ACCELERATING THE DRYING RATE OF SOFTGEL CAPSULES

Abstract

The instant invention provides a process for reducing the drying time of softgel capsules by incorporating drying accelerators based on organic sulfonic acids and salts thereof into the formulations used to make the capsules.

Claims

1. A softgel capsule having incorporated in the shell an amount of an organic sulfonate salt which is effective to accelerate the drying rate of said capsule but not effective to provide a pharmacological effect.

2. The softgel capsule of claim 1, wherein said organic sulfonate salt is an aromatic sulfonate salt.

3. The softgel capsule of claim 1, wherein said organic sulfonate salt is an aliphatic sulfonate salt.

4. The softgel capsule of claim 2, wherein said aromatic sulfonate salt is selected from the group consisting of unsubstituted and substituted benzene sulfonates and unsubstituted and substituted naphthalene sulfonates.

5. The softgel capsule of claim 4, wherein said salts are selected from the group of alkaline metal salts and alkaline earth salts.

6. The softgel capsule of claim 3, wherein said aliphatic sulfonate salt is derived from an ester of an aliphatic dibasic acid having the formula ##STR00008## in which R is an aliphatic carbon chain containing at least one sulphonic group, but free from other substituents, and X is an alcohol or phenol radical not connected by a carbon to carbon bond with R.

7. The softgel capsule of claim 3, wherein said aliphatic sulfonate salt is derived from an ester of an aliphatic dibasic acid having the formula ##STR00009## in which R is an aliphatic carbon chain containing at least one sulphonic group but free from other substituents, and X is hydrogen or an alcohol or phenol radical not connected by a carbon to carbon bond with R, at least one X being such an alcohol or phenol radical and Me is hydrogen or a base.

8. The softgel capsule of claim 3, wherein said aliphatic sulfonate salt is derived from an ester of an aliphatic dibasic acid having the formula ##STR00010## in which R is an aliphatic carbon chain containing at least one sulphonic group, but free from other substituents, and X is an alcohol or phenol radical not connected by a carbon to carbon bond with R.

9. The softgel capsule of claim 3, wherein said aliphatic sulfonate salt is derived from an ester of an aliphatic dibasic acid having the formula ##STR00011## in which R is an aliphatic carbon chain containing at least one suiphonic group, but free from other substituents, X is an alcohol or phenol radical not connected by a carbon to carbon bond with R, and Me is hydrogen or a base.

10. The softgel capsule of claim 3, wherein said aliphatic sulfonate salt is derived from an ester of an aliphatic dibasic acid having the formula ##STR00012## in which R is an aliphatic carbon chain containing at least one sulphonic group and free from mercapto groups and X is an alcohol or phenol radical and Y is a different alcohol or phenol radical.

11. The softgel capsule of claim 3, wherein said aliphatic sulfonate salt is derived from an ester of an aliphatic dibasic acid having the formula ##STR00013## MeSO.sub.3—R in which R is a carbon chain free from mercapto groups, Me is a base, X is an alcohol or phenol radical and Y is a different alcohol or phenol radical.

12. The softgel capsule of claim 6, wherein said organic sulfonate salt is sodium docusate.

13. A softgel capsule having incorporated therein another smaller tablet or smaller capsule wherein said smaller tablet or smaller capsule has solid or encapsulated active ingredients that are not compatible with another solid or encapsulated active in the softgel capsule and wherein said capsule incorporates a drying accelerator.

14. The capsule of claim 13 wherein said drying accelerator is sodium docusate.

15. In the process of manufacturing softgel capsules of claim 1 by the rotary die process, the improvement which comprises incorporating an organic sulfonate salt in the capsule shell formulation said organic sulfonate being present in effective amounts to accelerate the drying rate of said capsules.

16. The use of an organic sulfonate salt to enhance the drying rate of softgel capsules wherein said sulfonate is ester of an aliphatic dibasic acid having the formula ##STR00014## in which R is an aliphatic carbon chain containing at least one sulphonic group, but free from other substituents, and X is an alcohol or phenol radical not connected by a carbon to carbon bond with R.

17. The softgel capsule product of claim 13, wherein said product is selected from the group consisting of: (a) one softgel capsule contains an omega oil and the other solid form incorporated into the softgel capsule containing the omega oil contains a statin; (b) one softgel capsule contains a non-steroidal antiinflammatory and the other solid form incorporated into the softgel capsule containing the non-steroidal antiinflammatory contains an antihistamine; and (c) one softgel capsule contains an omega oil and the other solid form incorporated into the softgel capsule containing the omega oil contains a salicylate.

18. The softgel capsule of claim 17, wherein said omega oil is an omega-3 oil and the statin is selected from the group consisting of mevastatin, lovastatin, pravastatin, fluvastatin, simvastatin, rosuvastatin, cerivastatin and atorvastatin and derivatives and analogs thereof.

19. The softgel capsule of claim 17, wherein said non-steroidal antiinflammatory acid is selected from the group consisting of: ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid and tolfenamic acid, diflunisal, flufenisal and piroxicam and said antihistamine is selected from the group consisting of: diphenhydramine, loratadine, cetirizine, fexofenadine, hydroxyzine, cyproheptadine, chlorphenamine, clemastine and desloratadine.

20. The softgel capsule of claim 17, wherein said salicylate is acetylsalicylic acid.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0036] FIG. 1 shows the apparatus to make the capsules of the invention.

[0037] FIG. 2 illustrates the drying curves for soft gel capsules (SGC) with added sodium docusate SD at different S/G levels.

[0038] FIG. 3 describes the hardness of soft gel capsules (SGC) with added SD at different S/G levels.

[0039] FIG. 4 shows the drying curves soft gel capsules (SGC) at different added sodium docusate (SD) concentrations (S/G 1.5).

[0040] FIG. 5 illustrates the hardness of soft gel capsules (SGC) at different SD concentrations (S/G 1.5) and drying times.

[0041] FIG. 6 is a front view of the complete apparatus of the invention showing all the elements of the apparatus.

[0042] FIG. 7 is also a front view of the apparatus of FIG. 1 without the spreader boxes and casting drums.

[0043] FIG. 8 is a front view of the mechanism for filling the capsules with other capsules.

[0044] FIG. 9 is also a front view of how the smaller capsules are dispensed into the larger capsule.

[0045] FIG. 10 shows the smaller capsule hopper having capsules which are fed via guiding channels into the larger capsule.

[0046] FIG. 11 shows a representative end product of the invention containing two capsules inside another capsule wherein the larger capsule incorporates a sulfonate additive.

[0047] FIG. 12 are representative examples of products contemplated by the invention similar to the ones in FIG. 6.

SUMMARY OF THE INVENTION

[0048] The invention provides a softgel capsule having incorporated in the shell an amount of an organic sulfonate salt which is effective to accelerate the drying rate of said capsule but not effective to provide a pharmacological effect.

[0049] The present invention also relates to the use of organic sulfonate salts to accelerate the drying of softgel capsules.

[0050] The invention further features accelerating the drying rate of soft gelatin capsules by incorporating in the gelatin formulation an ester of an aliphatic dibasic acid having the formula

##STR00001##

in which R is an aliphatic carbon chain containing at least one sulphonic group but free from other substituents, and X is hydrogen or an alcohol or phenol radical not connected by a carbon to carbon bond with R, at least one X being such an alcohol or phenol radical.

[0051] The invention further relates to accelerating the drying rate of soft gelatin capsules by incorporating in the gelatin formulation an ester of an aliphatic dibasic acid having the formula

##STR00002##

[0052] in which R is an aliphatic carbon chain containing at least one sulphonic group but free from other substituents, and X is hydrogen or an alcohol or phenol radical not connected by a carbon to carbon bond with R, at least one X being such an alcohol or phenol radical and Me is hydrogen or a base.

[0053] The invention also describes accelerating the drying rate of soft gelatin capsules by incorporating in the gelatin formulation an ester of an aliphatic dibasic acid having the formula

##STR00003##

in which R is an aliphatic carbon chain containing at least one sulphonic group, but free from other substituents, and X is an alcohol or phenol radical not connected by a carbon to carbon bond with R.

[0054] The invention further relates to accelerating the drying rate of soft gelatin capsules by incorporating in the gelatin formulation an ester of an aliphatic dibasic acid having the formula

##STR00004##

[0055] in which R is an aliphatic carbon chain containing at least one suiphonic group, but free from other substituents, X is an alcohol or phenol radical not connected by a carbon to carbon bond with R, and Me is hydrogen or a base.

[0056] The invention is also directed to accelerating the drying rate of soft gelatin capsules by incorporating in the gelatin formulation an ester of an aliphatic dibasic acid having the formula

##STR00005##

[0057] in which R is an aliphatic carbon chain containing at least one sulphonic group and free from mercapto groups and X is an alcohol or phenol radical and Y is a different alcohol or phenol radical.

[0058] The invention further describes accelerating the drying rate of soft gelatin capsules by incorporating in the gelatin formulation an ester of an aliphatic dicarboxylic acid having the following formula

##STR00006##

MeSO.sub.3—R in which R is a carbon chain free from mercapto groups, Me is a base, X is an alcohol or phenol radical and Y is a different alcohol or phenol radical.

[0059] The present invention provides gelatin formulations incorporating organic sulfonate salts additives which reduce the drying time of soft gelatine capsules. The additive may also e included in the fill formulation that goes inside the shells. Additionally, the invention is intended to include capsules made from alternate sources of gelatin such as cellulosic materials, gums, vegetable sources of equivalent materials that are similar to gelatin.

[0060] The present invention provides gelatin formulations incorporating organic sulfonate salts additives which reduce the drying time of soft gelatine capsules. The additive may also e included in the fill formulation that goes inside the shells. Additionally, the invention is intended to include capsules made from alternate sources of gelatin such as cellulosic materials, gums, vegetable sources of equivalent materials that are similar to gelatin.

[0061] The instant invention also provides a process for reducing the drying time of softgel capsules by incorporating drying accelerators based on organic sulfonic acids and salts thereof into the formulations used to make the capsules. It should be noted that the invention includes hydrophilic, lipophilics, self-emulsifying, solutions and suspensions as the fill contents.

[0062] The softgel capsules are evaluated for physical and chemical stability under accelerated conditions based on the capsules obtained with the selected gelatin formulations.

[0063] By way of background, it is known that the drying time of the sodium docusate and calcium docusate CBG product (as an active pharmaceutical in the capsule) is 24-48 h, compared to similar hydrophilic formulations with drying times in some cases up to 144 h.

[0064] It is known that some surfactants have the property of acting as permeation enhancers of polymer films, favoring the mobilization of water and increasing the speed of drying.

[0065] In the process of manufacturing soft gelatin capsules, drying is the process step with longer processing times and costs associated with time and energy consumption. For this reason, an effective measure in the reduction of the drying times will represent benefits in the reduction of the manufacturing costs, as well as in the optimization of this stage of manufacture and in the increase of the productive capacity of the manufacturing plant.

[0066] In the method of the invention, the amount of organic sulfonate salt is between 0.1 mg to about 20 mg. The amount used is sufficient to enhance the drying rate of the softgel capsule.

[0067] The present invention is also directed to the use of sodium docusate as an accelerator of drying of softgel capsules. The docusate is present in amounts to accelerate the drying rate but not in amounts to exert a pharmacological effect.

[0068] The present invention also responds specifically to the long-felt need heretofore unmet by the prior art, and especially with a view to overcoming the inherent inadequacies of combination of pharmaceuticals that are not compatible for oral delivery to mammals. The composition is a pharmaceutical combination i.e., a capsule within a capsule providing the convenience and reliability of oral administration, while providing near simultaneous delivery in vivo of incompatible substances. The composition is shelf stable when formulated and it includes a sulfonate additive to accelerate the drying rate of the soft gel capsules.

[0069] The foregoing, and other advantages of the present invention, are realized in one aspect thereof in an oral pharmaceutical composition that is a combination of incompatible active ingredients. The composition comprises a double soft capsule which includes one pharmaceutical in a first capsule which is enclosed in a second soft capsule also containing a second active ingredient. The soft capsules are preferably made of gelatin wherein the shell composition includes an organic sulfonate to accelerate the drying of the capsules. The active ingredients may be combined with acceptable grade carriers.

[0070] In another aspect, the invention is a method of simultaneously delivering incompatible compounds to mammals in vivo. Such delivery is achieved by administering orally to a mammal a double soft capsule containing a first substance in a first capsule, which is enclosed with a second substance, incompatible with the first substance, in a second larger soft capsule which outer shell includes an organic sulfonate additive that accelerates the drying of said capsules.

[0071] In another embodiment, this invention provides a method for preparing shelf-stable compositions of incompatible substances, which includes the use of multiple capsules of variable composition. Such method is accomplished manually or by the apparatus of the invention further described below.

[0072] As used herein, the term “incompatible” is meant to refer to substances which deleteriously react with one another when combined in desired levels or concentrations.

[0073] The invention also provides an apparatus for making softgel capsules having incorporated therein other solid dosage forms selected from the group consisting of pellets, smaller capsules, smaller tablets, sustained release solid dosage forms, immediate release solid dosage forms, extended release solid dosage forms and zero order release solid dosage forms, said apparatus comprising: (a) two spreader boxes; (b) two casting drums; (c) a pair of rotary dies having means for suction; (d) a liquid fill system; (e) a wedge for heating gelatine ribbons and feeding said fill; and (f) two lateral dispensing devices said lateral dispensing devices including hoppers having said solid dosage forms, channel guides for transporting said solid dosage forms and a grasping claw for dispensing said solid dosage form into the softgel pocket formed in the rotary dies.

[0074] The invention further provides a dispensing device for dispensing and feeding solid dosage forms into a softgel capsule said dispensing and feeding device including a hopper having said solid dosage forms, channel guides for transporting said solid dosage forms and a grasping claw for dispensing said solid dosage form.

[0075] The instant invention also provides a method for making softgel capsules having incorporated therein other solid dosage forms, said method comprising: casting a gel forming composition to make films; (b) passing said films through a pair of rotary dies having vacuum means to make pockets; (c) feeding smaller solid dosage forms into said pockets using a lateral dispensing and feeding system that uses a grasping claw; (d) filling said pockets with a medicine formulation in liquid form via a wedge segment; and (e) forming said capsule by sealing the pockets together wherein said capsules include in the shell composition an organic sulfonate to accelerate the drying rate of said capsules.

[0076] The invention is also a process for making a softgel capsule having incorporated therein another capsule, said process comprising: (a) feeding film sheets between a first die roll and a second die roll wherein each of the die rolls have capsule pockets in a plurality of rows and said capsule pockets have at least one orifice for application of suction; (b) applying suction while said film is in place in the capsule pockets; (c) feeding via guide channels through a lateral dispensing device having a hopper and a grasping claw preformed smaller capsules onto the film sheets overlying the die rolls at positions having the capsule pockets; (d) filling said capsule pockets also via a wedge segment with a liquid medical formulation; and (e) cutting the film sheets about the capsule pockets to form said soft gel capsules having capsules in combination with a suitable liquid pharmaceutical combination.

[0077] The invention further provides softgel capsules incorporated into an outer softgel capsule, and tablets or other solid forms incorporated into an outer softgel capsule, microgranules incorporated into an outer softgel capsule, and any combination between softgels, tablets and/or microgranules incorporated into an outer softgel capsule.

[0078] The instant invention also provides a softgel capsule having incorporated therein another solid dosage form selected from the group consisting: (a) one capsule contains an omega oil and the other solid dosage form is a capsule having a statin; (b) one capsule contains a non-steroidal antiinflammatory and the other solid dosage form contains and antihistamine; and (c) one capsule contains and omega oil and the other solid dosage form contains a salicylate and wherein the capsule making composition includes a an organic sulfonate to accelerate the drying rate of the resulting capsules.

[0079] Other advantages and a fuller appreciation of the specific adaptations, compositional variations, and physical and chemical attributes of the present invention will be gained upon an examination of the following detailed description of the invention, taken in conjunction with the accompanying drawings and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

[0080] The soft gelatin shells of the instant invention can be prepared by combining appropriate amounts of gelatin, water, plasticizer, drying accelerant and any optional components in a suitable vessel and agitating and/or stirring while heating to about 65° C. until a uniform solution is obtained. This soft gelatin shell preparation can then be used for encapsulating the desired quantity of the solubilized fill composition employing standard encapsulation methodology to produce one-piece, hermetically-sealed, soft gelatin capsules.

[0081] In a nut shell, the formation of soft gelatin capsules is carried out in a stamping process wherein the capsule wall is assembled from two gelatin halves which are stamped out of a gelatin band and then molded. Preferably, there is utilized the rotary die process operating under the rotary die method. Herein two endless gelatin bands run against two adjacent and mutually counter-rotating molding rollers. While the gelatin bands are being pressed into the molded and so create the capsule halves, the flowable filler is provided into the thus formed capsule through an exact dosing wedge. There follows the sealing together of the capsule halves, their stamping out, a wash procedure for the freeing of attached oil, a rotational dryer step as well as an adjacent shelf drying.

[0082] More specifically, the fill formulation of the instant invention is encapsulated into one-piece gelatin sheath or shell that includes a plasticizer to control the softness and flexibility of the sheath, water, and optionally, other additives, such as flavorants, colorants, opacifiers, etc. The softgel capsules may be produced in a known manner with a rotary die process in which a molten mass of a gelatin sheath formulation is fed from a reservoir onto drums to form two spaced sheets or ribbons of gelatin in a semi-molten state. These ribbons are fed around rollers and brought together at a convergent angle into the nip of a pair of roller dies that include opposed die cavities. A fill formulation to be encapsulated is fed into the wedge-shaped joinder of the ribbons.

[0083] The gelatin ribbons are continuously conveyed between the dies, with portions of the fill formulation being trapped between the sheets inside the die cavities. The sheets are then pressed together, and severed around each die so that opposed edges of the sheets flow together to form a continuous gelatin sheath around the entrapped medicament. The part of the gelatin sheet that is severed from the segments forming the capsules is then collected for recycling, and the soft capsules are dried.

[0084] Various sheath formulations known in the prior art may be used to encapsulate the fill formulations of the present invention. For example, suitable sheath formulations may include from about 30 to about 50% by weight gelatin; at least 18% by weight, and preferably up to about 40% by weight, of a plasticizer; and from about 20 to about 50% by weight water. These formulations, when formed into capsules and dried, will result in capsule sheaths comprised of from about 40 to about 75% by weight gelatin; from about 18% to about 40% by weight plasticizer; and from about 5 to about 15% by weight water.

[0085] The gelatin will normally have a bloom in the range of from about 140 to about 280, and may be Type A or B gelatins or a mixture thereof. Limed bone, acid bone, fish and/or pig skin gelatins may be used.

[0086] The gelatin capsules are formed into the desired shape and size so that they can be readily swallowed. The soft gelatin capsules of the instant invention are of a suitable size for easy swallowing and typically contain from about 100 mg to about 2000 mg of the solubilized pharmaceutical active composition. Soft gelatin capsules and encapsulation methods are described in P. K. Wilkinson et al., “Softgels: Manufacturing Considerations”, Drugs and the Pharmaceutical Sciences, 41 (Specialized Drug Delivery Systems), P. Tyle, Ed. (Marcel Dekker, Inc., New York, 1990) pp. 409-449; F. S. Hom et al., “Capsules, Soft” Encyclopedia of Pharmaceutical Technology, vol. 2, J. Swarbrick and J. C. Boylan, eds. (Marcel Dekker, Inc., New York, 1990) pp. 269-284; M. S. Patel et al., “Advances in Softgel Formulation Technology”, Manufacturing Chemist, vol. 60, no. 7, pp. 26-28 (July 1989); M. S. Patel et al., “Softgel Technology”, Manufacturing Chemist, vol. 60, no. 8, pp. 47-49 (August 1989); R. F. Emerson, “Softgel (Soft Gelatin Capsule) Update”, Drug Development and Industrial Pharmacy (Interphex '86 Conference), vol. 12, no. 8 & 9, pp. 1133-1144 (1986); and W. R. Ebert, “Soft Elastic Gelatin Capsules: A Unique Dosage Form”, Pharmaceutical Technology, vol. 1, no. 5, pp. 44-50 (1977); these references are incorporated by reference herein in their entirety. The resulting soft gelatin capsule is soluble in water and in gastrointestinal fluids. Upon swallowing the capsule, the gelatin shell rapidly dissolves or ruptures in the gastrointestinal tract thereby introducing the pharmaceutical actives into the physiological system.

[0087] The particular sulfonate salts used in the invention include metal sulfonates derived from Benzenesulfonate, Camphorsulfonate, Sterylsulfate, 4-Chlorobenzenesulfonate, 6,7-Dihydroxycoumarin-4-methanesulfonate, 1,2-Ethanedisulfonate Edisylate, Lauryl sulfate, Ethanesulfonate, Methanesulfonate, 1,5-Naphthalenedisulfonate, Toluene 4-sulfonate, alkoxy-naphthalene sulfonates and sulfosuccinate salts having the structure as shown below:

##STR00007##

[0088] The above structure is known as sodium docusate which is an stool softener when administered at dosages of 50-100 mg. However in the present invention when docusate is used the amount are below the pharmacological effect level.

[0089] It should be noted that the metal counterion for the above sulfonate salts can be sodium, potassium, calcium, magnesium, lithium. Ammonium salts could also be used as well as amine salts. Additionally the acid forms of all of the above could be used in the practice of the invention.

[0090] Within the context of the foregoing description of the invention all capsules manufactured according to the invention include an organic sulfonate in the gelatin composition used to make the capsules that accelerates the drying rate of the capsules.

[0091] The present invention provides an innovative and efficient system for the manufacture of capsules with two or more internal components. Although the internal components may be incompatible the invention is also intended to provide internal components that are compatible but are intended to be released at different intervals.

[0092] The present invention provides an advanced drug delivery system that places different pharmaceuticals forms in a single dosage combination. The invention allows delivering incompatible pharmaceutical actives in the form of solid, liquid, microgranules, gels, hard shell or soft gel capsules within an outer softgel capsule.

[0093] The novel dosage system allows for combining different therapeutic entities that have never been combined before, via oral, ovules, or suppositories.

[0094] For the multi-drugs regimen patients and due to the incompatibility of some actives that can not be combined in a single dose, the instant invention offers a universe of possibilities for current and future new drugs combinations and supplies different releasing delivery.

[0095] In the present invention, existing and proven delivery systems are combined in a highly reliable, easy to use and affordable manufacture that give the resulting dosage form unique characteristics to deliver single or multiple APIs regardless of physical-chemical compatibility and/or stability liabilities.

[0096] For the multi-drugs regimen patients this delivery system is a viable alternative; due to the manufacturing of IR plus MR combinations in tablets and hard-gelatin capsules while enhancing dosing accuracy and by-passing dissolution barriers and coating issues. It allows the formulation of combination products, highly needed to assure patient compliance and allow synergic clinical effects in a safe and stable dosage form.

[0097] Some of the most important advantages are:

[0098] Fast and sustained release in a single dose.

[0099] Gastric or intestinal release in the same dose.

[0100] Fewer intakes to be administered.

[0101] Simplicity of regimen reduces mistakes.

[0102] Impossible to be falsified.

[0103] Reduces number of Rx's prescribed by Physician.

[0104] Smaller number of presentations to maintain.

[0105] The invention further provides soft-gelatin capsules as a immediate-release (IR) delivery system, that upon rupture, it releases immediate or modified release (MR) tablets, capsules, softgels, granules and/or microgranules. Compatible and/or incompatible pharmaceutical active ingredients, and/or blends of IR and MR dosage forms of the same or different active pharmaceutical ingredients (APIs) can be dosed simultaneously in a single capsule. These capsules may be designed to be administered orally, vaginally or rectally, as needed.

[0106] Referring in detail to the apparatus shown in FIG. 6, reference numeral 1 illustrates a medicine hopper having a cover 2 and a medicine feeder 3 connected with a clamp. The apparatus further includes a medicine distributor system 4, pump 5 to pump medicine and further includes plonger 6. The apparatus also includes a fitting distributor connection 7, medicine tubing/hoses 8, a segment coupling connection 9, a support segment 10, and wedge segment 11.

[0107] The apparatus has lateral hoppers 12 and 13 containing smaller capsules or other solid dosage forms that are intended to be encapsulated by the soft gels being formed in the rotary dies. The lateral hopper dispensing system includes acrylic or other material knob fasteners 14 and acrylic substrate 15 having guide channels/tracks 16 for the smaller capsules or other smaller solid dosage forms such pellets or minitablets, etc. The lateral dispensing system of the invention includes a grasping claw 17 for dispensing the smaller capsules coming through channels/track 16. The apparatus further includes the conventional aspects of making softgel capsules which includes a gelatin film 18, guiding rollers 19, tensioner 20, rotary mold 21, a vacuum system 22, capsule exit 23 after the capsule is formed, a yoke support arm 24, housing 25, spreader gel dispensing boxes and casting drum 27.

[0108] FIG. 7 illustrates the apparatus of FIG. 6 without the spreader gel dispensing boxes and casting drums. The reference numerals in FIG. 7 are identical as those in FIG. 6.

[0109] The film-forming materials of the invention comprise at least one component selected from the group consisting of gelatin, starch, carrageenans, gums or synthetic materials such as hydroxypropyl-methylcellulose (HPMC), other hydroxyalkylated celluloses and the like. The film-forming material typically has an aqueous base and is considered to be ingestible. As used herein, the term “ingestible” is used to indicate a film-forming material that dissolves under conditions simulating the human digestion tract or water.

[0110] FIG. 8 shows the dispensing and feeding of solid dosage forms or capsules that come from hoppers 12 and 13 (not shown-See FIGS. 6 and 7) controlled by grasping claw 17 with volume capacity for accurate dosing fixed within the capsule. The smaller dosage form or smaller capsules is fed through guide channels 16 and deposited inside a half pocket as the softgel capsule is being formed in rotary die 21. The grasping claw 17 releases each capsule into each packet as the rotary die moves. The final capsule is also filled with additional pharmaceutical actives in liquid form injection tubing 8. After filling the formed capsule 23 falls-through to a conveyor belt and then transported for drying.

[0111] FIG. 9 further illustrates in more details the feeding of solid dosage forms or capsules into the rotary molding process for making softgel capsules containing inetrnally other dosage forms such as smaller capsules, pellets, small tablets, etc. The feeding of the internal capsule is made by an independent dispenser having guide channels 16 so that as capsules are deposited in the pocket of the rotary die/mold 21, the wedge segment 11 is used to simultaneously dispense a liquid medicine product to fill the capsule. As is well known gelatin film 18 is used to form the softgel pocket in the rotary die/mold 21.

[0112] FIG. 10 shows one of the lateral hoppers having smaller solid dosage forms or smaller capsules to be filled inside another softgel capsule. The hopper 12 having capsules 13, are released from the hopper and deposited and guided through guidechannels 16 which in turn leads to the pocket in the rotary mold that is in a tangential position.

[0113] FIG. 11 illustrates a finished capsule of the invention. One or more smaller capsules may be encapsulated in any way into another immersed in a liquid or solution containing a pharmaceutical active ingredient.

[0114] The resulting products of the invention include softgel capsules having incorporated therein another solid dosage form selected from the group consisting: (a) one capsule contains an omega oil and the other solid dosage form is a capsule having a statin; (b) one capsule contains a non-steroidal antiinflammatory and the other solid dosage form contains and antihistamine; and (c) one capsule contains and omega oil and the other solid dosage form contains a salicylate.

[0115] Typically the omega oil is an omega-3 oil and the statin is selected from the group consisting of mevastatin, lovastatin, pravastatin, fluvastatin, simvastatin, rosuvastatin, cerivastatin and atorvastatin and derivatives and analogs thereof.

[0116] The non-steroidal antiinflammatory acid is selected from the group consisting of: ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid and tolfenamic acid, diflunisal, flufenisal and piroxicam.

[0117] The antihistamine is selected from the group consisting of: diphenhydramine, loratadine, cetirizine, fexofenadine, hydroxyzine, cyproheptadine, chlorphenamine, clemastine and desloratadine.

[0118] The salicylate is typically acetylsalicylic acid.

[0119] The present invention provides delivery systems which are combined in a highly reliable, easy to use and affordable manufacture that give the resulting dosage form unique characteristics to deliver single or multiple APIs regardless of physical-chemical compatibility and/or stability labilities. The soft-gelatin delivery system can be filled with hydrophilic or lipophilic media to suspend various IR and/or MR dosage forms in drug solutions or plain liquid phases.

[0120] The delivery system of the invention is a viable alternative to the manufacturing of IR plus MR combinations in tablets and hard-gelatin capsules while enhancing dosing accuracy and by-passing dissolution barriers and coating issues. It also solves compatibility and stability issues for multivitamins, cold remedies, nutraceuticals and multiple other OTC medications. The invention also allows the formulation of combination products, highly needed to assure patient compliance and allow synergistic clinical effects in a safe and stable dosage form.

[0121] The invention also allows for ease of identification by color coding the shell, fill and/or contents minimizing counterfeiting risks.

[0122] The shell of the soft gelatin capsule may be formed from plasticized gelatin or other functional polymeric materials that are typically used for encapsulation of liquids, fluids, pastes or other fill materials.

[0123] The outer shell of the soft gelatin capsule may be coated with one or more coatings, including but not limited to, immediate release coatings, protective coatings, enteric or delayed release coatings, sustained release coating, barrier coatings, and combinations thereof. The one or more coatings on the outer shell of the soft gelatin capsule may be useful to provide controlled release of the soft gelatin capsule, protect the soft gelatin shell from degradation, or deliver one or more active ingredients which may be the same or different as those in the liquid phase and solid dosage form. Alternatively, additives such as pectin or synthetic polymers may be incorporated into the soft gelatin capsule shell to slow the dissolution on ingestion. Such coatings or additives to the soft gelatin shell phase are well described in the literature and known to those experts in the field. The one or more coatings outer shell of the soft gelatin capsule may be applied by any conventional technique, including but not limited to, pan coating, fluid bed coating or spray coating.

[0124] The liquid fill phase of the soft gelatin capsule may comprise one or more liquids for carrying the solid dosage form that are compatible with the soft gelatin shell and do not interfere with or degrade the solid dosage form. The liquid fill phase may consist of one or more combinations of fluids that may be broadly categorized as hydrophilic or lipophilic.

[0125] A lipophilic liquid fill phase may be an oil form of an active ingredient, an active ingredient or multiple active ingredient preparation that may be solutions, suspensions, emulsions, micro-emulsions, self-emulsifying systems, and other liquids that will be known to those who are expert in the field of soft gelatin capsules formulation. Examples of useful oils include omega-3 fatty acids, vegetable oils, mineral oils or other food grade oil. Vegetable oils may include castor bean oil, coconut oil, peanut oil, palm kernel oil, canola oil, avocado oil, evening primrose oil, rice bran oil, borage oil, sunflower oil, soybean oil, palm oil, corn oil and safflower oil. Preferred oils are omega-3 fatty acids triglycerides or ethyl esters. Examples of omega-3 fatty acids include alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid.

[0126] Hydrophilic liquid fill phases are typically based on polyethylene glycols commonly referred to as PEG 400 or PEG 600 with lesser amounts of glycerol, propylene glycol and water in proportions designed to affect the moisture balance between the liquid fill phase and the capsule shell. Such combinations are commonly known to experts in the field.

[0127] Other hydrophilic materials used to a lesser extent that are, but not limited to, methoxypolyethylene glycols, diethyleneglycol monoethyl ether tetrahyrofurfuryl alcohol polyethylene glycol, propylene carbonate, n-methyl-2-pyrrolidone, polyoxyethylene-poly-oxypropylene copolymers benzyl alcohol and ethyl alcohol.

[0128] The fill formulation may be prepared using established procedures employed for manufacture of pharmaceutical solutions, suspensions and semi-solids, and recognized by those experts in the field of soft gelatin formulation.

[0129] Individual or multiple liquid phases may be introduced into the capsule by means of a single, dual or multiple wedge design that facilitates in-situ capsule filling of multiple phases.

[0130] The liquid fill phase may include different liquid phases which are layered side-by-side in the soft gelatin capsule. Each layered phase may incorporate an active ingredient or multiple active ingredients.

[0131] The fill materials may also include excipients known in the art of soft gelatin encapsulation such as dispersants, surfactants, plasticizers, flavoring agents, opacifying agents, preservatives, embrittlement inhibiting agents, colorants, dyes and pigments, and disintegrants.

[0132] The solid phase may be in the form of preformed tablets, caplets, capsules, slugs of solid materials, granules or other solid dosage forms. Preferably, the solid phase is comprised of a preformed solid dosage form. More preferably, the preformed solid dosage form is a pharmaceutical finished dosage form, which is a dosage form suitable for administration to human or animal subject, the pharmaceutical characteristics of which are acceptable and may be approved by regulatory authorities previously or subject to assessment by regulatory agencies.

[0133] The shape and size of the solid dosage form can vary in accordance with the invention. The shape of the capsule may be, but is not limited to, round, oval, oblong, or a non-standard shape. The solid dosage form is sized to be less than the total internal volume of the soft gelatin capsule.

[0134] The solid dosage form may be coated with one or more coatings, including but not limited to, immediate release coatings, protective coatings, enteric or delayed release coatings, sustained release coatings, barrier coatings, moisture shield coatings and combinations thereof.

[0135] The one or more coatings on the solid dosage form are useful to provide controlled release of an active ingredient in the solid dosage form, protect the solid dosage form from interactions with the liquid fill phase, or deliver one or more active ingredients. Preferably, the solid dosage form is film coated. The one or more coatings on the solid dosage form may be applied by any conventional coating technique recognized in the pharmaceutical industry, including but not limited to, pan coating, fluid bed coating or spray coating. Optionally, the coated or uncoated solid dosage form may be enrobed in gelatin film according to well known conventional tablet enrobing techniques.

[0136] Typical immediate release coating films are hydro-alcoholic film coatings or cellulose film coating systems as used in various pharmaceutical solid oral dosage forms. Typical coating systems may be aqueous, alcohol or organic solvent based or combinations containing hydroxy-propyl-methyl cellulose and derivatives, and polyvinyl alcohol and derivatives. Examples of film coated tablets include: Amoxicillin, Azithromycin, Atenolol, Amlodipine, Acelofenac, Amtriptyline, Ampicillin HCl, Ciprofloxacin, Cefadroxil HCl, Celecoxib, Cimitidine, Calcium Tablets, Certizine HCl, Clarithromycin, Chloroquine Phosphate, Erythromycin estolate, Erythromycin striate, Enalpril Maleate, Elctronxib, Ferrous, fumarate, Famotidine, Flupenthixol, Fluoxetine Felodipine, Gatifloxacin, Gliclazide, Ibuprofen, Indapamide, Ketorolac, Ketoprofen, Levofixation, Levocetrinzie, Losartan, Potassium, Levamisole, Metormin, Methylopa, Metra+Tetraozole, Metronidozole, Methyl, Corn blamine, Mefenamic acid, Metropralal Nifedipne, Norfloxacin, Nifedopine, Norfloxacin, Norflax+Tindazole, Oflaxacin, Oflaxacin+Omidazole, Olazzapine, Orridazole, Oflexacin+Omidazole Paracetamol, Pravastain, Prmethazine, Quinine, sulphate, Primaquine, Ramipril, Tindazole, Tiri+Doxicycline, Tiri+Tetracyline, Valdecoxib, Verapamil, herbal and Neutraceuticals.

[0137] Typical protective coatings may include, but is not limited to, antioxidants, chelating agents, colours or dyes.

[0138] Typical enteric coatings of the solid dosage form may consist of, but not limited to, one or more of the following recognized coating agents: methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, sodium alginate/alginic acid and stearic acid. Examples of enteric coated tablets include: Aspirin and Clopidogrel combination, Aspirin, Bisacodyl, Diclofenac-sodium, Doxylamine succinate, Esomeprazole, Garlic Tablets, Lansoprazole, Omeparazole, Pantoprazole, Pentoxyfilline, Pancreatin, Rabeprazole, Serratiopeptidase, and Sodium Valproate.

[0139] Sustained release tablets may be film coated, enteric coated, or polymer matrix formulated. Sustained release film coatings may include, but is not limited to, a water insoluble material such as a wax or wax-like substance, fatty alcohols, shellac, zein, hydrogenated vegetable oils, water insoluble celluloses, polymers of acrylic and/or methacrylic acid, and any other slowly digestible or dispersible solids known in the art. Examples of sustained release dosage forms include: Acetazolamide Pellets, Aminophylline, Amitriptyline Pellets, Captoprill, Diclofenac Sodium, Diltiazem, Gliclazide, Iron, Levodopa, Lithium Carbonate, Metformin, Methyldopa, Nifedipine, Salbutamol Sulphate, Theophylline, Verapamil HCL, vitamin supplements, mineral supplements, and vitamins with Zinc.

[0140] Moisture shield coatings provide moisture barriers for moisture sensitive or hygroscopic drugs. Such coatings may be applied to solid dosage forms to protect the solid dosage form moisture resulting from, for example, the soft gelatin encapsulation process of which utilizes water as a processing aid and primary plasticizer of the gelatin or functional polymer capsule shell system. Examples of dosage forms incorporating moisture shield coatings include, but are not limited to: Amitriyptyline HCl, Amoxycillin and Clavulanic Acid combination, Atorvastatin and Calcium combination, Calcium Tablets, Clopidogrel, Ethambutol, Glucosamine and Chondritin combination, certain Herbal products, Multivitamins, Ranitidine HCl, Rifampicin and other hygroscopic drugs.

[0141] The active ingredients introduced in the liquid phase and solid dosage form of the multi phase soft gelatin capsules of the present invention may comprise APIs, nutritional supplements, substances used for therapeutic purposes, functional excipients or combinations of active ingredients and functional excipients that control or otherwise affect the release of the active ingredient(s) into the gastrointestinal tract or site of absorption. Each of the liquid phase and solid dosage form may contain one or more active ingredient(s). The active ingredient(s) in the liquid phase and the active ingredient(s) in the solid dosage form may be the same or different.

[0142] The present invention contemplates the use of any active ingredients known in the art. It is well within the knowledge of a skilled person in the art to select a particular combination of active ingredients or medicaments. In some embodiments, active ingredients may include, but are not limited to, the following: APIs, nutraceuticals, nutritional supplements, therapeutic substances, and functional excipients.

[0143] APIs may include, but are not limited to, the following: analgesics, anti-inflammatory agents, anti-helminthics, anti-arrhythmic agents, anti-asthma agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-dementia agents, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, immunosuppressants, anti-protozoal agents, anti-pyretics anti-thyroid agents, anti-tussives, anxiolytics, sedatives, hypnotics, neuroleptics, neuroprotective agents, beta-blockers, cardiac inotropic agents, cell adhesion inhibitors, corticosteroids, cytokine receptor activity modulators, diuretics, anti-Parkinson's agents, gastrointestinal agents, histamine H-receptor antagonists, HMG-CoA reductase inhibitors, keratolytics, lipid regulating agents, muscle relaxants, nitrates and other anti-anginal agents, non-steroid anti-asthma agents, nutritional agents, opioid analgesics, sex hormones, stimulants, and anti-erectile dysfunction agents.

[0144] Nutraceuticals may include, but are not limited to, 5-hydroxytryptophan, acetyl L-carnitine, alpha lipoic acid, alpha-ketoglutarates, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (Vitamin B12), dimethylaminoethanol, fumaric acid, germanium sequioxide, glandular products, glucosamine HCl, glucosamine sulfate, hydroxyl methyl butyrate, immunoglobulin, lactic acid, L-Carnitine, liver products, malic acid, maltose-anhydrous, mannose (d-mannose), methyl sulfonyl methane, phytosterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0145] Nutritional supplements may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements or a combination thereof.

[0146] Vitamins may include, but are not limited to, the following: ascorbic acid (Vitamin C), B vitamins, biotin, fat soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbates, mixed tocopherols, niacin (Vitamin B3), orotic acid, para-aminobenzoic acid, panthothenates, panthothenic acid (Vitamin B5), pyridoxine hydrochloride (Vitamin B6), riboflavin (Vitamin B2), synthetic vitamins, thiamine (Vitamin B1), tocotrienols, vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oils and oil soluble vitamins.

[0147] Herbal supplements may include, but are not limited to, the following: arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginko biloba, ginseng, goldenrod, hawthorn, kava-kava, licorice, milk thistle, psyllium, rauowolfia, senna, soybean, St. John's wort, saw palmetto, turmeric, valerian.

[0148] Minerals may include, but are not limited to, the following: boron, calcium, chelated minerals, chloride, chromium, coated minerals, cobalt, copper, dolomite, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvate, zinc and other minerals.

[0149] Preferred nutritional supplements include, but are not limited to, the following: B vitamins and Vitamin B complex, beta-carotene, calcium, collagen, Co-Q-10, cranberry, echinacea, flax seed oil, folic acid, garlic, ginger, ginseng, glucosamine, chondroitin, green tea, iron, lecithin, lutein, lycopene, magnesium, melatonin, milk thistle, niacin, Omega-3 oils, potassium, probiotics, saw palmetto, selenium, St John's wort, tocopherols, valerian, vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, zinc and combinations thereof. Preferred nutritional supplement combinations include: Co-Q-10 and Omega-3 oils; echinacea, garlic and ginger; glucosamine and chondroitin; vitamin D and calcium; vitamin D, calcium and magnesium; vitamin D, calcium, magnesium and zinc; and vitamin E and other tocopherols.

[0150] Soft gelatin capsules containing solid and liquid phases according to the invention provide a number of significant benefits for the administration of active ingredients.

[0151] The multi phase soft gelatin dosage form of the present invention can be used to deliver two or more active ingredients that otherwise would interact with each other. One or more active ingredients are dissolved in the liquid fill phase and the other active ingredient(s) in the solid dosage form.

[0152] Another use of the present invention is to provide effective control of the release of single or multiple APIs introduced in the solid dosage form and liquid phase. The liquid phase provides the capability of immediate release of the API in the liquid phase by virtue of a solution, pre-dispersed or self-emulsifying formulation. The solid phase may be coated to provide delayed release of the API in the solid phase.

[0153] When two or more capsules and or tablets are prescribed, their combination into one dosage form provides patient benefits and administration advantages of convenience and costs.

[0154] Analgesics such as ibuprofen and acetaminophen differ in their mode of action and related therapeutic effects such that combined administration provides improved analgesia and safety. The present invention provides the capability to engineer combinations of solid dose components of acetaminophen, ibuprofen or other combinations as individual solid forms or combined in one solid form with a liquid phase that may contain either or other active ingredients.

[0155] The present invention may be useful as a polypill. A polypill is a medication that contains a combination of active ingredients, reducing the number of tablets or capsules that need to be taken. Combined medications in the form of a polypill are useful for the treatment of cardiovascular disease and diabetes.

[0156] The present invention may reduce problems, such as time and expense, associated with combining two or more APIs into one dosage form. New combinations in one dosage form require development of new formulations and require pharmaceutical and clinical studies to demonstrate safety, efficacy and potency. The present invention provides the capability to incorporate more than one API into a unit dosage form utilizing established forms of the API or APIs that may be in liquid or solid phases. The present invention allows retention of the established tablet, caplet or capsule form of an API. This provides the capability to retain the pharmaceutical characteristics of the solid dosage form in combination with a liquid or fluid phase. Key characteristics include: physical and chemical stability, API release profile of the tablet or caplet, bioavailability and clinical performance. Retention of the established clinical performance by incorporation of the original solid may avoid the need to conduct extensive Phase III clinical studies that would otherwise be required with a new formulation.

[0157] By combining a number of established, off patent or generic medications, the present invention may be useful to treat cardiovascular conditions and provides the prospect of low cost treatment.

[0158] The present invention may be useful for the combined administration of unit doses of HMG-CoA inhibitors (statins) and Omega-3 fatty acids. The statins may be in the form of tablets or capsules containing single ingredient HMG-CoA inhibitors, or statins in combination with other active ingredients. Commercially available statins include LIPITOR™ or TORVAST™ (atorvastatin calcium) sold by Pfizer, LESCOL™ or LESCOL XL™ (fluvastatin sodium) sold by Novartis, MEVACOR™, ALTOCOR™ or ALTOPREV™ (lovastatin) sold by Merck, LIVALO™ or PITAVA™ (pitavastatin) sold by Kowa, PRAVACHOL™ SELEKTINE™ or LIPOSTAT™ (pravastatin sodium) sold by Bristol Myers Squibb, CRESTOR™ (rosuvastatin calcium) sold by AstraZeneca, ZOCOR™ or LIPEX™ (simvastatin) sold by Merck. Examples of established tablet dosage forms containing two or more active ingredients include VYORTIN™ (simvastatin+exetimibe) sold by Merck, ADVICOR™ (lovatatin+niacin) sold by Merck, CADUET™ (atorvastatin calcium and amlodipine besylate) sold by Pfizer, and SIIVICOR™ (simvastatin+niacin) sold by Merck. The Omega-3 fatty acids may be in the form of ethyl esters or tri-glycerides.

[0159] The present invention may permit the use of a smaller dosage form than those commercially sold. Encapsulation of a solid dosage form in a soft gelatin capsule provides protection against dissolution of the solid dosage form prior to reaching the intended target site. Thus, an encapsulated solid dosage form may not need to be as durable as compared to commercially available solid dosage forms. The present invention may reduce the need for excipients which function to prevent early dissolution of the solid dosage form when ingested, permitting the use of a smaller and cheaper solid dosage form.

[0160] The following are examples of the benefits of the present invention for the administration of combinations of medicines that may be in the form of a solid dosage form and liquid fill phase in a soft gelatin capsule.

[0161] The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

EXAMPLES

[0162] The following examples are intended to demonstrate the usefulness of preferred embodiments of the present invention and should not be considered to limit its scope or applicability in any way.

Example 1

Soft Gelatin Capsule Containing a Placebo Fill

[0163] A soft gelatin mixture is prepared from the following ingredients.

TABLE-US-00001 INGREDIENT WEIGHT % Gelatin 48.00 Glycerin 14.00 Organic Sulfonate 0.02 mg to 20 mg Water QS 100

[0164] The above ingredients are combined in a suitable vessel and heated with mixing at about 65° C. to form a uniform solution. Using standard encapsulation methodology, the resulting solution is used to prepare soft gelatin capsules. The resulting capsules are dried in trays and/or tumbler and the time of drying is compared to the capsules not including organic sulfonate salts. The capsules containing organic sulfonate salts such as sodium docusate enhance the drying rates when compared to capsules not containing organic sulfonate salts.

Example 2

[0165] Using carbohydrate gums suitable for making softgel capsules similar formulations are manufactured as in Example 1.

Example 3

Experimental Objectives

[0166] 1. To evaluate the effect of adding sodium docusate 100% USP in the gelatin masses at different concentration levels on the drying time of a prototype of soft gelatin capsule containing a hydrophilic fill content.

[0167] 2. To evaluate the effect of the plasticizers on the drying time of a prototype of soft gelatin capsule added of sodium docusate 100% USP

[0168] Samples

[0169] The fill content contains polyethyleneglycol as main component, propyleneglycol not exceeding 10% and a water soluble color to test the dissolution in the capsules. Water was not added to the fill content formulation in any of the samples. The target dose was 285 mg/capsule for a 5.5 oval capsule size.

[0170] The gelatin formulation contains gelatin 150 bloom, type B at standard use level and sorbitol-glycerol (S-G) mixtures as plasticizer. The ratio S/G ranged from 0.7-1.55 and the ratio gelatin plasticizer remained constant. SD content was tested in each sample by means of the assay method under docusate sodium capsules (USP 41).

TABLE-US-00002 TABLE 1 Tested Systems Sorbitol/Glycerol Sample ratio Fill content SD mg/capsule blank 0.67 Blank (w/o SD) N.A S/G low level 0.67 SD 1.5% + fill 4   S/G high level 1.5 SD 1.5% + fill 5.1 blank 1.5 Blank (w/o SD) N.A SD low level 1.5 SD 2.0% 2.7 N.A. Not apply

Results

Example 3A

Effect of the Sorbitol/Glycerol Ratio in the Drying Time of a Hydrophilic SGC Prototype Added with Sodium Docusate in the Gelatin Formulation

[0171] Samples in FIG. 2 contain the same amount of SD 100% USP added in the shell (1.5%) and SD in polyethyleneglycol 50% added in the fill, but low and high levels of the ratio sorbitol/glycerol as plasticizer. Drying curves of the samples were compared in FIG. 1 to evaluate the effect of the ratio S/G in the SD migration from the fill to the shell and the effect on drying. It was observed that the drying of the sample S/G low level was faster in correspondence to a high assay value of sodium docusate in the shell (27% higher). That explains that sorbitol promotes the migration of sodium docusate to the shell. Both samples with docusate addition met the specification for water content in the fill at 24 h compared to the blank sample that did not met it during the tested period (96 h).

[0172] The acceptance criteria for hardness (7-9N) was met for sample S/G low level and S/G high level at 72 and 48 h, respectively (FIG. 3). The more the glycerol content in the shell formulation (sample S/G low level), the longer the time to meet the hardness specification. Low hardness values are also related with the polyethyleneglycol in the fill content that migrates to the shell and acts as a plasticizer. It was also observed that the samples showed clumping at accelerated conditions. For this reason, the level of PEG in the fill content should be limited to 20% to avoid over plasticizing the shell and the SD should be added only in the shell formulation.

Example 3B

Effect of the Concentration of Sodium Docusate (SD) 100% USP in the Drying Time of a Hydrophilic SGC Prototype

[0173] To evaluate the effect of SD concentration, SGC were obtained at two SD levels using as plasticizer the mixture S-G at its high tested level.

[0174] As concluding results, the lowest drying time (48 h) for the prototype SGC was obtained at 2.0% and 2.5% of sodium docusate in the gelatin mass. The drying curves were compared through the similarity facto (F1) and SD samples were found to be comparable. In contrast, the moisture in the shell and the fill was significant different comparing the docusate-added samples with the blank sample (F1>15). In the FIG. 3, the drying curves for water content in the fill are shown for the blank samples and the gelatin masses added with docusate. The specification for the water content in the fill is 9-12% was met at 48 h hours for both samples added with docusate and it was not met by the blank sample in the tested period (168 h). The drying process reduced the water content in the fill from 19-21% after encapsulation to 10-11.8% at 48 h in the capsules added with docusate. The blank at the same time registered 13.7% water in the fill content. The water content in the shell decreased from 13.7-16.5% to 13.8-14.1% at 48 h compared to 14.6% for the blank at the same drying time.

[0175] As it can be seen in the FIG. 4, the moisture content in the fill for the samples with SD reaches a steady state from 48 h (RSD 0.7-1.1).

[0176] Samples were also tested for hardness (FIG. 5) and mechanical resistance (burst test) to determine the effect of SD on these physical properties. The specification for hardness (7-9 N) was met for the samples with docusate at 48 h. For the low level of SD, the hardness remains stable (RSD 0.08) in the tested period (up to 168 h), meanwhile for high level of SD and blank samples increase up to 9.1 and 9.4N, respectively.

[0177] The results for mechanical resistance showed the highest values for the blank sample and similar values for docusate samples from 96 h (95-102 N). In spite of the seal is about a 50% weaker in the docusate samples compared to the blank sample, the capsules did not show leakers during the predrying or the drying step or in their handling.

CONCLUSIONS

[0178] The selected plasticizer system was sorbitol-glycerol in the high tested S/G range. It showed migration in less extent between the fill content and the shell. Capsules obtained using this plasticizer level met the hardness specification at 48 h.

[0179] The effect of the addition of SD to gelatin masses on reducing the drying time of SGC was demonstrated through the drying curves of the SD samples, that were different compared to the blank sample (F1>15). The blank sample did not met the specification for the moisture content in the fill in the tested period while the SD samples met the specification at 48 h, reached the steady state from this time and met the hardness criteria at 48 h.

[0180] In regards the SD concentration, there was not difference between the low and high SD level when compared through the similarity factor (F1).

[0181] The contents of all references cited in the instant specifications and all cited references in each of those references are incorporated in their entirety by reference herein as if those references were denoted in the text.

[0182] While the many embodiments of the invention have been disclosed above and include presently preferred embodiments, many other embodiments and variations are possible within the scope of the present disclosure and in the appended claims that follow. Accordingly, the details of the preferred embodiments and examples provided are not to be construed as limiting. It is to be understood that the terms used herein are merely descriptive rather than limiting and that various changes, numerous equivalents may be made without departing from the spirit or scope of the claimed invention.