BACKGROOMD OF THE INVENTION

The present invention is concerned with the us of starch as a complexant with iodine for preparing dr powder pharmaceutical formulations useful in th preparation of capsules or tablets.

More particularly, the invention is concerne with the administration of molecular iodine (I ₂ ) t patients suffering from iodine deficiency diseases b administering to said patients a starch iodine complex i a dry formulation.

Heretofore, iodine deficiency diseases hav been treated by administering to patients, in nee thereof, an aqueous solution containing elemental iodin (I ₂ > (U.S. Patent No. 4,816,255 to Ghent et al. issue March 28, 1989 and O90/07339, Ghent et al. publishe July 12, 1990) .

The administration of aqueous molecular iodin to patients has several disadvantages including the nee for specialized dispensers utilizing selective membrane thereby preventing the patient from ingestin crystallized iodine. Standardization of daily dosage i also a problem associated with these dispensers. Se U.S. Patent No. 4,384,960 to Polley. In WO90/07339,

Ghent et al. published July 12, 1990, a method wa described for providing an aqueous solution of elementa iodine free of any micro or macro particles of iodine.

In this method iodine crystals were placed in a seale plastic bag or container which was exposed to water a about 20°C. The iodine crystals sublime, and iodin vapour passes through the plastic and into the water t

produce a pure solution of elemental iodine without an particulate matter. The temperature of the water effect the rate of sublimation of the prilled iodine, an therefore effects the time of stabilization of the pur solution at the required concentration. Therefor standardization of daily dose is also a problem with thi prior art method. Furthermore, this prior art method o preparing the pure solution of elemental iodine is not a convenient method for use by the general public.

In view of the problems associated with the prior art methods, a therapeutic effective amount of elemental iodine in a convenient form and standardized dose has been desired.

SUMMARY STATEMENT OF THE INVENTION

The present invention therefore relates to the preparation of a dry form of iodine, which may be encapsulated in capsule or pill form, for therapeutic oral administration to patients.

More particularly, the invention relates to the use of starch, and more particularly to the use of starch containing a high proportion of amylose, as a complexant with iodine to provide means to prepare a dry powder formulation in capsule or tablet form for oral administration to patients suffering from or for prevention of various iodine deficiency diseases and the like.

The present invention also relates to a dry pharmaceutical composition useful in the treatment of iodine deficiency diseases including breast dysplasia.

breast cancer, endometriosis and premenstrual syndrome as well as other iodine related diseases, said compositio comprising the dry starch-iodine complex and, if desired, in combination with one or more suitable adjuvants. The present invention also relates to the treatement of iodine deficieny diseases by administering an effective amount of the dry pharmaceutical compositon.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 is a molecular representation of the amylose-iodine complex wherein the iodine molecules depicted as solid spheres fit within the cavity of the amylose helices.

DESCRIPTION OF THE PPmπgRTtTgn ^WfROI-TMRtiTS

In view of the apparent disadvantages to the administration of aqueous molecular iodine, it became evident that it would be desirable to administer the iodine in capsule or tablet form. The present invention is directed to dry pharmaceutical formulations containing iodine and the administration of the same in capsule or tablet form. This mode of administration of iodine is believed to be superior to those prior art methods and overcomes the various disadvantages experienced by the administration of elemental iodine in aqueous form.

Starch, in general, contains a mixture of a water-soluble straight-chain fraction called amylose, and a water-insoluble branched fraction called amylopectin. Depending upon the source of the starch, these two fractions appear in different proportions. Upon treatment of acid or under the influence of enzymes, the

components of starch are hydrolysed progressively t dextrin, which is a mixture of low-molecular-weigh polysaccharides, (+)-maltose, and finally D-(+)-glucose Both amylose and a ylopectin are made up of D-(+)-glucos units, but differ in molecular size and shape.

Of particular interest, to the presen invention, is the structure of amylose which is a linea 1,4-acetal polymer of glucose. Thus, amylose is made u of chains of many D-(+)-glucose units, each C-l of eac glucose unit joined by an α-glycoside linkage to the c- of the next glucose unit. It is the alpha linkage at th acetal carbon which has a profound effect on the overal shape of the giant amylose molecule which gives it it unique physical properties and the interactions th amylose molecule may have with smaller molecules.

Amylose is a helical molecule, with glucose residues that coil back on each other, creating a loosely overlapping spiral with a central cavity or tube. A variety of small molecules including triiodide ions (1 ₃ ") or polyiodide ions (15 ^" ) up to (In ^" ) form stable complexes with amylose. As is known, the starch-iodine complex has a deep blue-violet colour that can be used to test for the presence of either amylose or iodine. Furthermore, the decolorization of an amylose/iodine complex has been used as a test for amylase activity for some time. From structural evidence, it is apparent that the colour arises because of interactions between rows of I ₃ ~ molecules oriented end to end inside the tubular cavity of amylose structure (see Organic Chemistry. Ke p- Vellaccio, Worth Publishers, Inc., copyright 1980, p. 994) .

It is the unique physical properties of the

amylose molecule which forms a part of starch which has led us to believe that starch would be ideally suited as a complexant for iodine to prepare dry pharmaceutical formulations which may be encapsulated in capsule o tablet form for oral administration. These dry formulations of iodine would be superior to known aqueous iodine solution used in the treatment of iodine deficiency diseases such as breast dysplasia, breas cancer, endometriosis and premenstrual syndrome. Such aqueous formulations, containing elemental iodine (I ₂ ) , are contemplated in U.S. Patent No. 4,816,255 to Ghent et al issued March 28, 1989, and WO90/07339, published July 12, 1990. Dry powder formulations of the present form in capsule or tablet form are also useful in the treatment of radiation sickness from nuclear fallout and the like and are more easily administrable in oral form to patients.

The present invention is concerned with utilizing starch as a complexant with iodine to form an iodine-starch complex and more specifically with the use of the amylose component of starch to form an amylose- iodine complex as depicted in Fig. 1. (Taken from Organic Chemistry. Kerap-Vellaccio, Worth Publishers, Inc. 1980, p. 994.)

It is mostly the linear component of starch which is responsible for the uptake of iodine. This starch-iodine complex exists in a helical configuration as depicted in Fig. 1 within which the triiodide ions (I ₃ "") or polyiodide ions (I ₅ - up to In ^" ) reside. The most common complex however is the triiodide ion-amylose complex. The molecular weight or molecular weight distribution of the starch (amylose) plays a critical factor in the ability of starch to complex iodine.

The minimum length of the amylose chain t produce its characteristic blue colour is about 30-40 D glucose units, providing a cavity corresponding closel in length to an 11-atom polyiodide chain. The brand, lot, quality, source, time of harvesting and place o growth are all factors which will influence the linea amylose content of the starches. In the presen invention, starch containing a high proportion o amylose is preferred. As such the amount of iodine i the complex is determined by the amount of iodine supplied to the complex rather that the amount of iodine that can be bound by the starch amylose. A preferred starch for use in the preparation of the starch-iodine formulation is ≠l Hylon starch. This starch is a purified "specialty" starch produce by Nacan Products of Toronto, Ontario, Canada, a subsidiary of National Starch & Chemical Company of New Jersey. The starch is made from a hybrid corn called Hylon ≠7 and contains 70 percent amylose and 30 percent amylopectin.

In the preparation of the iodine-starch

(amylose) complex, since the iodine will ultimately be used to treat human patients, high quality re-sublimed iodine should be employed in the preparation.

In determining a method for the production of the desired iodine-starch complex, the effect of temperature on the capacity of starch to absorb iodine must be examined. The effective temperature is best described by Hatch .Analytical Chemistry, vol. 54, 2002

(1982) . At higher temperature (especially at 60°C) , there is a temperature-dependant change in the structure and (or) number of starch helices available for reaction with iodine (triiodide ions) . In fact, the thermal

decoloration of the blue starch-iodine complex is th result of thermally induced deterioration or unravellin of the starch helices from around the iodine (triiodid ions (13 ^" ) or others) . This phenomenon is calle hysteresis effect and is reversible at least up to 40°C It has been found with the starch-iodine complex of th present invention that the molecule will begin to unrave at 40°C. Colorimetric changes begin to occur at abou 50 ^β C to 60 ^β C, with complete discolorization occurring a about 60 ^β C to about 80 ^β C.

As noted above, the iodine found in the starch iodine complex is primarily in the form of triiodide ion (I ₃ "") . However, as noted in the prior art, the iodin used for the treatment or prevention of iodine deficienc diseases is elemental or molecular iodine, I ₂ Therefore, the present invention is primarily concerne with the preparation of a dry formulation of iodine fo oral consumption, which will supply elemental iodine (I ₂ for treatment of iodine deficiency diseases and th like. It was unexpectantly found that a dry starch iodine complex containing primarily I ₃ " would upon th administration to patients provide the required I ₂ fo the necessary treatment or prevention of iodin deficiency diseases.

In order to understand how I ₂ is supplied t the patient, one must understand how iodine i predominately triiodide form is released from starch.

There ar three different methods for releasing th iodine from the starch molecule which include: a) thermally with temperatures greater than 40°c, which induces the unfolding of the amylos helices; b) by acid hydrolysis of starch down to D-glucos

in aqueous solutions; or c) by α-amylase treatment.

For a detailed description of the last tw methods see, for example, Robyt, Starch. Chemistry an Technology, p. 94.

It is the latter treatment, i.e. that of α- amylase which is involved in the in vivo degradation of starch. Salivary α-amylase degrades starch (amylose) to higher oligosaccharides and ultimately to glucose. In the stomach, the further α-amylase activity causes further starch degradation and liberation of iodine (I ₃ ~) . The other enzymes which further degrade these fragments are glucosidases (α-l→4 and α-l→6) . These enzymes are secreted by the brush border cells of the lining of the small intestine and by the pancreas. These enzymes do not have any action on starch per se, but their combined action completes the job of converting starch into D-glucose.

In one embodiment of the present invention, the starch-iodine complex is encapsulated, for example with gelatin. The encapsulated starch-iodine complex reaches the stomach intact. The stomach acids soften the gelatin capsule so that its contents, i.e., the starch-iodine complex, is released in the upper small bowel. The complex is then acted upon by the upper small bowel contents including α-amylase, bile and pancreatic enzymes containing amylase and glucosidases. The amylase, aided by bile, will digest the amylose and thereby release the I ₃ ~ from the complex.

I ₃ ~ cannot exist as a molecule (uncomplexed) and immediately changes to I ₂ and I~. The I~ is picked

up by the sodium, potassium and proteins of the foo stuffs to produce iodides, while the I ₂ is absorbed as I apparently in the same fashion as I ₂ administered in a aqueous vehicle.

It can be seen from the foregoing, that th starch-iodine (I ₃ ~) complex was found, according to th present invention, to be ideally suited to produce a dr formulation for oral administration of iodine due to th immediate conversion of the triiodide ion to I ₂ _Ln vivo.

The starch-iodine complex of the presen invention, in capsule form, has been used as replacement to treat women who were formally treated fo iodine deficiency disorders with the aqueous formulation. The ^* results obtained with the dry formulation are th same as those already reported for the aqueou formulation.

While this invention is described in detai with particular reference to certain preferre embodiments thereof, the following examples are offere to illustrate but not limit the invention.

EXAMPLE 1

The starch-iodine complex of the presen invention can generally be prepared by the followin method. In this method, the preferred starch, #7 Hylo is used. This specialized starch is exposed to aqueou molecular iodine (AMI) at room temperature (20°C) (300 milligrams iodine per liter) in a ratio of 1 gram o starch to 100 milliliters AMI for 12 hours at 20°C.

The iodine solution is prepared by exposing 5 grams of prilled iodine to ion-free water at 20 ^β C for 4

days.

The chemical reaction of this combination is I ₂ +H ₂ 0=HOI+I~+I ₂ +I ₃ ~.

The proportion of I and I ₃ " are temperatur dependant as noted above, with an increased temperatur increasing the amount of 1 ₃ "♦

The solution is passed through a micropor filter and is then ready for combining with the starch. The AMI solution combines with the amylose of starch an produces a complex of primarily I ₃ "" with the amylose helices. The I ₂ and I" present in the AMI solution are compressed in the helices to X- ₃ ~. It is this combination that produces the colorimetric change to blue.

After exposure of the AMI to starch for 12 hours, the supernatant water is decanted and tested for presence of iodine.

The resulting starch-iodine complex is vacuum dried at room temperature and then mechanically pulverized. It is now ready for encapsulation, preferably at a strength of 3 milligrams of iodine in 100 milligrams of the complex.

The above dosage of 3 milligrams of iodine in 100 milligrams of the complex is the preferred daily dosage for the treatment of iodine deficiency diseases such as breast dysplasia, breast cancer, endometriosis and premenstrual syndrome as disclosed WO90/07339 to Ghent et al, published July 12, 1990. A daily dosage of up to about .08 milligrams per kilogram body weight is appropriate.

The ideal complex would contain sufficien amount of iodine in the starch-iodine complex to yield milligrams of I ₂ in 100 milligrams starch so that direc encapsulation without fillers could be used. However, the amount of iodine/amylose configuration could b changed if encapsulation required it.

It is to be understood that the recommende daily dosage of l ₂ for the treatment of other iodin related diseases such as with the thyroid includin radiation sickness etc. may be other than the preferre dosage disclosed hereinabove and thus variation of th amount of aqueous molecular iodine supplied to starch ma be increased or decreased depending on the dosag required. Specialty starches such as ≠7 Hylon starc with its high amylose content are uniquely suited fo complexing of an increased amount of iodine and a indicated previously the amount of iodine in the comple is a function of the amount of iodine supplied to th complex rather than the amount of iodine that can b bound by the starch amylose. Other less amylose ric starches may be used however provided there is sufficien amylose present to supply the desired dosage of iodine.

Although the use of additional pharmaceutica adjuvants is believed not to be required, suitabl pharmaceutical adjuvants, fillers, excipients etc. ma form part of the pharmaceutical composition if desired.

EXAMPLE 2

A dry starch-iodine complex suitable fo therapeutic use can also be made by a allowing the vapou of prilled iodine to come in contact with the starch.

The preferred starch, Hylon #7, (100 grams) wa exposed to 20 grams of prilled iodine in such a fashio that there is no direct contact between the tw components. The iodine sublimes and complexes with th starch due to the minute amount of moisture in th starch.

The process is carried out in a sealed container and the contact between the starch and iodine vapour is maintained for 10 days at 20 °C. The end point is colorimetrically judged at 3 milligrams of iodine complexed with 100 milligrams of starch.

Since the present invention is subject to many modifications, variations and changes in detail, it is intended that all matters in the foregoing description or shown in the accompanying drawing be interpreted as illustrative and not in a limiting sense.