Coenzyme Q10 formulation and process methodology for softgel capsules manufacturing Number:6,955,820 from the United States Patent and Trademark Office (PTO) owispatent

Title: Coenzyme Q10 formulation and process methodology for softgel capsules manufacturing

Abstract: A formulation of Coenzyme Q₁₀, beta-carotenes, Vitamin E, and medium chain triglycerides in rice bran oil and an optional thickener, such as bee's wax, is provided in a soft gel capsule so that a maximum of the Coenzyme Q₁₀ is absorbed by the human body. Generally, about 60 mg of Coenzyme Q₁₀ is the normal amount provided daily to a healthy sedentary adult.

Patent Number: 6,955,820 Issued on 10/18/2005 to Udell

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Inventors:	Udell; Ronald G. (Beverly Hills, CA)
Assignee:	Soft Gel Technologies, Inc. (Los Angeles, CA)
Appl. No.:	641328
Filed:	August 14, 2003

Current U.S. Class:	424/451; 424/452; 424/456
Intern'l Class:	A61K 009/48; A61K 009/64
Field of Search:	424/451,452,455,456

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References Cited [Referenced By]

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U.S. Patent Documents

4824669	Apr., 1989	Folkers et al.
5500416	Mar., 1996	Miyazawa et al.
6020383	Feb., 2000	Stone et al.
6054136	Apr., 2000	Farah et al.
6069167	May., 2000	Sokol.
6203818	Mar., 2001	Vester.
6545184	Apr., 2003	Lipshutz.
6616942	Sep., 2003	Udel.
6623734	Sep., 2003	Udell et al.
6664287	Dec., 2003	Avery et al.
2004/0106674	Jun., 2004	Rich et al.
Foreign Patent Documents
3512054	Oct., 1986	DE.
0 888 774	Jan., 1999	EP.
0 888 774	Jan., 1999	EP.

Other References

R. Chopra et al, "A New Coenzyme Q10 Preparation with Enhanced Bioavailability", FASEB Journal, 11 (3), pp. A586, 1997, Abstract. M. Weis, et al., "Bioavailability of Four Oral Coenzyme Q10 Formulations in Healthy Volunteers", Molec. Aspects. Med., vol. 15, (Supplement) pp. s273-s280, 1994.

Primary Examiner: Page; Thurman K.
Assistant Examiner: Tran; S.
Attorney, Agent or Firm: Dorsey & Whitney, Rothenberger; Scott D.

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Parent Case Text

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CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 09/536,597, filed on Mar. 28, 2000 now U.S. Pat. No. 6,616,942 which claims priority from U.S. Provisional Application Ser. No. 60/126,656, filed Mar. 29, 1999, the contents of which are herein incorporated by reference in their entirety.

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Claims

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1. A method of producing a soft gel capsule for delivery of Coenzyme Q10 into a human body including:

heating rice bran oil to at least 50° C. then adding:

Coenzyme Q10;

beta-carotenes;

Vitamin E;

adding bee's wax to the heated rice bran oil;

mixing the bee's wax and the rice bran oil and

adding medium chain triglycerides to the heated rice bran oil under a vacuum;

mixing the resultant mixture for at least 1 hour;

cooling the mixed resultant mixture to at least 30° C.;

shielding the cooled mixed resultant mixture with nitrogen while returning the cooled mixed resultant mixture to atmospheric pressure; and

encapsulating the cooled mixed resultant mixture in a soft gel capsule.

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Description

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BACKGROUND OF THE INVENTION

This invention relates to an improved formulation and process methodology of Coenzyme Q₁₀ in producing soft gel capsules of this formulation. Coenzyme Q₁₀(CoQ₁₀ or Ubiquinone) is a large molecular weight (863.63 grams) lipid compound that is produced in the liver and perhaps other body organs. The total body content is estimated to be 1.4 to 1.8 grams, depending on the age and the physical fitness of the individual. Although CoQ₁₀ is found in the mitochondria and other organelles of every living cell, it appears to be most abundant in tissues with a high number of mitochondria and a high level of metabolic activity. For example, in the metabolically inactive blood there is approximately 4 mg, in the heart, and in the skeletal muscle 1000 mg. The blood acts as a CoQ₁₀ reservoir and transport media between endogenous CoQ₁₀ synthesis in the liver, exogenous CoQ₁₀ absorption from digested food substances in the intestinal tract, and the body cells. Endogenous synthesis appears to be responsible for 56 percent and exogenous sources for 44 percent of the body's CoQ₁₀ requirements. These numbers are currently being studied and endogenous CoQ₁₀ synthesis may be significantly deficient in the elderly. These deficiencies are not related to the total caloric intake, but rather to the vitamin content of ingested foods. The body requires multiple vitamins for the synthesis of CoQ₁₀.

CoQ₁₀ requirements of the body are also variable between individuals and are dependent on age, physical activity, and disease. It is estimated that the body CoQ₁₀ utilization is between 5 and 9 mg per day. Intercellular CoQ₁₀ is required for the synthesis of energy and therefore essential for life. Energy synthesis occurs in the mitochondria, where CoQ₁₀ provides an electron for the electron transport chain in the cytochrome system, in which adenosine tripohosphate (ATP) is synthesized. As CoQ₁₀ gives up an electron for ATP synthesis, it gets oxidized. If CoQ₁₀ is used as an antioxidant, it gets oxidized and is no longer available to provide electrons and function in the synthesis of ATP. Under conditions of high metabolic stress, endogenous sources may become inadequate to meet the body's CoQ₁₀ requirement for ATP synthesis. Under such conditions, dietary CoQ₁₀ supplementation has been shown to be an effective source. An improved soft gel formulation and process of CoQ₁₀ soft gel capsule manufacturing has uses to treat heart failure, chronic fatigue and patients with psoriasis and planter warts. In all cases, it has been found that the improved soft gel formulation at ingestion rates of 30-100 mg/day of CoQ₁₀ have been proven to be superior to commercially available 60 mg dry powder capsules, and existing 100 mg/day CoQ₁₀ soft gel formulations.

An appropriate CoQ₁₀ dosage for a normal individual compared to the dosage necessary for a diseased individual has been difficult to ascertain. Recommended doses of 10 to 30 mg/day were found to be ineffective for patients with significant CoQ₁₀ deficiencies. In the past 15 years, it has become generally accepted that poor intestinal absorption of certain CoQ₁₀ formulations limits their effective use. For this reason, 50 and 150 mg CoQ₁₀ containing tablets or capsules are commercially available to the consumer, at a considerably higher cost.

Folkers et al (U.S. Pat. No. 4,824,669) addresses a soft gel capsule with CoQ₁₀ and at least one vegetable oil. This formulation was determined to increase blood CoQ₁₀ levels to 2.5 μg/ml compared to 1.6 μg/ml for an equivalent 100 mg dose of dry powder CoQ₁₀. Many different CoQ₁₀ formulations have appeared which are claimed to increase intestinal absorption. However, intestinal absorption data, collected under near basal conditions, which compare CoQ₁₀ alone in oil with dry powder CoQ₁₀, are conclusive that oil is a better delivery agent.

SUMMARY OF THE INVENTION

The present invention comprises a stable and nontoxic soft gel Coenzyme Q₁₀ formulation and process methodology of Coenzyme Q₁₀ for maximum Coenzyme Q₁₀ levels in the human body for a given input. A preferred soft gel formulation includes Coenzyme Q₁₀ (hereinafter CoQ₁₀), Vitamin E, beta-carotene, bee's wax, medium chain triglycerides available as MCT Myglyol S12, and rice bran oil formulated to maximize the body's absorption by maintaining the CoQ₁₀ in what may be a supersaturated solution in easily absorbed materials, that can provide healthful effects, as opposed to just fillers. It is important as much of the supplied CoQ₁₀ be absorbed, rather than just taking megadoses at frequent intervals as the wholesale cost of CoQ₁₀ dry powder in quantity is as much as $2000 per kg. Not only is a relatively large percentage of the CoQ₁₀ absorbed, but the volume of the soft gel capsule is minimized, making it easier to swallow and requiring smaller shipping and storage space. Recent studies indicate the preferred soft gel CoQ₁₀ formulation should be administered twice a day in dosages of about 30 mg CoQ₁₀ in 220 mg capsules, as that amount of CoQ₁₀ is about the maximum the body of a healthy sedentary adult can use for maintenance of a preferred blood level. For those who have deficiencies of CoQ₁₀, studies have shown that twice a day administration of about 60 mg CoQ₁₀ in 435 mg capsules is advantageous. In special instances of CoQ₁₀ deficiency, twice a day ingestion of 100 mg CoQ₁₀ containing soft gel capsules can be tolerated.

It is therefore an object of the present invention to provide a soft gel formulation of CoQ₁₀ and a methodology of formulation processing that produce a significantly greater bioavailability percentage of ingested CoQ₁₀ than existing soft or dry formulations.

Another object of the present invention is to provide a soft gel formulation of CoQ₁₀ and methodology of administration that produces greater absorption of CoQ₁₀ into the intestine.

Another object is to minimize the ingested volume required to maintain a given CoQ₁₀ blood content.

Another object is to provide a process that keeps CoQ₁₀ in solution in readily absorbed materials, that themselves have beneficial effects.

These and other objects and advantages of the present invention will become apparent to those skilled in the art after considering the following detailed description of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The unique formulation of the present invention of a stable and non-toxic soft gel Coenzyme Q₁₀ where the amount of Coenzyme Q₁₀ is balanced with antioxidants and absorption agents to maximize the percentage of Coenzyme Q₁₀ in a capsule of a given size, that is delivered to the blood stream from the intestines. The formulation includes: Coenzyme Q₁₀, Vitamin E, beta-carotene, bee's wax, medium chain triglycerides (MCT) such as MCT Myglyol S12, and rice bran oil. The preferred soft gel Coenzyme Q₁₀ formulation of the present invention is prepared in accordance with the following sequence of ingredients and process.

Rice bran oil, a carrier suspension agent for soft gel formulation useful for absorption of lipophilic ingredients such as Coenzyme Q₁₀, is heated to 50 to 60° C. Bee's wax is then added. 50° C. is above the melting point of bee's wax and the wax and oil is mixed until a uniform mixture is formed. Bee's wax thickens the rice bran oil and acts as a suspension agent for subsequent ingredients. Without bee's wax, the other ingredients, which are to suspended inside a transparent gel capsule, might separate or congregate under the effect of gravity, and appear faulty or spoiled to the consumer.

Subsequently, the mixture is cooled to 35 to 45° C. Coenzyme Q₁₀, beta-carotenes including alpha and beta carotenes, cryptoxanthin, lutein and zeaxanthin (available commercially as Betatene, available from Cognis Nutrition), Vitamin E, and medium chain triglycerides (MCT) are then simultaneously added to the oil-wax mixture under a vacuum (to eliminate oxidation) and mixed together for one to two hours. beta-carotenes improves the solubility and adds antioxidant value. Vitamin E is an antioxidant preservative that prevents peroxidation of the final product, adds antioxidant value, and is fat soluble. Although Vitamin E is available commercially in 30 IU, 100 IU, 200 IU, 400 IU, and 1000 IU concentrations, for the present invention concentrations from 350 IU to 400 IU are usable, with 372 IU being the preferred concentration, which results in a concentration from 30 to 100 IU in the soft gel capsule. Medium chain triglycerides are fatty acids that improve the lipid environment and enhance absorbibility like the rice bran oil. The bee's wax primarily increases viscosity to keep insoluble components from settling to one side of the soft gel capsule, but it also improves solubility. For instances where viscosity (and in turn gel capsule cosmetics) is not a concern, it can be eliminated.

The resultant mixture is cooled to 25 to 30° C. A nitrogen gas blanket is introduced to shield the mixture for oxygen and the pressure is returned to atmospheric. The mixture is then encapsulated in a soft gel capsule.

Formula 1

	Ingredient	Amount Range	% in formula
	1. Vitamin E 372 IU	0.161 g-2.50 g	37%-51%
	2. Beta Carotene	0.00525 g-0.118 g	1.2%-2.5%
	(20% from D. salina)
	3. MCT Myglyol 812	0.5 g-1.0 g	12%-21%
	4. Rice Bran Oil	0.193 g-.50 g	10%-44%
	5. Yellow Bee's Wax	0.015 g-.2 g	1%-4%
	6. CoQ10	0.5-2.0 g	10%-15%

Formula 2

	Ingredient	Amount Range	% in formula
	1. Vitamin E 372 IU	0.161 g-2.50 g	38.5%-53%
	2. Beta Carotene	0.00525 g-0.118 g	1.25%-2.6%
	(20% from D. salina)
	3. MCT Myglyol 812	0.5 g-1.0 g	12%-22%
	4. Rice Bran Oil	0.193 g-.50 g	10%-46%
	5. CoQ10	0.5-1.0 g	11%-16%

The bioavailability or intestinal absorption of CoQ₁₀ has been a major controversy in the international CoQ₁₀ research community. Previous data indicate that only 1 to 3 percent of dry powder CoQ₁₀ formulations are absorbed through the lacteals in the intestines and appear in the blood over a twelve hour interval. In general, blood levels of 1.2 to 1.6 μg/ml have been reported, when taking 30 to 60 mg/day dry powder CoQ₁₀ formulation for 30 days. It has been reported that when a dry powder CoQ₁₀ formulation is taken with a fat, such as peanut butter, steady-state blood levels of 2.0 to 2.8 μg/ml are measurable.

Multiple clinical trials were conducted in the United States and Europe using the Folkers (U.S. Pat. No. 4,824,669) soft gel. With a dosage of 100 mg/day, multiple investigators have reported group mean blood levels of 2.3 to 3.5 μg/ml depending on the laboratory conducting the measurement.

As observed in recent trials, the bioavailability results found for the present soft gel indicate it provides approximately 50 percent, and with two 30 mg CoQ₁₀ containing capsules, 100 percent, of the daily CoQ₁₀ requirements of a normal sedentary individual. It would take at least three of the dry powder 30 mg CoQ₁₀ capsules to produce the same effects as one soft gel, and six to produce the same effect as two 30 mg CoQ₁₀ containing soft gel capsules of the present invention. Regardless of the absorption mechanism, the significantly higher basal blood CoQ₁₀ levels (167%) and the 273% greater absorption rate were found in previous studies to establish that the present soft gel formulation is indeed a superior product to dry CoQ₁₀ formulations. This may be particularly true for those individuals whose daily CoQ₁₀ requirement is elevated due to high physical activity, an increased use of CoQ₁₀ as an antioxidant, and disease associated with known CoQ₁₀ deficiencies.

Cellular CoQ₁₀ content is a function of the number and quality of the cellular mitochondria. For example, the failing heart muscle has 2.2 μg CoQ₁₀ per mg of tissue and a blood CoQ₁₀ deficiency of 0.3-0.5 μg/ml. The normal hearts conditioned heart has 6.3 μg/gm per mg of tissue, and a low basal blood level of 0.5-0.6 μg/ml. These results indicate that supplemental CoQ₁₀ enters the cell. This observation has also been reported for skeletal muscles of trained and non-trained athletes.

The subjective and objective responses to supplemental CoQ₁₀ in the normal individual appear more rapidly compared to that of the physically unfit or the diseased individual with a CoQ₁₀ deficiency. The most probable reason for this observation is that the metabolic machinery (mitochondria) is viable in the non-diseased normal volunteer, whereas the mitochondria are atrophied in the cells of deconditioned and/or diseased individuals. Therefore, it takes time in the diseased individual to build up the mitochondria to a more normal activity level and to normalize their distribution in the organ system involved.

In summary, studies have statistically proven that the present soft gel CoQ₁₀ formulation used at 60 mg CoQ₁₀/day is superior to dry powder CoQ₁₀ formulations, and prior art soft gel formulations.

Thus, there has been shown novel formulations, which fulfill all of the objects and advantages sought therefor. Many changes, alterations, modifications and other uses and applications of the subject invention will become apparent to those skilled in the art after considering the specification. All such changes, alterations and modifications which do not depart from the spirit and scope of the invention are deemed to be covered by the invention which is limited only by the claims that follow.

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