Patent 6,949,258

The invention is directed to an oral biological preparation for specific delivery in colon, especially an oral insulin preparation for specific delivery in colon.

OBJECT OF THE INVENTION

The object of the invention is to seek and develop an oral preparation of protein or polypeptide drugs especially insulin.

BRIEF DESCRIPTION OF THE INVENTION

The inventor has found that protein or polypeptide drug is mixed with an absorption promoter and a stabilizer to form a water-in-oil emulsion or water/oil/water complex emulsion or aqueous solution, then the emulsion or aqueous solution is filled into a specific capsule shell of the invention to obtain the oral biological preparation locally delivered in colon. When the oral biological preparation is an oral insulin preparation, the bio-availability thereof is 18-21% (rat). The reduction rate of blood sugar after delivering the aqueous solution preparation in colon for 0.5 hours is 72.7% . The above discoveries bring the invention to be achieved.

The first aspect of the present invention relates to an oral biological preparation for specific delivery in colon, which comprises: 1) a drug selected from proteins or polypeptides, an absorption promoter and a stabilizer and 2) a specific capsule shell, characterized in that the capsule shell contains a metal salt of pectin containing 5-12% by weight of metal and 6-10% by weight of water.

The invention also relates to an oral insulin preparation for specific delivery in colon, which comprises: 1) insulin, an absorption promoter and a stabilizer and 2) a specific capsule shell, characterized in that the capsule shell contains a metal salt of pectin containing 5-12% by weight of metal and 6-10% by weight of water.

The invention also relates to a capsule shell for specific delivery of drug in colon, characterized in that the capsule shell contains a metal salt of pectin containing 5-12% by weight of metal and 6-10% by weight of water.

The invention also relates to a process for the preparation of the specific capsule shell, which comprises:

1) Mixing lower methoxy-pectin with a cross-linking agent selected from a group consisting of formaldehyde, glutaraldehyde, sodium alginate, gelatin, arabia gum, peach gum, methylcellulose, ethylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, chitosan or acrylic resin, a plasticizer selected from propylene glycol, glycerin, diethyl phthalate, dibutyl sebate, tributyl citrate or castor oil, and water, holding and degassing at 50° C. to form a glue liquid,

2) Coating clean mold rods with a liquid paraffin as lubricant) then dipping in the glue liquid of step i) for 15 seconds to 1 minute, and drawing out from the glue liquid;

3) Dipping the solidified mold rods of step ii) into an 0.1-10% (w/w) ethanol solution of a metallic salt such as CaCl₂ to calcify, and holding at 40-80° C. for 10 minutes to 5 hours;

4) Drying the solidified mold rods of step iii) by air blowing at 30-60° C. and 30-40% humidity until the water content is 6-10 wt %.

5) When necessary, dipping the mold rods of step iv) into a 1-10% (w/v) solution of polyvinylpyrrolidone for a moment, drawing out and drying with hot air, then dipping into a 1-10% (w/v) solution of acrylic resin for a moment, drawing out and drying with hot air, demolding and cutting according to the needed size to obtain said capsule shells.

The invention further relates to a process for the preparation of oral biological preparation, especially oral insulin preparation for specific delivery in colon, comprising mixing protein or polypeptide drugs such as insulin with a pharmaceutically acceptable absorption promoter and a stabilizer, encapsulating into a specific capsule shell. The insulin used in the invention is natural insulin, synthetic insulin, or insulin obtained by genetic engineering.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention, the amount of insulin is 1 Iu/kg to 20 Iu/kg.

According to the invention, the absorption promoter and the stabilizer are selected from sodium cholate, sodium glycyicholate, sodium taurocholate, sodium deoxycholate, capric acid, sodium caprate, caprylic acid, oleic acid, beta-cyclodextrin, EDTA-Na₂ hydroxypropyl beta-cyclodextrin, polycarboxyethylene glycol, sodium dodecylsulfate, Brij, Tween, Span, eudesmol, menthol, camphol, muscone, enoxolone, glycyrrhetic acid, azone, propylene glycol, glycerin, ethanol, citric acid, sodium salicylate, PEG, fusidic acid, pyrrolidone, benzyl alcohol, linoleic acid, benzyl benzoate, myristyl myristate or ethyl oleate, and urea, etc.

According to the invention, the metal salt of pectin is selected from calcium pectinate, iron pectinate, or zinc pectinate, preferably calcium pectinate.

According to the invention, the specific capsule shell is preferably calcium pectinate containing 5-12% of calcium.

According to the invention, the oral biological preparation is preferably in the form of capsule.

According to the invention, the oral biological preparation comprises 0.05-20% (w/w) of drug, 5-50% (w/w) of absorption promoter, 0.1-30% (w/w) of stablizer and specific capsule shell.

According to the invention, the oral biological preparation is preferably an oral insulin capsule. When the amount of insulin in the capsule is 1 Iu/kg, the bio-availability of which is 18.6% (rat), when the amount of insulin in the capsule is 5 Iu/kg, the bio-availability is 20.3% (rat).

According to the invention, the preparation contains no proteinase inhibitor, as a result, the oral insulin preparation of the invention may not cause the disturbance of gastrointestinal function, and comparing with control indometacin, the insulin preparation of the invention may not cause injury of colic mucosa, even at a dose of as high as 10 Iu/kg. Therefore, the oral insulin preparation of the invention is safe and effective.

The invention therefore further relates to an oral insulin capsule preparation, which comprises 1-10 Iu/kg of insulin, an absorption promoter, a stabilizer, and a specific capsule shell, wherein the specific capsule shell contains calcium pectinate containing 5-12% by weight of calcium and 6-10% of water by weight.

The following examples further describe the invention, but are not intended to limit the invention in any manner.

EXAMPLE 1

Insulin microemulsion (W/O type, water-in-oil type)

Component

Amount

Oil phase:
Oleic alcohol	8	g
Oleic acid	2	g
Lecithin	1	g
Tween-80	4	g
Aqueous phase:
Insulin	6	mg
Sodium salicylate	3	g
Sodium deoxycholate	2	g
Phosphate buffer	3	ml

Dilute hydrochloric acid

appropriate amount

The above insulin was added to the phosphate buffer solution, an appropriate amount of dilute hydrochloric acid was added thereto until the insulin was completely dissolved, and then the sodium salicylate and sodium deoxycholate were added to the solution to obtain the aqueous phase. The lecithin was dissolved in the oleic alcohol, then oleic acid and Tween-80 were added to the solution, stirred to obtain the oil phase. The aqueous phase was added drop-wise to the oil phase under stirring to obtain the insulin microemulsion.

EXAMPLE 2

Insulin Complex Emulsion

The insulin complex emulsion is composed of an oil phase, an inner aqueous phase, and an outer aqueous phase, wherein the oil phase is identical as that of example 1, the inner aqueous phase is consisted of 6 mg of insulin, an appropriate amount of dilute hydrochloric acid, and 30 ml of phosphate buffer, the outer aqueous phase is consisted of 2 g of sodium deoxycholate, 3 g of sodium salicylate, and 50 ml of phosphate buffer. Firstly, insulin microemulsion consisted of oil phase and inner aqueous phase was prepared based on the method as described in example 1, then the so obtained microemulsion was added drop-wise to the outer aqueous phase under stirring to obtain semi-transparent insulin complex emulsion.

EXAMPLE 3

Insulin aqueous solution

Component

Amount

Insulin	6	mg
Sodium deoxycholate	2	g
Sodium salicylate	3	g

Dilute hydrochloric acid

appropriate amount

Phosphate buffer

6 mg of insulin was dissolved in an appropriate amount of dilute hydrochloric acid, and the other components were added thereto to obtain the insulin aqueous solution.

Claim 1 of 5 Claims

1. An oral insulin preparation comprising (a) insulin; (b) a capsule shell comprising calcium pectinate containing 5-12 wt % of calcium, an acrylic resin and 6-10 wt % of water; and (c) a plurality of compounds selected from the group consisting of sodium cholate, sodium glycycholate, sodium taurocholate, sodium deoxycholate, capric acid, sodium caprate, caprylic acid oleic acid, beta-cyclodextrin, EDTA-Na₂, hydroxypropyl beta-cyclodextrin, polycarboxyethylene glycol, sodium dodecysulfate, Brij, Tween, Span, Eudesmol, menthol, camphol, muscone, enoxolone, glycyrrhetic acid, azone, propylene glycol, glycerin, ethanol, citric acid, sodium salicylate, PEG, fusidic acid, pyrrolidone, benzyl alcohol, linoleic acid, benzyl benzoate, myristyl myristate, ethyl oleate, and urea.

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