel shell, add opacifier, strengthened vitamin K ₁Stability, with vitamin K ₁Be dissolved in the vegetable oil, be molecular state and exist, promoted vitamin K ₁Stripping has in vivo improved human bioavailability, thereby has avoided the deficiency of tablet, has promoted the absorption of medicine and has shortened onset time.Compare with injection, clinical use is more convenient, and is safer.Through preparation process research and quality standard research, prove that it is feasible that this product is made soft capsule.Through study on the stability, prove that it is stable that this product is made soft capsule.Vitamin K ₁Soft capsule preparation technology is simple, compares with tablet, injection, and production cost is lower, is more suitable for applying to prevent the vitamin K deficiency hemorrhagic disease of newborn on a large scale in clinical.

Description of drawings

Fig. 1 is a vitamin K of the present invention ₁The technological process of production of soft capsule.

The specific embodiment

Embodiment 1

This product is a soft capsule, and every dress 0.3g contains vitamin K ₁Be 10mg.

Preparation prescription: (by 10000 inventorys)

Vitamin K ₁100.0g

Soybean oil 2900.0g

Gelatin is an amount of

Glycerol is an amount of

0.3% of titanium dioxide gelatin amount

0.3% of chocolate palm fibre gelatin amount

Make 10000

Method for making:

1. change glue and get 0.35 part of 1 part in gelatin, 1 part in water and glycerol.Titanium dioxide is added in the glycerol, wear into uniform suspension with colloid mill.Gelatin is added an amount of water make its imbibition.The water of remainder is put in the colloidal sol pot, be heated to 70 ℃, add expansible gelatin, the suspension and the water-soluble colorant of mixing, stir, dissolving, mixing be incubated 1-2 hour and leaves standstill, and the evacuation scumming is with clean filter cloth filtration, 50-60 ℃ of heat preservation for standby use.The viscosity of the glue that is made into is 4.5-5.2 ° of E, and water content is 47-49%.

2. batching lucifuge operation.Take by weighing the vitamin K of above-mentioned recipe quantity ₁Add in the soybean oil of recipe quantity, stir, abundant mixing, medicinal liquid is standby.

3. pelleting lucifuge operation.The medicinal liquid of gelatin solution and mixing is pressed into ball (41 ℃ of sprinkler bodies, 49 ℃ in glue box) by encapsulating machine, every ball dress 300mg.

4. typing is rolled cage at temperature 22-24 ℃ with the soft capsule that presses by drying with dry, relative humidity is 45-60%RH typing 3-4 hour, typing is after tentatively pick soft capsule petroleum ether (60 ℃) defat of putting in order, primary drying uses and rolls cage, temperature 26-28 ℃, relative humidity is 25-30%RH, and dry air air inlet relative humidity is 20%RH, dry 4 hours; Redrying is used the tunnel drying drying room, and temperature 26-28 ℃, relative humidity is 20-25%RH, and dry 3 hours, natural cooling, finished product is through being up to the standards, and packing is packed promptly.

Embodiment 2

Except the soybean oil consumption is 900.0g, surplus with embodiment 1.

Embodiment 3

Except the soybean oil consumption is 1900.0g, surplus with embodiment 1.

Embodiment 4

Except the soybean oil consumption is 3900.0g, surplus with embodiment 1.

Embodiment 5

Except replace soybean oil with Semen Maydis oil, surplus with embodiment 1.

Embodiment 6

Except replace titanium dioxide with ferrum oxide, surplus with embodiment 1.

Claims

1, the vitamin K of treatment or prevention hemorrhagic disease of newborn ₁Soft capsule is by vitamin K ₁1 weight portion, gelatin is an amount of, glycerol is an amount of, diluent 9 to 39 weight portions, the coloring agent that accounts for the opacifier of gelatin amount 0.3% to 0.5% and account for gelatin amount 0.2% to 0.3% are made.

2, according to the vitamin K of claim 1 ₁Soft capsule, wherein this diluent is a vegetable oil.

3, according to the vitamin K of claim 2 ₁Soft capsule, wherein this vegetable oil is soybean oil or Semen Maydis oil or Fructus Canarii albi wet goods.

4, according to the vitamin K of claim 1 ₁Soft capsule, wherein this opacifier is titanium dioxide or ferrum oxide etc.

5, according to the vitamin K of claim 1 ₁Soft capsule, wherein this coloring agent is the chocolate palm fibre.

6, according to the vitamin K of claim 1 ₁Soft capsule, wherein the consumption of this diluent is 29 weight portions, this opacifier accounts for 0.3% of gelatin amount, 0.3% of this colorant comprises gelatin amount.

7, vitamin K according to claim 1 ₁The preparation of soft capsule method is characterized in that:

(1) changes glue and get 0.35 part of 1 part in gelatin, 1 part in water and glycerol, opacifier is added in the glycerol, wear into uniform suspension, gelatin is added an amount of water make its imbibition with colloid mill.The water of remainder is put in the colloidal sol pot, be heated to 70 ℃, add expansible gelatin, the suspension and the water-soluble colorant of mixing, stir, dissolving, mixing be incubated 1-2 hour and leaves standstill, and the evacuation scumming is with clean filter cloth filtration, 50-60 ℃ of heat preservation for standby use; The viscosity of the glue that is made into is 4.5-5.2 ° of E, and water content is 47-49%;

(2) the batching lucifuge is operated, and takes by weighing the vitamin K of above-mentioned recipe quantity ₁Add in the diluent of recipe quantity, stir, abundant mixing, medicinal liquid is standby;

(3) pelleting lucifuge operation is pressed into ball with the medicinal liquid of gelatin solution and mixing by encapsulating machine;

(4) typing is rolled cage at temperature 22-24 ℃ with the soft capsule that presses by drying with dry, relative humidity is 45-60%RH typing 3-4 hour, typing is after tentatively pick soft capsule 60 ℃ of defats of petroleum ether of putting in order, primary drying uses and rolls cage, temperature 26-28 ℃, relative humidity is 25-30%RH, and dry air air inlet relative humidity is 20%RH, dry 4 hours; Redrying is used the tunnel drying drying room, and temperature 26-28 ℃, relative humidity is 20-25%RH, and dry 3 hours, natural cooling, finished product is through being up to the standards, and packing is packed promptly.

8, according to the preparation method of claim 7, wherein this diluent is a soybean oil, and this opacifier is a titanium dioxide, and this coloring agent is the chocolate palm fibre.