US20010033873A1

US20010033873A1 - Composition and method useful for treating colic

Info

Publication number: US20010033873A1
Application number: US09/758,895
Authority: US
Inventors: Sergei Shushunov
Original assignee: LEV Laboratories Ltd
Current assignee: LEV Laboratories Ltd
Priority date: 1999-04-16
Filing date: 2001-01-11
Publication date: 2001-10-25
Anticipated expiration: 2020-03-09
Also published as: AU2297702A; US6703022B2; MXPA01010449A; WO2000062768A1; EP1173159A1; US6346250B2; US20020182273A1; EP1173159A4

Abstract

The invention provides compositions and methods that are useful for treating colic in mammals (e.g. human infants).

Description

PRIORITY OF INVENTION

This application claims priority of invention under 35 U.S.C. §119(e) from U.S. provisional application Ser. No. 60/129,617, filed 16 April 1999.[0001]

BACKGROUND OF THE INVENTION

Infantile colic is characterized by episodes during which an infant is irritable, cries or screams excessively, and draws up the legs. Episodes of colic tend to be worse in the evenings and do not respond to the usual means of comforting, such as feeding, cuddling, or diaper changing.

Infantile colic is common, occurring in approximately one in ten babies. It often first appears around the third or fourth week after birth, and usually clears up on its own by the age of twelve weeks. It is thought to be due to a spasm in the intestines, although there is no proof of this, and the cause of the presumed spasm is unknown. See The American Medical Association Encyclopedia of Medicine, Charles B. Clayton ed. 1989, Random House, New York, page 288.

In the past, colic has been treated with antispasmodic drugs, but these drugs are now not usually recommended for babies under 6 months of age. The most common treatment for colic today is to simply wait for the baby to grow out of the condition.

Z. Weizman et al. The Journal of Pediatrics, 1993, 122, 650-652 evaluated the effect of a beverage prepared from natural flavors, glucose, and dried extracts of 1) chamomile (Matricaria chamomilla), 2) vervain (Verbena officinalis), 3) licorice (Glycyrrhiza glabra), 4) fennel (Foeniculum vulgare) and balm-mint (Melissa officinalis) on infantile colic in a prospective double-blind study. It was found that the tea eliminated colic in 57% of the infants, whereas placebo was helpful in only 26% of the infants. Additionally, the mean colic score was reported to have been significantly improved in tea-treated infants.

Although some success in treating colic has been reported using herbal extracts, such preparations are not ideally suited for treating infantile colic. For example, it is difficult to accurately determine the dose of the active ingredient(s) in an extract or tea. It is also difficult to provide a reproducible dose using these materials. Finally, use of extracts and teas is limited due to the presence of contaminates that are present as a result of the manner in which the extracts and teas are prepared. The difficulties in determining an accurate dosage, and the presence of impurities are especially problematic for the treatment of infants, since infants can be significantly effected by small variations in dose or by the presence of small quantities of impurities.

Thus, there is currently a need for compositions and methods that are useful for treating colic. In particular, there is a need for methods and compositions that can conveniently be used for treating infants suffering from colic.

SUMMARY OF THE INVENTION

The present invention provides compositions that are useful for treating colic. Accordingly, the invention provides a composition comprising an aqueous emulsion of fennel oil.

The invention also provides a composition comprising 1) milk or infant formula and 2) fennel oil.

The invention also provides a therapeutic method for treating colic in a mammal comprising administering to a mammal in need of such therapy an effective amount of fennel oil.

The invention also provides a therapeutic method for treating colic in a mammal (e.g. a human) comprising administering to a mammal in need of such therapy an effective amount of a composition of the invention.

The invention also provides fennel oil having an estragole concentration of less than 2%.

The invention also provides the use of 1) fennel oil, 2) water, milk, or formula, and optionally 3) an emulsifying agent to prepare a medicament useful for treating colic. Preferably, the medicament is in the form of an emulsion.

Representative compositions of the invention have been shown to be useful for treating colic (e.g reducing or eliminating one or more of the associated symptoms). The compositions provide a measurable, reproducible, and convenient source of fennel oil, that can readily be administered to infants. Thus, the compositions overcome difficulties associated with the use of extracts and teas.

DETAILED DESCRIPTION

Fennel oil is typically obtained from the dried ripe fruit of Foeniculum vulgare Miller (Fam Umbelliferae) by steam distillation. It comprises anethole [C₁₀H₁₂O] as the chief constituent (typically 50-90%, although amounts can vary depending on source), as well as d-pinene, phellandrene, dipentene, fenchone, methylchavicol, estragole, anisaldehyde and anisic acid. See Remmingtons Pharmaceutical Sciences, 18th ed. Alfonso R. Gennaro editor, 1990, Mack Publishing, Easton Pennsylvania 1294; and PDR For Herbal Medicines p 850-852 [PLEASE PROVIDE FULL CITE FOR MATERIAL YOU PROVIDED]. Fennel oil is commercially available from a variety of sources including Good Hope Botanicals, 830 Sweetser Ave., E, Novato, Calif., 94945, USA).

Estragole (1-allyl-4-methoxybenzene), is typically present in a concentration of 2-5% by weight in fennel oil from natural sources. Because estragole has been reported to produce mutagenic and carcinogenic effects in mice at certain doses (N. R. Drinkwater, J. Natl. Cancer Inst., 1976, 57(6), 1323-1331), the compositions of the invention preferably comprise fennel oil from a source that provides oil with a low concentration of estragole.

Additionally, applicant has discovered that compositions of the invention can be prepared from fennel oil wherein the concentration of estragole has been reduced. The concentration of estragole in fennel oil from a natural source can be reduced using any suitable separation technique known in the field of chemistry. For example, the concentration of estragole in fennel oil can conveniently be reduced by subjecting the oil to fractional distillation to remove estragole. Accordingly, fennel oil can be prepared having an estragole concentration of less than 2%, less than about 1%, less than about 0.5%, less than about 0.25%, less than about 0.2, or less than about 0.1 weight percent.

The invention thus provides fennel oil having a reduced estragole concentration (e.g. a concentration of less than 2%, less than about 1%, less than about 0.5%, less than about 0.25%, less than about 0.2, or less than about 0.1 weight percent), which is useful for preparing the compositions of the invention.

Additionally, the concentration of anethole, a likely active ingredient in the compositions of the invention, can vary from 50-90% by weight in fennel oil from natural sources. As a result of this variability, it can be difficult to prepare compositions of the invention with a predictable anethole concentration using fennel oil from natural sources.

Applicant has discovered that the concentration of anethole in fennel oil can conveniently be standardized prior to preparing compositions of the invention. Anethole, in pure form, can be purchased commercially [PLEASE PROVIDE THE NAME AND ADDRESS FOR A SUPPLIER]. Thus, fennel oil with a standardized concentration of anethole can be prepared by adding anethole to a natural oil (or an oil with a reduced estragole concentration) until a specific anethole concentration is obtained.

Thus, fennel oil having a standardized anethole concentration of at least about 55%, at least about 60%, at least about 65%, at least about 70%, or at least about 75% by weight can be prepared. For preparing the compositions of the invention, fennel oil having a standardized anethole concentration of from about 55% to about 75% by weight (or preferably from about 60% to about 70%) can conveniently be used.

As used herein, the term “fennel oil” includes fennel oil obtained from natural sources, as well as fennel oil having a reduced estragole concentration, fennel oil having a standardized anethole concentration, and fennel oil having both a reduced estragole concentration and a standardized anethole concentration.

The term “milk” includes human milk, cow's milk and goat's milk, and the like.

The term “infant formula” includes infant and baby formulae that are suitable for administration to mammals (e.g. humans or human infants). For example, the term includes commercially available milk based and soy based formulae, and the like, which are supplied in a form that is ready to use, or in a powdered form that can be mixed with a suitable liquid (e.g. water) prior to use.

The compositions of the invention can conveniently be in the form of an emulsion, i.e. a system containing two or more immiscible liquids in which one is dispersed in the form of very small globules throughout the other. Suitable emulsions can be prepared using techniques that are known in the art, for example, using techniques similar to those described in Remmingtons Pharmaceutical Sciences, 18th ed. Alfonso R. Gennaro editor, 1990, Mack Publishing, Easton Pennsylvania 298-309, and 1519-1544. The invention also provides processes for preparing the novel emulsions of the invention comprising combining the components of the emulsion, and mixing to provide the emulsion.

The compositions of the invention can conveniently comprise one or more pharmaceutically acceptable or food grade stabilizing agents, i.e., emulsifying agents. Suitable emulsifying agents or stabilizers are known in the art, for example, see Remmingtons Pharmaceutical Sciences, 18th ed. Alfonso R. Gennaro editor, 1990, Mack Publishing, Easton Pa., page 302. One emulsifying agent that can conveniently be used is polysorbate-80.

The specific and preferred values and embodiments listed below are for illustration only; they do not exclude other defined values, other values within defined ranges, or other embodiments disclosed herein.

Specifically, the invention also provides a composition for treating colic consisting essentially of fennel oil and water.

Specifically, the invention also provides a composition for treating colic consisting essentially of 1) milk or infant formula and 2) fennel oil.

Specifically, the invention also provides a composition for treating colic consisting essentially of 1) fennel oil, 2) water, and 3) one or more pharmaceutically acceptable stabilizers.

Specifically, the invention also provides a composition for treating colic consisting essentially of 1) milk or infant formula, 2) fennel oil, and 3) one or more pharmaceutically acceptable stabilizers.

Specifically, the invention also provides a composition for treating colic consisting of fennel oil and water.

Specifically, the invention also provides a composition for treating colic consisting of fennel oil, water, and one or more a pharmaceutically acceptable emulsifying agents.

Specifically, the invention also provides a composition for treating colic consisting of 1) milk or infant formula, and 2) fennel oil.

Specifically, the invention also provides a composition for treating colic consisting of 1) milk or infant formula, 2) fennel oil, and 3) one or more pharmaceutically acceptable stabilizers.

Specifically, the invention also provides a composition for treating colic comprising about 0.1 weight percent fennel oil and about 99.9 weight percent water.

Specifically, the invention also provides a composition for treating colic comprising about 0.1 weight percent fennel oil, about 0.1 weight percent polysorbate-80 and about 99.8 weight percent water.

Specifically, the composition of the invention can be in the form of an emulsion.

Specifically, in the compositions of the invention the fennel oil is preferably present in at least 0.05 weight percent.

Specifically, in the compositions of the invention the fennel oil is preferably present in at least 0.1 weight percent.

Specifically, in the compositions of the invention the fennel oil is present in a weight percentage of about 0.01 to about 1.0 percent.

Specifically, in the compositions of the invention the fennel oil is present in a weight percentage of about 0.05 to about 0.5 percent.

Specifically, in the compositions of the invention the fennel oil is present in a weight percentage of about 0.1 to about 0.2 percent.

Specifically, in the compositions of the invention the fennel oil is present in a weight percentage of about 0.1 percent.

Specifically, in carrying out the therapeutic methods of the invention, about 0.1 to about 20 mg/kg of fennel oil can be administered per day. More specifically, about 1 to about 15 mg/kg of fennel oil can be administered per day. Preferably about 5 to about 12 mg/kg of fennel oil can be administered per day.

Preferred compositions of the invention may exclude sodium bicarbonate or other related antacids.

Specifically, the compositions of the invention described herein can be presented in the form of pharmaceutical compositions (or unit dosage forms) comprising an effective colic reducing amount of fennel oil.

The invention also provides a method for preparing a composition of the invention comprising, combining fennel oil and water, and mixing to obtain an emulsion. Optionally, an emulsifying agent can be added. The method can conveniently be carried out using a high speed mixer or homogenizer.

For administration, the concentration of fennel oil in a liquid composition will generally be from about 0.01 to about 1.0 percent by weight. More specifically, the concentration of fennel oil can be about 0.25 to about 0.5 percent by weight, or from about 0.05 to about 0.2 percent by weight. Preferably, the concentration of fennel oil will be about 0.1 percent by weight.

It may also be convenient to prepare concentrated solutions or emulsions, which can be diluted to an acceptable concentration (e.g. with water, milk or infant formula) prior to administration. Such concentrated solutions or emulsions may have the advantage of being easier to manufacture, store, or handle than solutions that are suitable for direct administration. Accordingly, the invention also provides compositions and emulsions containing fennel oil in concentrations that are multiples (e.g. 2, 5, 10, 20, 50, 75, or 90) of the concentrations that are conveniently administered.

The compositions of the invention can also contain a variety of inactive ingredients such as flavoring agents (e.g. cherry flavoring), sweetening agents (e.g. sucrose or fructose), preservatives, or dyes. Any material used in preparing a composition of the invention should be substantially non-toxic and suitable for consumption by the patient (e.g. a mammal).

The compositions of the invention have the advantage of providing a source of fennel oil that can conveniently be handled, shipped, stored, and administered. They also provide a source of fennel oil that can be administered in known and reproducible dosages, and that is free of unwanted contaminants. Thus, the compositions of the invention provide an advantage over teas and extracts. Additionally, the compositions of the invention have the advantage of providing fennel oil in a more concentrated form than is provided by a tea. For example, the concentration of fennel oil in a tea would typically be below about 0.01%.

A suitable dose of fennel oil can be in the range of from about 0.1 mg/kg per day to about 20 mg/kg per day. Specifically, a suitable dose can be in the range of about 1 mg/kg per day to about 15 mg/kg per day. More specifically, a suitable dose can be in the range of about 5 mg/kg per day to about 12 mg/kg per day. The desired dose can be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The amount of a composition of the invention required for treatment will ultimately vary based on the severity of the condition and on the size and age of the patient. The required dose will ultimately be determined by the attendant physician or clinician, using techniques that are known in the art.

The ability of a compound of the invention to treat colic can be determined using pharmacological or clinical models which are well known to the art (see Z. Weizman et al. The Journal of Pediatrics, 1993, 122, 650-652), or using Test A described below.

Test A.

A double blind, placebo controlled study was performed in order to evaluate the effects of a representative composition of the invention on colic. One hundred and twenty-one (121) infants under 12 weeks of age were randomized into treatment (n=62) and control (n=59) groups. Treatment group subjects received up to 1.5 ounces of an emulsion prepared from fennel oil (1 ml), polysorbate-80 (1 ml), and water (1000 ml). Control group subjects received placebo.

Colic was defined as a paroxysmal crying of 3 hours a day, at least 3 days a week, for 3 weeks (see Wessel MA Pediatrics, 1954, 14, 421-434). Only episodes of crying lasting more than 15 minutes were recorded. The outcome was measured as a decrease in cumulative weekly crying from baseline. Cure was considered when cumulative weekly crying dropped below 9 hours.

The treatment group had a cure rate of 65%, and the control group had a cure rate of 23.7%. Thus, the composition of the invention was found to be significantly more effective for treating colic than the placebo control.

The invention will now be illustrated by the following non limiting examples.

EXAMPLE 1

Preparation of a composition of the invention. One liter of fennel oil was combined in a mixing tank with one thousand liters of water, and the mixture was stirred at high speed with a homogenizer to provide an emulsion. [0060]

EXAMPLE 2

Preparation of a composition of the invention. One liter of fennel oil, one liter of polysorbate-80, and one thousand liters of water, were stirred together until an emulsion formed. The emulsion was found to be stable for an extended period of time (e.g. for months) [0061]

Example 3

The following illustrate representative compositions of the invention, for therapeutic or prophylactic use in mammals (e.g. humans).



	(I) Emulsion 1 (0.1 mg/ml)	mg/ml

fennel oil	0.1	mg
water	q.s.	ad
	1	ml

Amount

(ii) Solution 1
fennel oil	0.1	ml
polysorbate-80	0.1	ml
water	998	ml
(iii) Solution 2
fennel oil	1.0	ml
polysorbate-80	1.0	ml
water	998	ml
(iv) Solution 3
fennel oil	10.0	ml
polysorbate-80	5.0	ml
water	985	ml
(v) Concentrated Emulsion
fennel oil	25.0	ml
polysorbate-80	10.0	ml
water	965	mL

The above formulations may be obtained by conventional procedures well known in the pharmaceutical manufacturing art. Emulsions are prepared by mixing using techniques that are known in the art. “Fennel oil” can be fennel oil obtained from a natural source, fennel oil having a reduced estragole concentration, fennel oil having a standardized anethole concentration, or fennel oil having both a reduced estragole concentration and a standardized anethole concentration. [0063]
All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. [0064]

Claims

What is claimed is:

1. A composition comprising an aqueous emulsion of fennel oil.

2. The composition of

claim 1

further comprising one or more pharmaceutically acceptable or food grade emulsifying agents.

3. The composition of

claim 1

wherein the fennel oil has an estragole concentration of less than 2%.

4. The composition of

claim 1

wherein the fennel oil has an estragole concentration of less than about 1%.

5. The composition of

claim 1

wherein the fennel oil has an anethole concentration of at least about 55%.

6. The composition of

claim 1

wherein the fennel oil has an anethole concentration of from about 55% to about 75% by weight.

7. A composition comprising 1) milk or infant formula and 2) fennel oil.

8. The composition of

claim 7

which is an emulsion.

9. The composition of

claim 7

10. The composition of

claim 7

wherein the fennel oil has an estragole concentration of less than 2%.

11. The composition of

claim 7

wherein the fennel oil has an estragole concentration of less than about 1%.

12. The composition of

claim 7

wherein the fennel oil has an anethole concentration of at least about 55%.

13. The composition of

claim 7

14. The composition of

claim 2

which comprises about 0.1 weight percent fennel oil, about 0.1 weight percent polysorbate-80 and about 99.8 weight percent water.

15. The composition of

claim 9

which comprises about 0.1 weight percent fennel oil, about 0.1 weight percent polysorbate-80 and about 99.8 weight percent milk or infant formula.

16. A therapeutic method for treating colic in a mammal comprising administering to a mammal in need of such therapy an effective amount of a composition of

claim 1

.

17. The method of

claim 16

wherein about 0.1 to about 20 mg/kg of fennel oil is administered per day.

18. A therapeutic method for treating colic in a mammal comprising administering to a mammal in need of such therapy an effective amount of a composition of

claim 7

.

19. The method of

claim 18

wherein about 0.1 to about 20 mg/kg of fennel oil is administered per day.

20. Fennel oil having a reduced estragole concentration of less than 2%.

21. A therapeutic method for treating colic in a mammal comprising administering to a mammal in need of such therapy an effective amount of fennel oil.