WO2021029467A1

WO2021029467A1 - A solid dosage form for orally administration

Info

Publication number: WO2021029467A1
Application number: PCT/KR2019/010364
Authority: WO
Inventors: Hyung-Kyun Jun
Original assignee: Sam Chun Dang Pharm. Co., Ltd.
Priority date: 2019-08-14
Filing date: 2019-08-14
Publication date: 2021-02-18

Abstract

The present invention discloses a kind of solid dosage form of formulation for orally administering and the processed for preparing the formulation, which is stable in both in vivo and in vitro. It contains the self-nano emulsified drug delivery system, so that the micelle solubilization takes place after the formulation delivered into the duodenum. The formulation goes through the first-pass effect and then transports to not only blood vessel, but also the lymphatic vessel. Thus this formulation can minimize the insulin-induced weight gain and avoid the reactive hypoglycemia.

Description

A SOLID DOSAGE FORM FOR ORALLY ADMINISTRATION

The present invention relates to the field of oral pharmaceutical formulations, especially the solid dosage form of insulin.

Many drugs cannot be orally administered because the drug will either degrade or will not be orally bioavailable. Such as protein (eg. insulin), peptide (eg. liraglutide) and hormone drugs (eg. somatropin). The Self-Nano Emulsified Drug Delivery System (SNEDDS) can be used to protect the drug against degradation. Moreover, SNEDDS can also increases the solubilization and dissolution of the drug to have quick onset, and enhances drug absorption through structural or fluidity changes in the intestinal membrane.

Diabetes is a metabolic disease that causes high blood glucose level. The high blood glucose level is due to either failure to produce enough insulin or to the development of insulin resistance. Failure to produce enough insulin results in diabetes Type 1. Type 2 diabetes results from insulin resistance. Type 1 diabetes is typically treated with insulin or synthetic insulin analogs. Type 2 diabetes may require insulin if other medications fail.

The liquid dosage form of SNEDDS loading insulin is already can be found in the prior art. But the disadvantages are still remaining like low stability and high-cost for preparing. Therefore, the need to develop a non-invasive delivery system for insulin is still unmet and compels development of stable convenient oral dosage forms of insulin. Accordingly, there is a need for a therapeutically effective oral insulin formulation.

The present invention provides a solid oral pharmaceutical formulation of insulin with high stability, efficiency and low-cost for preparation. Besides, this formulation is suitable for both type 1 diabetes and type2 diabetes, and the efficacy in blood glucose-lowing can be achieved for more than 4 hours after single dose administration. The present invention provides the method for preparing this formulation as well.

The solid dosage form for orally administering comprising insulin, microcrystalline cellulose, stearic acid, magnesium aluminometasilicate, labraso, polyvinyl alcohol and titanium dioxide.

The formulation comprises at least 1.18% w/w insulin, at least 7.5% microcrystalline cellulose, at least 0.14% w/w stearic acid, at least 14.7% w/w magnesium aluminometasilicate, at least 44.12% w/w labraso, at least 8.46% w/w polyvinyl alcohol and at least 0.29% w/w titanium dioxide.

The magnesium aluminometasilicate includes Neusilin^® US2 and Neusilin^® UFL2.

A method of treating the disease of diabetes type 1 and type 2, hyperlipidaemia, inflammation, oxidative stress, atherosclerosis and Alzheimer, the method comprising administering to the patient an effective amount of the solid dosage form comprising insulin.

A method of preparing the solid dosage form for orally administering, the method comprising the steps of: (a)weighting granule 1, comprising insulin, microcrystalline cellulose, and stearic acid, and passing through a #35 sieve; (b) mixing granule 1 for at least 5 minutes, next tableting it to 7~8 KP intensity, and then passing through #16 mesh sieve and granulation; (c) weighting granule 2, comprising magnesium aluminometasilicate, polyvinyl alcohol, neotame, cherry flavoring agent and titanium dioxide; and passing through a #30 sieve; (d) mixing granule 2 for at least 5 minutes, pouring the labrasol on the mixing granule 2 and waiting for overnight; (e) coating mixing granule 2 by fluid bed granulation; and (f) forming the dosage form by final mixing granule 1 and granule 2.

The entire manufacturing process is very simple and easy to complete, so the production cost is greatly reduced. Because the formulation is a solid dosage form and does not contain any antacid, it is very stable when stored in vitro. After oral administrated into the human body, especially into the duodenum, the formulation of this invention is automatically emulsified to form colloid micelle with insulin loading inside under the participation of gastric juice. Thus the insulin is stable inside the micelle. Thereby completing the mission of lowering blood sugar. This way is more similar to the normal human metabolism.

FIG.1 is a graph of blood glucose levels (% of initial) over time, calculated as a percent of initial blood glucose values, for streptozotocin (STZ)-induced diabetic mice to which were orally administered 200 IU/kg of insulin(filled circles), or orally administered of water (open circles).

FIG.2 is a graph of blood glucose levels (% of control) over time, calculated as a percent of control blood glucose values, for streptozotocin (STZ)-induced diabetic mice to which were orally administered 200 IU/kg of insulin.

FIG.3 is a graph of blood glucose levels (% of initial) over time, calculated as a percent of initial blood glucose values, for genetic-deficient diabetic mice to which were orally administered 200 IU/kg of insulin (filled circles), or orally administered of water (open circles).

FIG.4 is a graph of blood glucose levels (% of control) over time, calculated as a percent of control blood glucose values, for genetic-deficient diabetic mice to which were orally administered 200 IU/kg of insulin.

While the present disclosure is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated and/or described, and should not be construed to limit the scope or breadth of the present disclosure. The headings used throughout this disclosure are provided for convenience only and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

The present invention provides a pharmaceutical formulation which is effective in adjusting blood glucose levels by providing suitable amount of insulins in a subject, when administered to said subject's gastrointestinal tract by oral administration of a pharmaceutical formulation according to the present invention.

Disclosed herein is a formulation that includes insulin, microcrystalline cellulose, stearic acid, magnesium aluminometasilicate, labraso, polyvinyl alcohol, neotame, cherry flavoring agent and titanium dioxide.

The entire manufacturing process is very simple and easy to complete, so the production cost is greatly reduced. Because the formulation is a solid dosage form and does not contain any antacid, it is very stable when stored in vitro. After oral administrated into the human body, especially into the duodenum, the formulation of this invention is automatically emulsified to form colloid micelle with insulin loading inside under the participation of gastric juice. Thereby completing the mission of lowering blood sugar. This way is more similar to the normal human metabolism.

In one embodiment, formulation was prepared as follows:

	Material	Amount (mg)	w/w (%)
Part A	Insulin8 mg Insulin = 230 IU Insulin	8	1.18
	Microcrystalline Cellulose NF 102	51	7.5
	Stearic Acid	1	0.14
Granule 2	Neusilin^® US2 (magnesium aluminometasilicate)	75	11.03
	Neusilin^® UFL2(magnesium aluminometasilicate)	25	3.68
	Labrasol (PEG-8 CAPRYLIC/CAPRIC GLYCERIDES)	300	44.12
	Polyvinyl alcohol (Opadry amb II )	57.5	8.46
	Neotame	0.5	0.07
	Cherry Flavoring agent	10	1.47
	Titanium dioxide	2	0.29
	Total	530	100

Granule 1 was prepared by, accurately weighing all the granule 1 components and passed through a #35 sieve. After mixing for at least 5 minutes, mixing granule 1 was tableted to 7~8 KP intensity, and then pass through #16 mesh sieve and granulation.

Granule 2 was prepared by a wet granulation method，in which all the granule 2 compounds were weighed and passed through a #30 sieve. After mixing for at least 5 minutes, pouring the labrasol on the mixing granule 2 and waiting for overnight. And then coating mixing granule 2 by fluid bed granulation.

Formulation was prepared by combining granule 1 and granule 2 and then finally filled into capsules or compressed into tablets.

Because the formulation is a solid form with FDA approved polymeric excipients. As the results, firstly the solidified dosage form improves the stability of peptide/protein/hormone drug especially insulin. Secondly, the preparing steps is much easier than before and leads to the low-cost for production. Thirdly, it can be orally administered to a subject，which greatly decreases the inconvenience of patients compared to the injection. Last but not the least, it is highly adjustable in HLB even stable in low pH.

When this formulation was orally administered to a subject, the hydrophobic insulin along with some polymeric excipients or lipid component is delivered into the duodenum, the micelle solubilization process takes place. Thus the liquidcrystal liked W/W nano-emulsion especially colloidal micelle is formed with insulin entrapped in the core.

Because the micelle is formed in the gastrointestinal tract, some of the insulin may go through the first-pass effect, which can minimize the insulin-induced weight gain. And then some of the micelle with insulin inside will then get into the blood vessel, the others can be absorbed via the lymphatic system, bypassing the hepatic first -pass metabolism. Since the stearic acid we used is a long-chain fatty acid which can convert to triglyceride by re-esterification in the small intestine and incorporated into chylomicron, a large lipoprotein like insulin can be secreted into the lymph vessel by exocytosis. Therefore, this kind of delivery of insulin is mimic to physiologic situation, and it can minimize insulin-induced weight gain.

In another embodiment, in vivo hypoglycemic study with SMEDDS containing insulin after oral administration in diabetic mice to study the pharmacokinetic (PK) / pharmacodynamics (PD) profile.

For diabetes type 1, the formulation containing 200IU/kg of human insulin was administered by oral gavage to each of five STZ-induced DB mice (around 30g body weight). Four STZ-induced DB mice was orally administrated with same amount of water as the control group.

Blood samples were drawn from each mouse following gavage, and blood glucose levels in those samples were determined. The results of these blood glucose determinations are shown in FIG. 1. The formula for calculating is shown as follow:

To avoid the influence of other parameters like the initial glucose level and to show the real impact of oral insulin, a percent of control blood glucose values was calculated and shown in FIG.2. The formula for calculating is shown as follow:

The mice exert a exhibited a substantial drop in blood glucose level, beginning as soon as 15 minutes following oral gavage and enduring for not more than about 4 hours. During the first 15 minutes following administration, the blood glucose level was decreased about 40% compared with that at time zero. Blood glucose levels of control group show a great increase in the first 15minutes and then slowly decrease over the remaining study period.

For diabetes type 2, the formulation containing 200IU/kg of human insulin was administered by oral gavage to each of five genetic-deficient DB mice (BKS.Cg-Dock7m +/+ Leprdb/Jnarl, around 30g body weight). Four genetic-deficient DB mice was orally administrated with same amount of water as the control group.

Blood samples were drawn from each mouse following gavage, and blood glucose levels in those samples were determined. The results of these blood glucose determinations are shown in FIG. 3. The formula for calculating is the same with FIG.1.To avoid the influence of other parameters like the initial glucose level, a percent of control blood glucose values was calculated and shown in FIG.4. The formula for calculating is the same with FIG.2.

Due to first introducing dose by oral route, the initial raise of blood glucose on mice can be expected (i.e. no experience) which is widely seen in previous animal studies with oral administration. But compared to the about 230% increase of the control group in the early 30 minutes, about 50% increase of the tested group means that the mice still exert a exhibited a substantial drop in blood glucose level. And then the glucose level slowly decrease over the remaining study period for abound 4 hours.

According to the four figures, it is easily to say that this formulation is quick onset around 30 min and leads to more than 40% reduction of blood glucose comparing to the control group. So that it is effective in lowing blood glucose via oral administration in both type 1 & 2 DB animal model. And it is effective to maintain blood glucose in low level via single oral dose administration in type 2 DB animal model for more than 4 hours.

Since the formulation is useful for diabetes type 2. On the one hand, the insulin resistance is a core feature of diabetes type 2. On the other hand, the insulin resistance contributes to the hyperlipidaemia, inflammation, oxidative stress and atherosclerosis that accompany it. As a result, it is easy to draw a conclusion that the formulation is useful for the hyperlipidaemia, inflammation, oxidative stress and atherosclerosis.

Besides, the effectiveness of insulin in animals with Alzheimer disease model has been widely studied. Especially since 2006, clinical trials have been conducted to evaluate the clinical benefit of insulin in Alzheimer patients. It was found that moderate doses of intranasal insulin improved some memory symptoms in older adults with Alzheimer disease or mild cognitive impairment. Insulin exerts its actions in the body also mediate its roles in synaptic neurotransmission, neuronal and glial metabolism, and the neuroinflammatory response in the brain. The actions of insulin in the brains include central modulation of body metabolism and enhancement or regulation of memory and other cognitive and emotional functions. Thus the formulation is effective for Alzheimer patients.

Claims

A solid dosage form for orally administering comprising consisting of insulin, microcrystalline cellulose, stearic acid, magnesium aluminometasilicate, labrasol, polyvinyl alcohol and titanium dioxide.
The solid dosage form of claim 1, wherein the formulation comprises at least 1.18% w/w insulin, at least 7.5% microcrystalline cellulose, at least 0.14% w/w stearic acid, at least 14.7% w/w magnesium aluminometasilicate, at least 44.12% w/w labrasol, at least 8.46% w/w polyvinyl alcohol and at least 0.29% w/w titanium dioxide.
A method of treating the disease of diabetes type 1 and type 2, hyperlipidaemia, inflammation, oxidative stress, atherosclerosis and Alzheimer, the method comprising administering to the patient an effective amount of a formulation according to claim 1 or 2.
A method of preparing the solid dosage form for orally administering, the method comprising the steps of:

(a) weighting granule 1, comprising insulin, microcrystalline cellulose, and stearic acid;

(b) mixing granule 1 next tableting, and granulation;

(c) weighting granule 2, comprising magnesium aluminometasilicate, polyvinyl alcohol, neotame, cherry flavoring agent and titanium dioxide;

(d) mixing granule 2 and pouring labrasol on the mixing granule 2;

(e) coating mixing granule 2 by fluid bed granulation; and

(f) forming the dosage form by final mixing granule 1 and granule 2.
The method of claim 4, wherein granule 1 is passed through a #35 sieve after being weighted.
The method of claim 4, wherein granule 1 is mixed for at least 5 minutes.
The method of claim 4, wherein granule 1 is tableted to 7~8 KP intensity.
The method of claim 4, wherein granule 1 is passed through a #13 sieve after being tableted.
The method of claim 4, wherein granule 2 is passed through a #30 sieve after being weighted.
The method of claim 4, wherein granule 2 is mixed for at least 5 minutes.
The method of claim 4, wherein the mixing granule 2 is waited for overnight after pouring the labrasol.