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CN1761460A - Antiflatulents in combination with histamine H1-receptor antagonists for treating gastrointestinal disorders - Google Patents

Antiflatulents in combination with histamine H1-receptor antagonists for treating gastrointestinal disorders Download PDF

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CN1761460A
CN1761460A CNA2004800074531A CN200480007453A CN1761460A CN 1761460 A CN1761460 A CN 1761460A CN A2004800074531 A CNA2004800074531 A CN A2004800074531A CN 200480007453 A CN200480007453 A CN 200480007453A CN 1761460 A CN1761460 A CN 1761460A
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pharmaceutical composition
lactobacillus
colic
histamine
diphenhydramine
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大卫·伯勒尔
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LifeScape BioSciences Inc
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Abstract

Compositions and methods for providing relief from pain and/or discomfort associated with gastrointestinal disorders, including, for example, bloating, crying, gas, cramping, regurgitation, diarrhea and gastrointestinal pain, associated with colic comprising, at least one antiflatulent, at least one histamine H1-receptor antagonist, and optionally,one or more prebiotic and/or one or more probiotic.

Description

Antiflatulent and histamine H 1Receptor antagonist coupling treatment gastroenteropathy
The present invention requires to enjoy the U.S. Provisional Application No.60/455 that submitted on March 18th, 2003,417 priority, and it incorporates this paper by reference into.
Invention field
The present invention relates to treat the compositions and the method for gastroenteropathy.More specifically, the present invention relates to alleviate pain relevant and/or uncomfortable compositions and method with colic.It also relates to alleviation pain relevant with inflammatory bowel and infectious diarrhea and/or uncomfortable compositions and method.
Background technology
Colic is about 20 (20%) percent baby's of influence the developmental character gastroenteropathy of limit certainly.Though the cause of disease of colic still imperfectly understands, the medical expert thinks that its symptom slow (logy) may be relevant with overfeeding with the hormone in jejune digestive system, anaphylaxis, the breast milk.Colic is to be the syndrome of feature with the outbreak of the omen severe stomachache due to being cry and shout by the agitation of flatulence, belch (gas), cramp, regurgitation, diarrhoea and gastrointestinal tract pain and healthy babies.It is serious that colic outbreak is tended to become at night, and the common means of consoling are as feeding, show tender care for or more changing babies' napkin being inoperative.Colic is identical with girl, the first-born child and the child's in back next life influence to boy.It often appears at age in 2-4 week first, can continue 3 months or longer.
The baby who suffers from colic is usually expressed as crying and shout and can not stopping of longer time, thereby makes baby and caregiver all too irritated and nervous.Baby's colic thinks that father and mother seek one of modal reason of medical care at the child of life in first week.Though be optimum and self-limited course, baby's colic can produce serious spirit, emotion and physiological load to father and mother.Colic can influence father and mother's love knot, causes the marriage anxiety, causes unnecessary hospitalization, and causes the child to abuse (Balan, A.J., Management of infantile colic AmerPham Physician 1997 under some unfortunate situations; 55:235-241).Mother of colic infant may have the illusion of infanticiding (Levitsky, S.et al., Infant colic syndrome-maternal fantasies of aggression and infanticide Clin Pediatr2000; 39:395-400).In addition, colic is not to disappear in seamless slash, some children that suffer from baby's colic can run into gastrointestinal problems (Iacano in its later life, G., et al., Severe infantile colic and foodintolerance:a long-term prospective study.J PediatrGastroenterol Nutr 1991; 12:332-5).Need the pediatrician to seek, for baby and caregiver reduce the heavy burdens to treatment colic effective Therapeutic Method.
Can not cure colic at present.The therapeutic scheme of colic comprises medicine method and/or non-medicine method at present, and prerequisite is to need only their relief of symptoms a little.The treatment intervention commonly used of the colic that provides for father and mother is divided into four classes, comprises Diet Therapy, naturopathy, behavior therapy and Drug therapy.
Diet control comprises the professional advice of various nurture technology or uses hypoallergenic milk, Semen sojae atricolor or free from lactose prescription and early add food (Lothe, L., et al.cow ' s milk formula as a cause of infantilecolic:a double-blind study.Pediatrics 1982; 70:7-10; Forsyth BWC.Colic and the effectof changing formulas:a double-blind multiple-crossover study.J Pediatr 1989; 115,521-6; Treem, WR, et al.Evaluation of the effect of a fiber-enriched formula on infant colic.JPediatr1991; 119695-701).But the change of the use of soy formulations or nurture technology is not all effective to the colic of various situations.The data of studying these suggestions are summarized, find to use hypoallergenic original formulation such as partial hydrolysis or based on amino acid whose hypoallergenic original formulation only to the effective (Lucassen of about 25% baby, PLBJ, et al.Infantile colic:crying time reduction with a whey hydrolysate:a double-blind, randomizedplacebo-controlled trial.Pediatrics 2000; 106:1349-54; Estep, DC, et al.Treatment ofinfant colic with amino acid-based infant formula:a preliminary study.Acta Paediatr 2000; 89:22-7).
The naturopathy strategy of treatment colic comprises that physics change position is to alleviate gas generation/regurgitation, bosom, bag infancy, to apply abdominal pressure or stroke the baby.Additive method comprises takes sb's mind off sth so that the baby is minimized the attention of colic, for example be with the baby to ride, use stimulator, cradle or baby's swing (Lipton EL.Swaddlingand child care practice:historical, cultural and experimental observations.Pediatrics 1965 by bus; 35:521-67; Byrne JM, Horowitz FD.Rocking as a soothing intervention:the influence ofdirection and type ofmovement.Infant Behav Dev1981; 4:207-18).Another kind method is to play the baby's that can releive audiotape.But evidence suggests these methods and inoperative (Parkin PC in the medical literature, Schwartz CJ, Manuel BA.Randomized controlled trial of three interventions in themanagement of persistent crying of infancy.Pediatrics 1993; 92 (2): 197-201).These strategies are slightly oligodynamic alleviating on the colic symptom at most just.
The suggestion that colic is treated in behavior intervention is the least consistent Therapeutic Method of available effect.Some authors advocate the increase stimulus to the sense organ, and some other author promotion reduces this stimulation (Balon AJ.Management ofinfantile colic.Amer Pham Physician 1997; 55:235-242; Lucassen PLBJ, Assendelft WJJ, Gubbels JW, van Eijk TM, van Geldrop WJ, Effectiveness of treatments for infantile colic:systematic review.BMJ 1998; 316 (5): 1563-9; With Carey WB, " Colic "-primary excessivecrying as an infant-environmental interaction.Pediatr Clin North Am 1984; 31:993-1005).Other suggestions comprise early reacts to crying and shout or allows the baby cry and shout, to provide and console thing, carry out conventional nurture program, use the expression in the eyes contact or carry out interactive game.
The pharmaceutical intervention of treatment colic is to use prescribed and non prescribed medicine.The prescription drugs that uses comprises atropina and opiate (analgesic) at present, and they can provide alleviation, but are full of following risk, comprising: extrapyramidal sign, respiratory distress and constipation.For example, similar anticholinergic agent of effect and atropine such as hyoscyamine (LEVISINE TM, or GASTROSED TM) and Neoquess expansion pupil, increase heart rate, reduce saliva generation, alleviate gastrointestinal tract and urethra and bronchial spasm.Though anticholinergic agent be on the American market consistent show can effectively treat baby's colic prescription drugs only arranged, unfortunately, the baby that treated up to 5% has side effects, comprise dyspnea, asphyxia, epilepsy, faint, suffocate, stupor and muscle tone go down (Williams J, Watkin-Jones R.Dicyclomine:worrying symptoms associated with its use in some small babies.BMJ 1984; 288:901; Myers JH, Moro-Sutherland D, Shook JE.Anticholinergic poisoning in colicky infantstreated with hyoscyamine sulfate.Am J Emerg Med.1997; 15:532-5).In addition, report also that in the baby who takes two cyclammonium several examples dead (Garriott JC, Rodriguez R, Norton LE.Two cases of deathinvolving dicyclomine in infants.Clinical Toxicol 1984 are arranged; 22 (5): 455-462).
Reported that the nonprescription drugs that can effectively treat baby's colic comprises several analgesic or sleeping pill, comprised super physiological amount (high dose) diphenhydramine (BENADRYL ), phenobarbital, chloral hydrate, or even ethanol.But, the serious side effects relevant with several reagent may take place in suffering from the child of respiratory disorder, thereby limits its extensive use (Balon AJ.Management of infantile colic.Amer PhamPhysician 1997 in the treatment colic; 55:235-242; GurryD.Infantile colic.Australian Pham Phys 1994; 23 (3): 337-34632).
The safer nonprescription drugs of treatment colic comprises uses the clean or dimethyl polysiloxane of froth breaking, reduces the nonabsorbable nonprescription drugs of intestinal bubble size.Froth breaking has effect as safe as a house only, frequent recommended use, though several studies show that froth breaking does not have placebo good (Metcalf, TJ, et al., Pediatrics 1994July to the effect of baby's colic only; 94 (1): 29-34.Sferra, TJ, et al., Pediatr Clin North Am 1996 April; 43 (2): 489-510.Danielson, B.et al., Acta Paediatr Scand 1985 May; 74 (3): 446-50.Colon, AR, et al., AmFam Physician 1989 Dec; 40 (6): 122-4.).Therefore, nowadays the most common treatment method of colic is waited for that just the baby throws off one's illness.
Therefore, press for the chemical compound of pharmacology safely and effectively and compositions and the non-pharmacology technology that can be used to treat baby and child's colic.In order to satisfy this needs, the compositions and methods of the invention provide the Pharmaceutical composition (PROMETHADRYL ) of the safe and effective treatment of the energy multiple symptom relevant with child's colic with the baby.
Inflammatory bowel (IBD) relates to the generality term of a class disease of intestinal wall inflammation.Chronic IBD is divided into two big classes usually: Crohn disease and ulcerative colitis.Though there are some notable differences at the position of these diseases with the mode that influences intestinal wall, the two all causes stomachache and cramp, follows frequent, urgent, the loose bowel movement that blood, mucus and pus occur.The complication of the two comprises abscess and infection, fistula (fitula), hemorrhoid, intestinal wall perforation, nutrient malabsorption and loses weight.IBD increases the risk of human primary gastrointestinal cancers usually.In addition, this disease has systemic effect, comprises joint symptom and fatigue.IBD can be chronic, recurrent and debilitating disease.Many IBD patients face the probability of the medicine (steroid, immunosuppressive drug and salicyclic acid derivatives such as sulfasalazine and aminosalicylic acid) that life-time service has apparent side effect, for example regular infection, the anemia of wherein said side effect, are easy to scratch and anxious state of mind.Therefore, many people would rather have disease symptoms to be reluctant that also these side effect are arranged.Research (Munkholm, Gut 1994; 35) show that impaired gut barrier dysfunction or damage can give rise to diseases, IBD is for wherein a kind of.Contact between IBD and the impaired gut integrity is tangible.Therefore, in the IBD research field, to the enterobacteria balance with reduce toxic need attracting people's attention most.
Parasitize among the human gastrointestinal tract owing to surpass 400 kinds of known bacterial species, it is ecological and healthy that their population equilibrium influences intestinal greatly.Have and studies show that antibacterial can produce toxin and antitoxin, change the chemical composition of medicine and food, produce and the degraded vitamin, the degraded sitotoxin suppresses the growth of some pathogen.The product that derives from intestinal (the Alexander Ann Surg 1990 that also in increasing the systemic immunity inflammatory response, plays a role; 212 (4)).Zooscopy (the Pirzer Lancet 1991 that suffers from the inductive IBD of experiment; 338) support parasitic antibacterial and the avirulence toxin is the viewpoint of IBD inducement.Research (Giaffer J Med Microbiol 1991 to active Crohn disease patient; 35) show with static disease ulcerative colitis or normal control and compare visibly different intestinal flora.In these individualities, the aerobe especially concentration of escherichia coli and anaerobic bacteria bacteroides fragilis (bacteriodes fragilis) and bacteroides vulgatus (bacteriodes vulgatus) increases.In addition, in all Crohn disease patients, bacillus bifidus reduces.
At (Gionchetti Gastroenterology 1998 in addition; 114) in double blinding, the research of placebo, 40 patients of ulcerative colitis are with specific probiotic bacteria bifidobacterium longum, bifidobacterium infantis, short bifidus bacillus, bacillus acidophilus, lactobacillus casei, lactobacillus delbrueckii, Lactobacillus plantarum and streptococcus thermophilus preparation or placebo treatment.After six (6) individual months, all there has not been symptom behind the patient of 85% (17/20) probiotic bacteria treatment, and the recurrence of 100% (20) placebo group.
Therefore, contain that the froth breaking that is used for the treatment of flatulence/flatulence is clean, the diphenhydramine that is used for the treatment of the cramp/symptom of feeling sick, as the arabinogalactan (larch burch) of fiber source be used for the product P ROMETHADRYL  of the beneficial source of students material of beneficial bacteria species bacillus bifidus and lactobacillus, add that probiotic bacteria complex (PROMETHADRYL  PLUS) will be useful in the related indication treatment of IBD.
Infectious diarrhea is global health problem.In many developing countries, diarrhea disease is still baby and death of child and Disease Inducement (Snyder Bull World Health Organ 1982; 60, Ho JAMA 1988; 260).Used many probiotic bacteria prevention diarrhea diseases, success is different.Therefore, use selectivity probiotic bacteria material, add to help lend some impetus to the beneficial source of students material of beneficial bacteria (bacillus bifidus and lactobacillus) such as arabinogalactan or inulin and froth breaking clean (belch/flatulence) and diphenhydramine (cramp/feel sick), product P ROMETHADRYL  PLUS is beneficial to treatment and the relevant symptom of infectious diarrhea (comprising traveler's diarrhea).
Summary of the invention
The invention provides the compositions and the method that are used for the treatment of gastroenteropathy, described gastroenteropathy includes but not limited to sour dyspepsia, colic, diarrhoea, heartburn, irritable bowel syndrome, sour stomach, the belch relevant with the aforementioned state of an illness, gastric ulcer, esophagus, stomach or duodenal ulcer of digestive system disease, dyspepsia, flatulence, comprise a little less than the stomach of unknown reason of gastric cancer, comprise lymphadenomatous wellability gastropathy, Crohn disease, the eosinophilic granuloma, pulmonary tuberculosis, syphilis and sarcoidosis, abdominal injury, chronic pancreatitis, gallbladder (bilary) disease, the Zollinger-Ellison syndrome, motion sickness, otitis media and gastrointestinal other diseases and disease.
The present invention also provides compositions and the method that is used for the treatment of immunological diseases such as diabetes, cancer and HIV.The introducing of one or more beneficial source of students materials such as larch arabinogalactan or inulin promotes immune enhancing in the immune downtrod individuality (as diabetes, cancer and HIV patient), alleviate and inflammatory bowel (IBD), the relevant symptom of enteritis syndrome (IBS), alleviate Ia disease as irritated and frequent infectious diarrhea, increase medium chain fatty acid and generate, and increase the synthetic of folic acid (vitamin) by the formation that promotes beneficial source of students gastrointestinal tract ecology.This is especially favourable in the coexistence disease patient who impaired gastrointestinal tract health is shown the Secondary cases problem.
Usually, described pharmaceutical composition comprises at least a antiflatulent of effective dose, at least a histamine H 1Receptor antagonist and optional one or more beneficial sources of students such as larch arabinogalactan or inulin, and/or one or more probiotic bacterias; Described method is included in relevant pain of gastroenteropathy and/or uncomfortable the generation or afterwards, the patient who treats to needs uses at least a antiflatulent, at least a histamine H together or roughly together 1Receptor antagonist and optional one or more beneficial sources of students such as larch arabinogalactan or inulin, and/or one or more probiotic bacterias.Preferably, described compositions and method are used for the treatment of the easily sharp property syndrome of colic, intestinal, dyspepsia, stomach is weak and flatulence.
In a preferred embodiment, the invention provides pain relevant among the patient that alleviation need treat and/or uncomfortable compositions and method with colic.Usually, pharmaceutical composition comprises at least a antiflatulent and at least a histamine H of effective dose 1Receptor antagonist and optional one or more beneficial sources of students and/or one or more probiotic bacterias; Described method is included in pain and/or uncomfortable the generation or afterwards, the patient who treats to needs uses at least a antiflatulent, at least a histamine H together or roughly together 1Receptor antagonist and optional one or more beneficial sources of students and/or one or more probiotic bacterias, comprise alleviate relevant with colic, for example by flatulence, cry and shout (crying), belch (gas), cramp, regurgitation, diarrhoea, and gastrointestinal tract the pain pain or the discomfort that cause.
The present invention is based on following discovery: antiflatulent, histamine H 1Receptor antagonist and the larch arabinogalactan of choosing wantonly and/or the combination of one or more probiotic bacterias can be used effectively together or roughly together, to strengthen treatment to gastroenteropathy, preferably include alleviate relevant with colic, for example by flatulence, cry and shout, belch, cramp, regurgitation, diarrhoea, and gastrointestinal tract the pain pain or the discomfort that cause.Surprising is antiflatulent and histamine H 1The combination of receptor antagonist provides than using the more effective result of independent arbitrary feature.
In one embodiment of the invention, have the pharmaceutical composition that comprises the clean and diphenhydramine of froth breaking that is used for the treatment of colic.Preferably, said composition comprises larch arabinogalactan and/or one or more probiotic bacterias.Preferably, said composition is used for the treatment of colic, alleviate relevant with colic, for example by flatulence, cry and shout, belch, cramp, regurgitation, diarrhoea, and gastrointestinal tract the pain pain or the discomfort that cause, and with pharmaceutically acceptable carrier, antiflatulent, competitive histamine H 1Receptor antagonist and larch arabinogalactan.
More preferably, described compositions comprises the antiflatulent that can roughly change the tensile effective dose of bubble surface.More preferably, compositions comprises froth breaking only as antiflatulent.
Further preferably, compositions comprises at least a competitive histamine H that can roughly suppress the effective dose of respiratory tract, blood vessel and gastrointestinal tract smooth muscle contraction 1Receptor antagonist.Preferably, histamine H 1Receptor antagonist provides antimuscarinic activity (alleviating the GI cramp) and cholinolytic activity (alleviate and feel sick and the promotion calmness).More preferably, compositions comprises diphenhydramine as competitive histamine H 1Receptor antagonist.
Further preferably, compositions comprises one or more beneficial sources of students of the amount that can increase immunoregulatory activity in the gastrointestinal tract.Most preferably, compositions comprises larch arabinogalactan and/or inulin.
Further preferably, compositions comprises one or more probiotic bacterias of the amount that can promote healthy intestinal ecology and normal gastrointestinal tract function.
Preferably, the pharmaceutical composition of treatment colic is a peroral dosage form, and liquid dosage form more preferably is as suspension.
Further preferably, compositions does not contain dyestuff, alcohol, artificial sweetening agent such as glucide and aspartame, artificial flavors and artificial preservative substantially.
In another aspect of the present invention, have the method for treatment colic, comprise that described compositions comprises at least a antiflatulent, at least a histamine H to the compositions of patient's administering therapeutic effective dose of needs treatment 1Receptor antagonist and optional one or more beneficial sources of students such as larch arabinogalactan or inulin, and/or one or more probiotic bacterias.Preferably, antiflatulent, histamine H 1Receptor antagonist, beneficial source of students and probiotic bacteria are selected according to the treatment of colic.
Apparatus and combination by supporting in concrete record and/or this description in the appending claims can realize and realize at least a above-mentioned aspect/embodiment and advantage.Other aspects of the present invention/embodiment and attendant advantages part are in the following description mentioned, or by implementing or using the present invention and recognize.Be understandable that the general description of front and following detailed are exemplary and the property enumerated, do not resemble and limit the present invention claims.
The specific embodiment
The whole content of all patents, patent application and the document of quoting in this description is all incorporated this paper by reference into.Under inconsistent situation, be as the criterion with the present disclosure that comprises definition.
In preferred embodiments, the invention provides the new compositions and the method that are used for the treatment of gastroenteropathy such as colic, comprise at least a antiflatulent and at least a histamine H 1Receptor antagonist mixes with pharmaceutically acceptable carrier.In another preferred embodiment, the present invention relates to be used for the treatment of the new compositions and the method for gastroenteropathy such as colic, comprise at least a antiflatulent, at least a histamine H 1Receptor antagonist and one or more beneficial sources of students such as larch arabinogalactan and/or inulin mix with pharmaceutically acceptable carrier.Further preferably, compositions for example alleviate by specifically be the relevant flatulence of colic with gastroenteropathy, cry and shout, pain and/or discomfort that belch, cramp, regurgitation, diarrhoea and gastrointestinal tract pain cause.
Term used herein " antiflatulent " refers to reduce the material of the amount of flatulence in the harmonization of the stomach intestinal.The present invention considers that the unrestriced exemplary antiflatulent or derivatives thereof that uses comprises maltodextrin and organopolysiloxane, and is clean as dimethyl polysiloxane, methyl polysiloxane and froth breaking.
Term used herein " colic " is to be the syndrome of feature with the outbreak of the omen severe stomachache due to for example being cry and shout by flatulence, belch, cramp, regurgitation, diarrhoea and gastrointestinal tract pain and healthy babies or child's agitation.
Term used herein " gastroenteropathy " refers to pain and the symptom relevant with disease with various gastrointestinal diseases, described gastrointestinal disease and disease comprise following disease and disease: sour dyspepsia, colic, diarrhoea, heartburn, irritable bowel syndrome, sour stomach, the belch relevant with the aforementioned state of an illness, gastric ulcer, esophagus, stomach or duodenal ulcer of digestive system disease, dyspepsia, flatulence, comprise a little less than the stomach of unknown reason of gastric cancer, comprise lymphadenomatous wellability gastropathy, Crohn disease, the eosinophilic granuloma, pulmonary tuberculosis, syphilis and sarcoidosis, abdominal injury, chronic pancreatitis, gallbladder (bilary) disease, the Zollinger-Ellison syndrome, motion sickness, otitis media and gastrointestinal tract.
Term " histamine H used herein 1Receptor antagonist " refer to by specific inhibition H 1The material of histamine receptor performance pharmacological action.Antihistaminic is to reduce or to prevent the normal most physiological effecies that produce of histamine, comprises reversible, the competitive H that suppresses respiratory tract, blood vessel and gastrointestinal tract smooth muscle contraction 1Receptor antagonist.The present invention considers the exemplary histamine H that uses 1Receptor antagonist includes but not limited to acrivastine, astemizole, azatadine, azclastine, bromodiphenhydramine, brompheniramine, cetirizine, chlorine Qu Mitong, clemastine (clematine), Cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, fexofenadine, hydroxyzine, ketoffen, loratadine, norastemizole, phenindamine, pyrilamine, temelastine, terfenadine, tripelennamine, triprolidine and pharmaceutically effective derivant and salt.
Term used herein " pain and/or discomfort " refers to unhappiness sensation or the state relevant with acute or potential health disorder (as i or I).Pain and/or some uncomfortable symptoms include but not limited to flatulence, cry and shout, belch, cramp, regurgitation, regurgitation diarrhoea and gastrointestinal tract pain.
Term " pharmaceutically acceptable carrier or adjuvant " refer to can and antiflatulent of the present invention, histamine H 1Receptor antagonist and optional larch arabinogalactan and/or one or more probiotic bacterias are applied to the patient together and do not destroy its pharmacological activity and nontoxic carrier or adjuvant when using with the dosage of the present composition that is enough to the delivery treatments amount.
Term used herein " pharmaceutically acceptable salt " refers to comprise from pharmaceutically acceptable nontoxic alkali the salt of inorganic base and organic base preparation.Salt derived from inorganic base comprises sodium salt, potassium salt, lithium salts, ammonium salt, calcium salt, magnesium salt, ferrous salt, zinc salt, manganous salt, aluminum salt, iron salt, manganic salt etc.Salt derived from pharmaceutically acceptable organic nontoxic alkali comprises primary amine salt, secondary amine salt, tertiary ammonium salt and quaternary amine, replace amine, comprise naturally occurring replacement amine, cyclammonium and deacidite, as triethylamine, tripropyl amine (TPA), 2-dimethylaminoethanol, 2-DEAE diethylaminoethanol, lysine, arginine, histidine, caffeine, procaine, N-ethylpiperidine, Compocillin, choline, betanin, ethylenediamine, glycosamine, methylglycamine, theobromine, purine, piperazine, piperidines, polyamines resin etc.
Term used herein " beneficial source of students " refers to growth or active or the two a series of non-digestibility dietary supplement that haves both at the same time of specific bacteria in the selective stimulating colon such as lactobacillus or bacillus bifidus.The non-limitative example of benefit source of students comprises larch arabinogalactan, lactulose, lactose, oligosaccharide and inulin.
" probiotic bacteria " refers to help in the balance human body autochthonous microorganism level in the gastrointestinal tract especially to promote the antibacterial of the ecological and normal gastrointestinal tract function of healthy intestinal to term used herein.Probiotic bacteria participates in regulating function of intestinal canal, as mucosa secretion and utilization, alimentation, gastrointestinal tract dynamia and visceral bloodflow (Clin Nutr 1996; 15).Probiotic bacteria prevents that also potential pathogenic microbes growth is superfluous, stimulates intestinal immune system of defense (Clin Nutr 1996; 15).The probiotic bacteria example of non-restrictive illustrative comprises bifidobacterium species, as bifidobacterium (bifidobacterium bifidum), short bifidus bacillus (bifidobacterium brevis), bifidobacterium longum (bifidobacterium longus), bifidobacterium infantis (bifidobacterium infantis); Lactobacilli is as bacillus acidophilus (actobacillusacidophilus), bifidobacterium (Lactobacillus bifidus), Lactobacillus brevis (Lactobacillus brevis), Lactobacillus bulgaricus (Lactobacillus bulgaricus), lactobacillus casei (Lactobacillus casei), Deshi Lactobacillus (actobacillus delbruekii), lactobacillus lactis (Lactobacillus lactis), Lactobacillus plantarum (actobacillus plantarum), Lactobacillus reuteri (Lactobacillus reuteri), lactobacillus rhamnosus (Lactobacillus rhamnosus), Lactobacillus salivarius (Lactobacillus salivaius); Enterococcus faecalis (Enterococcusfaecium); Bu Shi yeast (Saccharomyces Boulardii) and streptococcus thermophilus (StreptococcusThermophilus).
Term used herein " does not contain substantially " and refers to fully or almost not or lack the state of special characteristic or chemical compound.
Term used herein " " refers to divide other dosage form to use active component to the patient, makes and can simultaneously or use active component in a period of time, thereby make the localization effects of benefited each dosage form of patient roughly together.For example, active component can be taken together, and the each interval several seconds is extremely at least about 30 minutes.
In a preferred embodiment, select the antiflatulent dimethicone, with the treatment colic, comprise the treatment flatulence, cry and shout, belch, cramp, regurgitation, diarrhoea, and relative gastrointestinal tract pain.Froth breaking is described as containing formula [(CH only 3) 3SiO-] nThe exhaustive methylation linear siloxanes polymer of repetitive and the mixture of silicon dioxide, affiliated polymer formula [(CH 3) 3SiO-] trimethylsiloxy (tremethylsiloxy) end-blocking unit stablized.Clean or the dimethyl polysiloxane of froth breaking also is called polysiloxanes or organopolysiloxane sometimes.Be not limited to theory, froth breaking is only by evacuating or preventing in the gastrointestinal tract around the flatulent defoamer of mucous airbag (gas pocket) the formation alleviation.It has been generally acknowledged that froth breaking its effect in the harmonization of the stomach intestinal only,, they are merged, by having the hiccups or being easier to discharge by flatulence to change the surface tension of bubble.
In another preferred embodiment, select histamine H 1Receptor antagonist is with the treatment colic, and comprise the treatment flatulence, cry and shout, belch, cramp, regurgitation, diarrhoea, and relative gastrointestinal tract pain.The non-selective antihistaminic diphenhydramine of the first generation non-selectively with maincenter and H on every side 1Receptors bind causes calm and CNS suppresses.In addition, because its cholinergic (OPIOIDS effect) effect, diphenhydramine has functions/drying by the exocrine gland that suppresses cholinergic innervation.It also has resisting emesis and antimuscarinic effect, and alleviates nauseating, motion sickness and vomiting.
Above-mentioned antiflatulent and histamine H 1Receptor agonist compounds can also and one or more beneficial sources of students such as larch arabinogalactan and/or inulin formulated in combination, be used or absorb.The larch arabinogalactan is the polysaccharide powder that derives from fallen leaves pinaster (larix species) timber, comprises about arabinogalactan of 98 (98%) percent.The larch arabinogalactan is commonly considered as the medicine of immunostimulation safely and effectively for department of pediatrics and adult's use through the source that U.S. food and Drug Administration (FDA) ratify to be used as dietary fiber.Thereby the larch arabinogalactan is commonly referred to be and produces the material of healthy antibacterial stimulation to host's clinical beneficial effect in the intestinal of host living beings.Healthy intestinal ecology increases immunne response, be protect from infection and yeast, fungus and pathogenic bacteria growth superfluous necessary, described pathogenic bacteria for example participate in duodenal ulcer helicobacter pylori, participate in the streptococcus and the sense of participation metachromia diarrheal clostridium of otitis media.In addition, the generation of the probiotics of larch arabinogalactan by promote being responsible for vitamin synthetic (as folic acid) and must medium chain fatty acid generate and promote normal intestinal ecology.
Inulin is the natural storage carbohydrates of finding in the multiple eating plant species, and described food plant species comprise Herba Cichorii, Carlina acaulis, fragrant-flowered garlic, Bulbus Allii Cepae, Radix Asparagi, Semen Tritici aestivi, Fructus Hordei Vulgaris, rye (Secale cereale L.), Bulbus Allii and Fructus Musae.Inulin belongs to the levan classification.Levan is the chemical compound with one or more fructosyls-fructose key.Inulin is almost completely or the material with β (2-1) fructosyl-fructose key of exclusiveness.As a rule, can find glucose moiety at the end of fructose chain.The same with the larch arabinogalactan, inulin is commonly referred to be the material that is used for producing at host's intestinal healthy antibacterial.When by digestion, inulin until arriving large intestine, generates various metabolism end product this colon micropopulation with its fermentation substantially not through digestive system with changing.Inulin also can be used as sweeting agent.
Antiflatulent and histamine H 1Receptor agonist compounds can also be prepared, use or absorb with one or more probiotic bacterias combinations.Probiotic bacteria is by being colonizated in small intestinal and expelling malignant bacteria to play a role, thereby recovers the balance of intestinal flora.Some probiotic bacterias also produce the material that suppresses pathogenic bacteria, with pathogenic bacteria competition nutrition, and the immune system of stimulation human body self.In breast-fed babies, bacillus bifidus accounts for more than 90% of total intestinal bacterium, and in the baby that milk powder is fed, bacillus bifidus (the Microbiol Immunol 1984 that do not preponderate; 28).As if some beneficial bacteria strain comprises lactobacillus and bacillus bifidus, preferably depend on arabinogalactan or other beneficial source of students materials (the J Food Microbiol 1994 that survives; 24).Other probiotic bacterias often are called and think " protectiveness " gastrointestinal tract antibacterial (Clin Nutr 1996 as lactobacillus rhamnosus, Lactobacillus plantarum and Lactobacillus reuteri; 15).
In addition, pharmaceutically acceptable carrier or adjuvant can be used in the pharmaceutical composition of the present invention.The example of the non-restrictive illustrative of pharmaceutically acceptable carrier or adjuvant comprises ion-exchanger; Aluminium oxide; Aluminium stearate; Lecithin; Self-emulsifying drug delivery systems (SEDDS) is as alpha-tocopherol cetomacrogol 1000 succinate or other similar polymer delivery matrices or system; Serum albumin is as the human serum albumin; Buffer substance is as phosphate; The partial glycerol ester admixture of glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid, water; Salt; Or electrolyte, as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose base material, Polyethylene Glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polypropylene oxide-block polymer, Polyethylene Glycol and lanoline.Cyclodextrin, for example α-, β-and the derivant of gamma-cyclodextrin or chemical modification, as comprise that the hydroxyalkyl cyclodextrin of 2-and 3-HP-or other dissolved derivants also can be advantageously used in and strengthen effective antiflatulent of treatment and histamine H among the present invention 1Sending of receptor antagonist (being with or without the larch arabinogalactan).
In addition, the effective antiflatulent of treatment, histamine H among the present invention 1Receptor antagonist and larch arabinogalactan can contain one or more asymmetric carbon atoms, therefore have racemoid and racemic mixture, single enantiomer, non-enantiomer mixture and independent diastereomer.Each chiral carbon can be R or S configuration.All these isomeric forms of these chemical compounds all comprise within the scope of the present invention.
Pharmaceutical composition of the present invention for example can be easily from antiflatulent, the histamine H of commercial source 1Receptor antagonist, larch arabinogalactan and probiotic bacteria preparation can be mixed with liquid, suspension or solid dosage forms or its combination.For example, pharmaceutical composition can be mixed with and contain antiflatulent and histamine H 1The single unit dose of liquid, suspension or the solid dosage forms of receptor antagonist and the larch arabinogalactan of choosing wantonly and/or one or more probiotic bacterias.Equally, the present invention considers to prepare independent composition dosage form, roughly uses or absorb each dosage together with identical or different dosage form, for example, take antiflatulent with liquid dosage form, take the larch arabinogalactan, take histamine H with solid dosage forms with the suspension dosage form 1Receptor antagonist, or its combination, or take with the dosage form of solid, liquid or suspension respectively or use them.The single unit dose that preferably comprises two kinds or all active component is mixed with liquid dosage form, as suspension.
But but roughly use with identical or different dosage form respectively together or when taking active component, its order of using or absorbing is not crucial.In other words, for example, antiflatulent and histamine H 1Receptor antagonist and optional larch arabinogalactan and/or one or more probiotic bacterias can absorb simultaneously, perhaps at first absorb antiflatulent, are histamine H then 1Receptor antagonist and larch arabinogalactan; Perhaps at first absorb histamine H 1Receptor antagonist is larch arabinogalactan and antiflatulent then; Perhaps at first absorbing the larch arabinogalactan, is histamine H then 1Receptor antagonist and antiflatulent.Preferably, " colic " behavior take place in or afterwards, as required with antiflatulent and histamine H 1Receptor antagonist and optional larch arabinogalactan and/or inulin and/or one or more probiotic formulations become can be used as the suspended mixture that single unit dose is absorbed simultaneously.
The example of the non-restrictive illustrative of the antiflatulent of commercial source comprises MYLICON , derives from Ft.Washington, the Johnson ﹠amp of Pennsylvania; Johnson-Merck Consumer Pharmaceuticals Co.; With the PHAZYME  that derives from GlaxoSmithKline.
The histamine H of commercial source 1The example BENADRYL  of the non-restrictive illustrative of receptor antagonist, deriving from the address is 235 East 42nd Street New York, NY10017, the Pfizer of USA, Inc..
Beneficial source of students and probiotic bacteria enriching substance that many commercial source are arranged.
Be understandable that compositions of the present invention also comprises pharmaceutically acceptable carrier or adjuvant and at least a antiflatulent, at least a histamine H 1Receptor antagonist or its pharmaceutically acceptable salt and optional larch arabinogalactan combination.In addition, pharmaceutical methods of the present invention comprises and contains that antiflatulent such as froth breaking are clean, histamine H 1The cooperative compositions of receptor antagonist such as diphenhydramine and the larch arabinogalactan of choosing wantonly, wherein active component exists with the effective dose that can alleviate pain relevant with gastroenteropathy such as colic and/or discomfort.In addition, the medication maximum dose of active component is based on body weight of being treated the patient and age.
Usually known froth breaking with safe department of pediatrics and adult's effect is used can change the tensile effective dose of bubble surface substantially only.Be not limited to theory, think that froth breaking reduces to prevent " turbulent flow " relevant with aerogenesis to cramp and gastrointestinal tract dynamia only.The compositions that the present invention is used for the treatment of colic comprises following prescription, and wherein the amount of antiflatulent is the about 120mg/ml of about 40mg/ml-.More preferably, the amount of antiflatulent is about 67mg/ml.
In baby's colic, diphenhydramine is used with the basic dosage regimen of respiratory tract, blood vessel and gastrointestinal tract smooth muscle contraction among obvious inhibition baby and the child.This foundation level of diphenhydramine reduces observed side effect when the high dose diphenhydramine is applied to baby and child.Dosage is enough high, stimulating required the replying that alleviates aspect colic symptom (Antimuscarinic) and the appropriateness calm (antiflatulent), but should be unlikely to influence the air flue contraction of bronchus air flue, otherwise may lose breathing.The compositions that is used for the treatment of colic among the present invention comprises following prescription, wherein histamine H 1Receptor antagonist and diphenhydramine are similar, and amount is the about 4.0mg/ml of about 1mg/ml-.More preferably, histamine H 1The amount of receptor antagonist is about 2.0mg/ml.
The beneficial source of students that has safe department of pediatrics and adult's effect is according to the literature used can increase in the gastrointestinal tract effective dose of immunoregulatory activity.The compositions that is used for the treatment of colic among the present invention randomly comprises one or more beneficial sources of students, and as larch arabinogalactan and/or inulin, its amount is the about 500mg/ml of about 25mg/ml-.More preferably, the amount of one or more beneficial sources of students is about 250mg/ml.
Known have one or more probiotic bacterias of safe department of pediatrics and adult's effect can promote that healthy intestinal is ecological and the effective dose of gastrointestinal function normalization is used.The compositions that is used for the treatment of colic among the present invention randomly comprises a kind of or many middle probiotic bacterias, and its amount is about 3,000,000 (3,000,000)-Yue 30,000,000,000 (30,000,000,000) colony-forming units (CFU), or about 2,500,000,000-5,000,000,000 living cells/dosage or about 20,000,000,000 living cells/skies.More preferably, the amount of one or more probiotic bacterias is about 3,000,000,000 (3,000,000,000) CFU, promptly is about 100mg/ml.
What the people was surprised in addition is that froth breaking compositions clean and diphenhydramine is better than the clean or diphenhydramine of independent froth breaking to the effect for the treatment of colic.Also shockingly find: the present invention uses less diphenhydramine to reach effective result, and has also reduced the potential safety hazard with independent use diphenhydramine.
According at present the clean department of pediatrics of froth breaking being recommended usage, the method for treatment colic comprises uses and/or absorbs antiflatulent such as the clean dosage of froth breaking is the about 80mg/1.2ml of the about 40mg/0.6ml-of every dosage.More preferably, the amount that antiflatulent such as froth breaking are used only and/or absorbed is about 40mg/0.6ml, and every day three (3) is inferior to six (6) inferior.Most preferably, the amount that antiflatulent such as froth breaking are used only and/or absorbed is about 40mg/0.6ml, and every day four (4) is inferior, four (4) hours to six (6) hours approximately at interval.
The method of treatment colic comprises: based on present department of pediatrics usage criteria to diphenhydramine, histamine H 1The daily dose of receptor antagonist is about 5mg/kg/ days-Yue 150mg/m for the child more than the 10kg 2/ day.All be lower than this dosage criteria (promptly being lower than 10kg or 22Ib), histamine H among the present invention owing to need carry out most children of colic treatment 1The amount of receptor antagonist is lower, treats useful dosage and is about 1.25mg/kg/ days.More preferably, histamine H 1Receptor antagonist and diphenhydramine are similar, and the amount of using and/or absorbing is the about 2.5mg/1.2ml of about 1.25mg/0.6ml-, and every day three (3) is inferior to six (6) inferior.Most preferably, histamine H 1The amount that receptor antagonist such as diphenhydramine are used and/or absorbed is about 1.25mg/0.6ml (promptly about 1.25mg/kg/ days or about 0.5mg/Ib), and every day four (4) is inferior, four (4) hours to six (6) hours approximately at interval.
The method of treatment colic randomly comprises: the amount of beneficial source of students such as larch arabinogalactan and/or inulin is the about 250g/1.2ml of the about 125mg/0.6ml-of every dosage.More preferably, the amount that the larch arabinogalactan is used and/or absorbed is about 125g/0.6ml, and every day three (3) is inferior to six (6) inferior.Most preferably, the amount that the larch arabinogalactan is used and/or absorbed is about 125g/0.6ml, and every day four (4) is inferior, four (4) hours to six (6) hours approximately at interval.The larch arabinogalactan is all thought safe at present all medication strategies.
The method of treatment colic also randomly comprises: the amount of probiotic bacteria is the about 9mg/0.6ml of the about 3mg/0.6ml-of every dosage.More preferably, the amount that one or more probiotic bacterias are used and/or absorbed is about 6mg/0.6ml, and every day three (3) is inferior to six (6) inferior.Most preferably, every day four (4) is inferior, four (4) hours to six (6) hours approximately at interval.Most preferably, one or more probiotic bacterias use and/or the amount of picked-up is about 5,000,000,000 living cells of about 2,500,000,000 living cells/0.6ml-/1.2ml, and every day three (3) is inferior to six (6) inferior.Most preferably, every day four (4) is inferior, four (4) hours to six (6) hours approximately at interval.
In addition, the method and composition of treatment baby's colic and child and adult's gastrointestinal disease comprises based on body weight of being treated the patient and age and uses/absorb active component: antiflatulent such as froth breaking only, histamine H 1Receptor antagonist such as diphenhydramine and optional one or more beneficial sources of students such as larch arabinogalactan and/or inulin, and/or one or more probiotic bacterias (mg/kg/ days).Based on the known method in the pharmaceutical field, as Remington:The Scienceand Practice of Pharmacy, 20th Ed.2000 Mack Publishing and Martindale-The CompleteDrug Reference, 33rd Ed.1999, Pharmaceutical Press, medical practitioner will know and use how many active component.For example, according to the build and the body weight of individuality, froth breaking be the accounts show a surplus of and is being the about 120mg/ml of about 40mg/ml-with the amount of using/absorbing; The diphenhydramine amount is the about 5mg/ml of 1mg/ml-; The amount of one or more beneficial sources of students is the about 1000mg/ml of about 250mg/ml-; The amount of one or more probiotic bacterias is the about 1000mg/ml of about 5mg/ml-.
Pharmaceutical composition can be to be suitable for oral form, but for example tablet, lozenge, water or oil suspension dispersed powders or granule, Emulsion, hard or soft capsule, syrup or elixir.Can be used for oral compositions according to known method preparation in the field of making pharmaceutical composition, this compositions can comprise one or more reagent, and for example sweeting agent, fumet, coloring agent etc. are to provide pharmaceutically exquisite and delicious preparation.
Tablet contains active component and is suitable for making the mixture of the pharmaceutically acceptable non-toxic excipients of tablet.These excipient can be inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating and disintegrating agent, for example alginic acid, cross-linked carboxymethyl cellulose sodium, corn starch; Or binding agent, for example Radix Acaciae senegalis, gelatin or starch, and lubricant, for example magnesium stearate or stearic acid.Tablet can not add coating, or is coated by known technology, delaying disintegrate and the absorption in gastrointestinal tract, thereby provides the continuous action of longer time.Tablet is masticablely maybe can not chew, by known technology design weight, effectiveness and the hardness in the pharmaceutical field.
Being used for oral prescription can also be hard gelatin capsule, and wherein for example calcium carbonate, calcium phosphate or Kaolin mix for active component and inert diluent; Or Perle, wherein active component and suitable oily medium such as Oleum Arachidis hypogaeae semen, liquid paraffin or mixed with olive oil.
Being used for oral prescription can also be lozenge, and wherein active component is mixed in the hard confectionery compositions.Suitable hard confectionery compositions can be spissated from various height, comprise corn syrup prepares as the sucrose solution of second neccessary composition.Other known hard confectionery compositions can use sucrose in addition through the good any appropriate sweet taste excipient of testing.
Aqueous suspension comprises active component and the suitable mixture of making the excipient of aqueous suspension.These excipient or its combination can be suitable suspending agents, but for example alginate, carboxymethyl cellulose, carboxyl polymethylene, carrageenin, silica sol, corn starch flow starch, gelatin, guar gum, Radix Acaciae senegalis, tragacanth gum, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, maltodextrin, methylcellulose, microcrystalline Cellulose, pectin, Polyethylene Glycol 800, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose or xanthan gum; Dispersion or wetting agent can be the naturally occurring phospholipid of any appropriate, lecithin for example, or the polycondensation product of oxyalkylene and fatty acid, Myrj 45 for example, or the polycondensation product of ethylene oxide and long-chain fatty alcohol, heptadecaethyleneoxycetanol for example, or ethylene oxide and derived from the polycondensation product of the part ester of fatty acid and hexitol, polyoxyethylene sorbitol monoleate for example, or ethylene oxide and derived from the polycondensation product of the part ester of fatty acid and hexitol and anhydride, for example Tween-81, or water.Aqueous suspension can also contain one or more suitable antiseptic, for example ethyl benzoate or n-Propyl benzoate, p-Hydroxybenzoate, the coloring agent that one or more are suitable, the fumet that one or more are suitable, as Cortex Cinnamomi, chocolate, fruit flavor (machine Fructus Pruni pseudocerasi, Fructus Vitis viniferae, orange, Fructus Fragariae Ananssae etc.), menthol, Herba Menthae, two or more combination of Rhizoma et radix valerianae and its, the sweeting agent that one or more are suitable, as calcium cyclamater, dextrose, fructose, galactose, glucose, glycerol, maltose, mannose, ribose, the starch solids of partial hydrolysis, the corn-syrup solids of partial hydrolysis, Sodium Cyclamate, sorbitol (sorbital), inulin, Sucralose, sucrose, xylitol or xylose and one or more suitable coloring agent.
But being fit to provides and dispersion or wetting agent, suspending agent and the mutually blended active component of one or more antiseptic with granule by adding the dispersed powders that entry prepares aqueous suspension.Suitable dispersion or wetting agent and suspending agent can be toply to have mentioned those.Also can there be other suitable excipient, for example sweeting agent, fumet and coloring agent.
Syrup and elixir can be prepared with suitable sweeting agent, and described sweeting agent for example is one or more in glycerol, Sorbitol, inulin, sucrose or the xylose.This prescription can also contain suitable obtundent, antiseptic such as citric acid and fumet and coloring agent.
In order to further specify the present invention and its advantage, the concrete non-limiting example below having provided should be understood these embodiment and just be used for explanation, does not limit the scope of the invention.
Embodiment 1
Preparation is used for the treatment of the combination of oral medication of baby's colic and treatment adult gastroenteropathy in the following non-limiting Examples.
Composition Percent by weight/volume (department of pediatrics) Percent by weight/volume (adult)
The clean diphenhydramine microcrystalline cellulose of froth breaking cross-linked carboxymethyl cellulose sodium citric acid wood sugar D-sorbite (70%w/w) natural perfume material-non-ethanol vanilla extract pure water 2g 62.5mg 1g 1g 50mg 500mg 5ml 2ml is supplemented to 30ml 1920mg 150mg 1g 1g 50mg 2g 30ml 5ml is supplemented to 120ml (4oz)
Above-mentioned department of pediatrics and adult's prescription are by known method preparation in the pharmaceutical field.
Pediatric formula provides active component dosage, comprises the clean and 1.25mg/0.6ml diphenhydramine of 40mg/0.6ml froth breaking.The alleviation body weight is that the pain and/or the uncomfortable typical daily dose of baby's colic of 5kg (11Ib) is about 0.6ml (about half dropper), every day four times, takes once in per four (4) to six (6) hours.For the baby of body weight for about 5-10kg (11-22Ib), typical doses is about 1.2ml (about 1 dropper), every day four times, takes once in per four (4) to six (6) hours.
Adult's prescription provides and has been used for alleviating pain and/or the uncomfortable active component dosage of body weight for adult's gastroenteropathy of the about 100kg of about 50kg-, comprise about 80mg/5ml (1)-clean and about 6.25mg/5ml of Yue 160mg/10ml (2) froth breaking (1)-Yue 12.5/10ml (2) diphenhydramine, every day four times, took once in per four (4) to six (6) hours.
Embodiment 2
Preparation is used for the treatment of the combination of oral medication of baby's colic and treatment adult gastroenteropathy in the following non-limiting Examples.
Composition Percent by weight/volume (department of pediatrics) Percent by weight/volume (adult)
The clean diphenhydramine larch of froth breaking arabogalactan cross-linked carboxymethyl cellulose sodium microcrystalline cellulose wood sugar citric acid D-sorbite (70%w/w) vanilla extract (non-ethanol) pure water 2g 62.5mg 1g 1g 1g 500mg 50mg 5ml 2ml is supplemented to 30ml 1920mg 150mg 1.2g 1g 1g 2g 50mg 30ml 5ml is supplemented to 120ml (4oz)
Above-mentioned department of pediatrics and adult's prescription are by known method preparation in the pharmaceutical field.
Pediatric formula provides active component dosage, comprises that about 40mg/0.6ml froth breaking is clean, about 1.25mg/0.6ml diphenhydramine and about 20mg/0.6ml larch arabinogalactan.The alleviation body weight is that the pain and/or the uncomfortable typical daily dose of baby's colic of 5kg (11Ib) is about 0.6ml (about half dropper), every day four times, takes once in per four (4) to six (6) hours.For the baby of body weight for about 5-10kg (11-22Ib), typical doses is about 1.2ml (about 1 dropper), every day four times, takes once in per four (4) to six (6) hours.
Adult's prescription provides and has been used for alleviating pain and/or the uncomfortable active component dosage of body weight for adult's gastroenteropathy of the about 100kg of about 50kg-, comprise that about 80mg/5ml (1)-Yue 160mg/10ml (2) froth breaking is clean, about 6.25mg/5ml (1)-Yue 12.5/10ml (2) diphenhydramine and the about 100mg/10ml larch of about 50mg/5ml-arabinogalactan, every day four times, took once in per four (4) to six (6) hours.
Embodiment 3
Preparation is used for the treatment of the combination of oral medication of baby's colic and treatment adult gastroenteropathy in the following non-limiting Examples.
Composition Percent by weight/volume (department of pediatrics) Percent by weight/volume (adult)
The clean diphenhydramine probiotic composition of froth breaking (approximately lactobacillus acidophilus, lactobacillus reuteri and the Bifidobacterium of equivalent) cross-linked carboxymethyl cellulose sodium microcrystalline cellulose wood sugar citric acid D-sorbite (70%w/w) vanilla extract (non-ethanol) pure water 2g 62.5mg 10; 000,000CFU 1g 1g 500mg 50mg 5ml 2ml is supplemented to 30ml 1920mg 150mg 20; 000,000CFU 1g 1g 2g 50mg 30ml 5ml is supplemented to 120ml (4oz)
Above-mentioned department of pediatrics and adult's prescription are by known method preparation in the pharmaceutical field.
Pediatric formula provides active component dosage, comprises that about 40mg/0.6ml froth breaking is clean, about 1.25mg/0.6ml diphenhydramine and about 6mg/0.6ml probiotic composition.The alleviation body weight is that the pain and/or the uncomfortable typical daily dose of baby's colic of 5kg (11Ib) is about 0.6ml (about half dropper), every day four times, takes once in per four (4) to six (6) hours.For the baby of body weight for about 5-10kg (11-22Ib), typical doses is about 1.2ml (about 1 dropper), every day four times, takes once in per four (4) to six (6) hours.
Adult's prescription provides and has been used for alleviating pain and/or the uncomfortable active component dosage of body weight for adult's gastroenteropathy of the about 100kg of about 50kg-, comprise that about 80mg/5ml (1)-Yue 160mg/10ml (2) froth breaking is clean, about 6.25mg/5ml (1)-Yue 12.5/10ml (2) diphenhydramine and the about 16.6mg/10ml probiotic composition of about 8.3mg/5ml-, every day four times, took once in per four (4) to six (6) hours.
Embodiment 4
Preparation is used for the treatment of the combination of oral medication of baby's colic and treatment adult gastroenteropathy in the following non-limiting Examples.
Composition Percent by weight/volume (department of pediatrics) Percent by weight/volume (adult)
The clean diphenhydramine larch of froth breaking arabogalactan probiotic composition (approximately lactobacillus acidophilus, Lactobacillus rhamnosus, lactobacillus reuteri and bifidobacterium breve, bifidobacterium longum and the bifidobacterium infantis of equivalent) cross-linked carboxymethyl cellulose sodium microcrystalline cellulose wood sugar citric acid 2g 62.5mg 1g 10,000,000CFU 1g 1g 500mg 50mg 1920mg 150mg 1.2g 20,000,000CFU 1g 1g 2g 50mg
Sorbitol (70%w/w) vanilla extract (non-ethanol) pure water 5ml 2ml is supplemented to 30ml 30ml 5ml is supplemented to 120ml (4oz)
Above-mentioned department of pediatrics and adult's prescription are by known method preparation in the pharmaceutical field.
Pediatric formula provides active component dosage, comprises that about 40mg/0.6ml froth breaking is clean, about 1.25mg/0.6ml diphenhydramine, about 20mg/0.6ml larch arabinogalactan and about 6mg/0.6ml probiotic composition.The alleviation body weight is that the pain and/or the uncomfortable typical daily dose of baby's colic of 5kg (11Ib) is about 0.6ml (about half dropper), every day four times, takes once in per four (4) to six (6) hours.For the baby of body weight for about 5-10kg (11-22Ib), typical doses is about 1.2ml (about 1 dropper), every day four times, takes once in per four (4) to six (6) hours.
Adult's prescription provides and has been used for alleviating pain and/or the uncomfortable active component dosage of body weight for adult's gastroenteropathy of the about 100kg of about 50kg-, comprise that about 80mg/5ml (1)-Yue 160mg/10ml (2) froth breaking is clean, about 6.25mg/5ml (1)-Yue 12.5/10ml (2) diphenhydramine, about 50mg/5ml-about 100mg/10ml larch arabinogalactan and the about 16.6mg/10ml probiotic composition of about 8.3mg/5ml-, every day four times, took once in per four (4) to six (6) hours.
Embodiment 5
Preparation is used for the treatment of the combination of oral medication of baby's colic and treatment adult gastroenteropathy in the following non-limiting Examples.
Composition Percent by weight/volume (department of pediatrics) Percent by weight/volume (adult)
The clean diphenhydramine microcrystalline Cellulose of froth breaking cross-linked carboxymethyl cellulose sodium 2g 62.5mg 1g 1g 4.8g 300mg 1g 1g
Citric acid xylose inulin (Jerusalem artichoke powder) (sweeting agent) natural perfume material-non-ethanol vanilla extract pure water 50mg 500mg 250mg/1.2ml dosage or 6.250g/30ml 2ml are supplemented to 30ml 50mg 2g 500mg/5ml dosage or 12g/120ml 5ml are supplemented to 120ml (4oz)
Above-mentioned department of pediatrics and adult's prescription are by known method preparation in the pharmaceutical field.
Pediatric formula provides active component dosage, comprises the clean and 1.25mg/0.6ml diphenhydramine of 40mg/0.6ml froth breaking.The alleviation body weight is that the pain and/or the uncomfortable typical daily dose of baby's colic of 5kg (11Ib) is about 0.6ml (about half dropper), every day four times, takes once in per four (4) to six (6) hours.For the baby of body weight for about 5-10kg (11-22Ib), typical doses is about 1.2ml (about 1 dropper), every day four times, takes once in per four (4) to six (6) hours.
Adult's prescription provides and has been used for alleviating pain and/or the uncomfortable active component dosage of body weight for adult's gastroenteropathy of the about 100kg of about 50kg-, comprise about 80mg/5ml (1)-clean and about 6.25mg/5ml of Yue 160mg/10ml (2) froth breaking (1)-Yue 12.5/10ml (2) diphenhydramine, every day four times, took once in per four (4) to six (6) hours.
Embodiment 6
Preparation is used for the treatment of the combination of oral medication of baby's colic and treatment adult gastroenteropathy in the following non-limiting Examples.
Composition Percent by weight/volume (department of pediatrics) Percent by weight/volume (adult)
The clean diphenhydramine larch of froth breaking arabinogalactan 2g 62.5mg 250mg/1.2ml dosage or 4.8g 300mg 500mg/5ml dosage or
Cross-linked carboxymethyl cellulose sodium microcrystalline cellulose wood sugar citric acid inulin (jerusalem artichoke powder) sweetener natural perfume material-non-ethanol vanilla extract pure water 6.250g/30ml bottle 1g 1g 500mg 50mg 250mg/1.2ml dosage or 6.250g/30ml 2ml are supplemented to 30ml 12g/120ml bottle 1g 1g 2g 50mg 500mg/5ml dosage or 12g/120ml 5ml are supplemented to 120ml (4oz)
Above-mentioned department of pediatrics and adult's prescription are by known method preparation in the pharmaceutical field.
Pediatric formula provides active component dosage, comprises that about 40mg/0.6ml froth breaking is clean, about 1.25mg/0.6ml diphenhydramine and about 20mg/0.6ml larch arabinogalactan.The alleviation body weight is that the pain and/or the uncomfortable typical daily dose of baby's colic of 5kg (11Ib) is about 0.6ml (about half dropper), every day four times, takes once in per four (4) to six (6) hours.For the baby of body weight for about 5-10kg (11-22Ib), typical doses is about 1.2ml (about 1 dropper), every day four times, takes once in per four (4) to six (6) hours.
Adult's prescription provides and has been used for alleviating pain and/or the uncomfortable active component dosage of body weight for adult's gastroenteropathy of the about 100kg of about 50kg-, comprise that about 80mg/5ml (1)-Yue 160mg/10ml (2) froth breaking is clean, about 6.25mg/5ml (1)-Yue 12.5/10ml (2) diphenhydramine and the about 2000ml/10ml larch of about 100mg/5ml-arabinogalactan, every day four times, took once in per four (4) to six (6) hours.
Embodiment 7
Preparation is used for the treatment of the combination of oral medication of baby's colic and treatment adult gastroenteropathy in the following non-limiting Examples.
Composition Percent by weight/volume (department of pediatrics) Percent by weight/volume (adult)
The probiotic composition of the clean diphenhydramine designated ratio of froth breaking (bacillus acidophilus's (about 40%); Lactobacillus rhamnosus, lactobacillus casei (LGG) and Lactobacillus plantarum (being total to about 15%); Bifidobacterium (about 35%); Bifidobacterium breve, bifidobacterium longum and bifidobacteria infantis (being total to about 10%); And streptococcus thermophilus (about 5%)) microcrystalline cellulose cross-linked carboxymethyl cellulose sodium wood sugar citric acid inulin (jerusalem artichoke powder) (sweetener) vanilla extract (non-ethanol) pure water 2g 62.5mg 5,000,000,000 living cells (CFU)/1.2ml or 1,250 hundred million living cells/30ml bottle 1g 1g 500mg 50mg 250mg/1.2ml dosage or 6.250g/30ml 2ml are supplemented to 30ml 4.8g 300mg 10,000,000,000 living cells (CFU)/5ml or 2,400 hundred million living cells/120ml (cc) bottle 1g 1g 2g 50mg 500mg/5ml dosage or 12g/120ml 5ml are supplemented to 120ml (4oz)
Above-mentioned department of pediatrics and adult's prescription are by known method preparation in the pharmaceutical field.
Pediatric formula provides active component dosage, comprises that about 40mg/0.6ml froth breaking is clean, about 1.25mg/0.6ml diphenhydramine and about 6mg/0.6ml probiotic composition.The alleviation body weight is that the pain and/or the uncomfortable typical daily dose of baby's colic of 5kg (11Ib) is about 0.6ml (about half dropper), every day four times, takes once in per four (4) to six (6) hours.For the baby of body weight for about 5-10kg (11-22Ib), typical doses is about 1.2ml (about 1 dropper), every day four times, takes once in per four (4) to six (6) hours.
Adult's prescription provides and has been used for alleviating pain and/or the uncomfortable active component dosage of body weight for adult's gastroenteropathy of the about 100kg of about 50kg-, comprise that about 80mg/5ml (1)-Yue 160mg/10ml (2) froth breaking is clean, about 6.25mg/5ml (1)-Yue 12.5/10ml (2) diphenhydramine and about 10,000,000,000 living cells of about 5,000,000,000 living cells/5ml-/10ml probiotic composition, every day four times, took once in per four (4) to six (6) hours.
Embodiment 8
Preparation is used for the treatment of the combination of oral medication of baby's colic and treatment adult gastroenteropathy in the following non-limiting Examples.
Composition Percent by weight/volume (department of pediatrics) Percent by weight/volume (adult)
Probiotic composition (bacillus acidophilus's (about 40%) of the clean diphenhydramine larch of froth breaking arabinogalactan designated ratio; Lactobacillus rhamnosus, lactobacillus casei (LGG) and Lactobacillus plantarum (being total to about 15%); Bifidobacterium (about 30%); Bifidobacterium breve, bifidobacterium longum and bifidobacteria infantis (being total to about 10%); And streptococcus thermophilus (about 5%)) cross-linked carboxymethyl cellulose sodium 2g 62.5mg 250mg/1.2ml dosage or 6.250g/30ml 5,000,000,000 living cells (CFU)/1.2ml or 1,250 hundred million living cells/30ml bottle 1g 4.8g 300mg 500mg/5ml dosage or 12g/120ml bottle 10,000,000,000 living cells (CFU)/5ml or 2,400 hundred million living cells/120ml bottle 1g
Microcrystalline Cellulose xylose citric acid inulin (Jerusalem artichoke powder) sweeting agent vanilla extract (non-ethanol) pure water 1g 500mg 50mg 250mg/1.2ml dosage or 6.250g/30ml 2ml are supplemented to 30ml 1g 2g 50mg 500mg/5ml dosage or 12g/120ml 5ml are supplemented to 120ml (4oz)
Above-mentioned department of pediatrics and adult's prescription are by known method preparation in the pharmaceutical field.
Pediatric formula provides active component dosage, comprises that about 40mg/0.6ml froth breaking is clean, about 1.25mg/0.6ml diphenhydramine, about 20mg/0.6ml larch arabinogalactan and about 6mg/0.6ml probiotic composition.The alleviation body weight is that the pain and/or the uncomfortable typical daily dose of baby's colic of 5kg (11Ib) is about 0.6ml (about half dropper), every day four times, takes once in per four (4) to six (6) hours.For the baby of body weight for about 5-10kg (11-22Ib), typical doses is about 1.2ml (about 1 dropper), every day four times, takes once in per four (4) to six (6) hours.
Adult's prescription provides and has been used for alleviating pain and/or the uncomfortable active component dosage of body weight for adult's gastroenteropathy of the about 100kg of about 50kg-, comprise that about 80mg/5ml (1)-Yue 160mg/10ml (2) froth breaking is clean, about 6.25mg/5ml (1)-Yue 12.5/10ml (2) diphenhydramine, about 100mg/5ml-about 2000mg/10ml larch arabinogalactan and about 30,000,000,000 living cells of about 5,000,000,000 living cells/5ml-/10ml probiotic composition, every day four times, took once in per four (4) to six (6) hours.
Embodiment 9
Commodity are called MYLICON TMThe froth breaking clear from J ﹠amp; J-Merck.Commodity are called BENADRYL TMDiphenhydramine derive from Park-Davis (n/k/a Pfizer).From about 1 monthly age to the colic process of about six (6) months tinkling of pieces of jade, the baby who suffers from colic roughly uses the MYLICON of about 40mg/0.6ml together TMBENADRYL with the about 2.5mg/1.2ml of about 1.25mg/0.6ml- TM, every day four times.After the Drug therapy, the baby be improved significantly, colic symptom (as belch, cramp, vomiting) alleviates, and cry and shout and the irritated time intermittently and shorten about 75%.The father and mother that treated the baby claim and make baby and father and mother obtain having a rest, recover other necessary daily routines.In addition, father and mother and the doctor who is treated the baby do not observe any side effect.
Though specifically described illustrative embodiment of the present invention, be appreciated that the present invention is not limited to those specific embodiments, under the condition that does not deviate from claims restricted portion and essence, those skilled in the art can carry out various changes and change.

Claims (41)

1. pharmaceutical composition for the treatment of gastroenteropathy comprises:
A. one or more antiflatulents;
B. one or more competitive reversible histamine H 1Receptor antagonist; With
C. pharmaceutically acceptable carrier.
2. the described pharmaceutical composition of claim 1, it also comprises one or more beneficial sources of students.
3. the described pharmaceutical composition of claim 1, it also comprises one or more probiotic bacterias.
4. the described pharmaceutical composition of claim 1, wherein said gastroenteropathy is selected from sour dyspepsia, colic, diarrhoea, heartburn, irritable bowel syndrome, sour stomach, the belch relevant with the aforementioned state of an illness, gastric ulcer, esophagus, stomach or duodenal ulcer of digestive system disease, dyspepsia, flatulence, comprise a little less than the stomach of unknown reason of gastric cancer, comprise lymphadenomatous wellability gastropathy, Crohn disease, the eosinophilic granuloma, pulmonary tuberculosis, syphilis and sarcoidosis, abdominal injury, chronic pancreatitis, gallbladder disease, the Zollinger-Ellison syndrome, motion sickness, otitis media.
5. treat the method for gastroenteropathy, comprise the compositions of the claim 1 of patient's administering therapeutic effective dose for the treatment of to needs.
6. the described method of claim 5, wherein said gastroenteropathy is selected from sour dyspepsia, colic, diarrhoea, heartburn, irritable bowel syndrome, sour stomach, the belch relevant with the aforementioned state of an illness, gastric ulcer, esophagus, stomach or duodenal ulcer of digestive system disease, dyspepsia, flatulence, comprise a little less than the stomach of unknown reason of gastric cancer, comprise lymphadenomatous wellability gastropathy, Crohn disease, the eosinophilic granuloma, pulmonary tuberculosis, syphilis and sarcoidosis, abdominal injury, chronic pancreatitis, gallbladder disease, the Zollinger-Ellison syndrome, motion sickness, otitis media.
7. treat the pharmaceutical composition of colic, comprise:
A. one or more antiflatulents;
B. one or more competitive reversible histamine H 1Receptor antagonist; With
C. pharmaceutically acceptable carrier.
8. the described pharmaceutical composition of claim 7, wherein said antiflatulent is selected from maltodextrin and organopolysiloxane.
9. the described pharmaceutical composition of claim 8, wherein said antiflatulent is to be selected from the clean organopolysiloxane of dimethicone, dimethyl polysiloxane, methyl polysiloxane and froth breaking.
10. the described pharmaceutical composition of claim 9, wherein said organopolysiloxane is that froth breaking is clean.
11. the described pharmaceutical composition of claim 10, the clean amount of wherein said froth breaking is the about 120mg/ml of about 40mg/ml-.
12. the described pharmaceutical composition of claim 11, the clean amount of wherein said froth breaking is about 80mg/ml.
13. the described pharmaceutical composition of claim 7, wherein said histamine H 1Receptor antagonist is selected from acrivastine, astemizole, azatadine, azclastine, bromodiphenhydramine, brompheniramine, cetirizine, chlorine Qu Mitong, clemastine, Cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, fexofenadine, hydroxyzine, ketoffen, loratadine, norastemizole, phenindamine, pyrilamine, temelastine, terfenadine, tripelennamine, triprolidine.
14. the described pharmaceutical composition of claim 13, wherein said histamine H 1Receptor antagonist is a diphenhydramine.
15. the described pharmaceutical composition of claim 14, wherein the amount of diphenhydramine is the about 4.0mg/ml of about 1.0mg/ml-.
16. the described pharmaceutical composition of claim 15, wherein the amount of diphenhydramine is about 2.0mg/ml.
17. the described pharmaceutical composition of claim 7, it also comprises one or more beneficial sources of students.
18. the described pharmaceutical composition of claim 17, wherein said beneficial source of students is selected from larch arabinogalactan, lactulose, lactose, oligosaccharide and inulin.
19. the pharmaceutical composition of claim 18, wherein said beneficial source of students is the larch arabinogalactan.
20. the pharmaceutical composition of claim 19, the amount of wherein said larch arabinogalactan is the about 500mg/ml of about 25mg/ml-.
21. the pharmaceutical composition of claim 20, the amount of wherein said larch arabinogalactan is about 250mg/ml.
22. the described pharmaceutical composition of claim 7, it also comprises one or more probiotic bacterias, is selected from bifidobacterium species, as bifidobacterium, short bifidus bacillus, bifidobacterium longum, bifidobacterium infantis; Lactobacilli is as bacillus acidophilus, bifidobacterium, Lactobacillus brevis, Lactobacillus bulgaricus, lactobacillus casei, Deshi Lactobacillus, lactobacillus lactis, Lactobacillus plantarum, Lactobacillus reuteri, lactobacillus rhamnosus, Lactobacillus salivarius; Enterococcus faecalis; Bu Shi yeast and streptococcus thermophilus.
23. the described pharmaceutical composition of claim 7, wherein said compositions do not contain dyestuff, alcohol, artificial flavors, artificial sweetening agent and artificial preservative substantially.
24. the described pharmaceutical composition of claim 7, wherein said pharmaceutical composition is a liquid dosage form.
25. the described pharmaceutical composition of claim 24, described liquid dosage form is a suspension.
26. the described pharmaceutical composition of claim 7, wherein said compositions is a solid dosage forms.
27. the method for treatment colic comprises that the patient to the needs treatment uses one or more antiflatulents and one or more competitive histamine H 1Receptor antagonist.
28. the described method of claim 27, wherein said antiflatulent is selected from maltodextrin and organopolysiloxane.
29. the described pharmaceutical composition of claim 28, wherein said antiflatulent are to be selected from the clean organopolysiloxane of dimethicone, dimethyl polysiloxane, methyl polysiloxane and froth breaking.
30. the described method of claim 29, wherein said organopolysiloxane are that froth breaking is clean.
31. the described method of claim 30, wherein said froth breaking is used 3-6 time with the amount of the about 50mg/0.6ml of about 25mg/0.6ml-clean every day.
32. the described method of claim 31, wherein said froth breaking is used 4 times with the amount of about 40mg/0.6ml clean every day.
33. the described method of claim 27, wherein said histamine H 1Receptor antagonist is selected from acrivastine, astemizole, azatadine, azclastine, bromodiphenhydramine, brompheniramine, cetirizine, chlorine Qu Mitong, clemastine, Cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, fexofenadine, hydroxyzine, ketoffen, loratadine, norastemizole, phenindamine, pyrilamine, temelastine, terfenadine, tripelennamine, triprolidine.
34. the described method of claim 33, wherein said histamine H 1Receptor antagonist is a diphenhydramine.
35. the described method of claim 34, wherein diphenhydramine is used 3-6 time with the amount of the about 2.0mg/0.6ml of about 0.50mg/0.6ml-every day.
36. the described method of claim 35, wherein diphenhydramine is used 4 times with the amount of about 1.25mg/0.6ml every day.。
37. the described method of claim 27, it also comprises one or more beneficial sources of students, is selected from larch arabinogalactan, lactulose, lactose, oligosaccharide and inulin.
38. the method for claim 37, wherein said beneficial source of students is the larch arabinogalactan.
39. the method for claim 38, wherein said larch arabinogalactan is used 3-6 time with the amount of the about 250mg/0.6ml of about 100mg/0.6ml-every day.
40. the method for claim 39, wherein said larch arabinogalactan is used 4 times with the amount of about 125mg/0.6ml every day.
41. the described method of claim 27, it also comprises one or more probiotic bacterias, is selected from bifidobacterium species, as bifidobacterium, short bifidus bacillus, bifidobacterium longum, bifidobacterium infantis; Lactobacilli is as bacillus acidophilus, bifidobacterium, Lactobacillus brevis, Lactobacillus bulgaricus, lactobacillus casei, Deshi Lactobacillus, lactobacillus lactis, Lactobacillus plantarum, Lactobacillus reuteri, lactobacillus rhamnosus, Lactobacillus salivarius; Enterococcus faecalis; Bu Shi yeast and streptococcus thermophilus.
CNA2004800074531A 2003-03-18 2004-03-05 Antiflatulents in combination with histamine H1-receptor antagonists for treating gastrointestinal disorders Pending CN1761460A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114748514A (en) * 2022-05-13 2022-07-15 浙江大学医学院附属邵逸夫医院 Application of three kinds of bifidobacteria in preventing or treating acute pancreatitis

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114748514A (en) * 2022-05-13 2022-07-15 浙江大学医学院附属邵逸夫医院 Application of three kinds of bifidobacteria in preventing or treating acute pancreatitis

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