~,?~ 2 DOSAGE FORM FOR ADMINISTERING
ORAL HYPOGLYCEMIC GLIPIZIOE

DISCLOSURE OF TECHNICAL FIELD

This invention pertains to a dosage form comprising the hypoglycemic drug glipizide. The invention concerns also a method for administering glipizide to a recipient in need of glipizide therapy.

DISCLOSURE OF BACKGROUND OF THE INVENTION

A clinical need exists for a dosage form for delivering an oral blood-glucose lowering drug to a patient needing this therapy.
Glipizide is an oral blood-glucose lowering drug and it is indicated for the control of hyperglycemia and its associated symptomatology in patients with non-insulin dependent diabetes mellitus. Glipizide is useful therapeutically as an oral hypoglycemic drug because it stimulates insulin secretion from the beta cells of pancreatic-islet tissue, it increases the concentration of insulin in the pancreatic vein, and because it exhibits extrapancreatic action such as the ability to increase the number of insulin receptors.
Glipizide is known chemically as N-[2-[4-[[[(cyclohexylamino) carbonyllamino1sulfonyllphenyllethyl]-5-methylpyrazinecarboxamide.
Glipizide is a white, odorless powder with a pKa of 5.9, and it is insoluble in both water and alcohol. These physical and chemical properties of glipizide do not lend the drug to formulation into a dosage form that can administer glipizide at a controlled and known rate per unit time. The properties of glipizide are disclosed in Martindale The Extra Pharmaco w eia, 29th Ed., p 390, (1989); and, AHFS Druq Information, pp 1741-45, (1989).
In the light of the above presentation, it will be appreciated by those versed in the pharmaceutical dispensing art to which this invention pertains, that a pressing need exists for a rate-controlled 4 5 ~ 2 dosage form that can dellver the valuable drug glipizide to a patlent ln cllnical need of blood-glucose lowering therapy.
The pressing need exlsts also for an oral dosage form that can deliver glipizide at a controlled rate in a substantially constant dose per unit time for its beneficial therapeutic effects, ar.d remains substantlally independent of the changing environment of the gastrointestinal tract. It will be appreciated further by those skilled in the dispensing art, that if such a novel and unique dosage form is made available that can administer gliplzide in a rate-controlled dose over time, and simultaneously provide blood-glucose lowering therapy, the dosage form would represent an advancement and a valuable contribution to the medical art.
DISCLOSURE OF AIMS OF THE INVENTION
Accordlngly, in view of the above presentation, it is an immediate aim of this invention to provide a dosage form for delivering glipizide in a rate controlled amount, and which dosage form substantially overcomes the deficiencies and omissions associated with the prior art.
Another aim of the present invention is to provide a dosage form for orally administering glipizide in a rate-controlled dose for blood-glucose lowering therapy.
Another aim of the invention is to provide a pharmaceutical dosage form that makes available controlled and sustained glipizide therapeutic activity to a patient in need of gliplzlde therapy.

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~45~ ~

Another alm of the inventlon ls to provlde a novel dosage form manufactured as an osmotlc devlce that can admlnlster gllpizide to a biological receptor slte to pr~duce the desired gliplzlde pharmacological effects.
Another aim of the present invention ls to provlde a dosage form manufactured as an osmotlc dosage form that mair..ains gllplzlde ln the dosage form untll released from the dosage form, thereby substantlally reducing and/or substantially elimlnating the unwanted influences of the gastrointestlnal envlronment of use and still provide controlled adminlstration of glipizide over time.
Another alm of the present lnventlon ls to provlde a dosage form that can deliver the aqueous insoluble drug gllplzlde at a controlled and beneflclal known rate over tlme.
Another alm of the present lnventlon ls to provlde a dosage form adapted for the oral admlnlstration of glipizide and which dosage form comprise a first compositlon and a contacting second compositlon that operate in comblnatlon for the controlled administratlon of glipizlde.
Another alm of the present lnventlon ls to provlde a complete pharmaceutlcal gllplzlde reglmen comprlslng a composltlon comprlslng gllplzlde that can be dlspensed from a drug dellvery dosage form, the use of whlch requlres lnterventlon only for lnltlatlon and posslbly for termlnatlon of the reglmen.

C' 4~ ~

Another alm of the lnventlon ls to provlde a method for treatlng hyperglycemla by orally admlnlsterlng gllplzlde ln a rate-controlled dose per unlt tlme to a warm-blooded anlmal ln need of hyperglycemla therapy.
Other features and advantages of thls lnventlon wlll be more apparent to those versed ln the dlspenslng arts from the followlng detalled speclflcatlon, taken ln con~unctlon wlth the drawlngs and the accompanylng clalms.
BRIEF DISCLOSURE OF THE DRAWINGS
In the drawlngs, whlch are not drawn to scale, but are set forth to lllustrate varlous embodlments of the lnventlon, the drawlng flgures are as follows:
Drawlng flgure 1 ls a vlew of a dosage form deslgned and shaped for orally admlnlsterlng gllplzlde to the gastrolntestlnal tract of a warm-blooded anlmal, lncludlng humans;
Drawlng flgure 2 ls an opened vlew of the dosage form of drawlng flgure 1 lllustratlng the structure of the dosage form comprlslng gllplzlde;
Z0 Drawlng flgure 3 ls an opened vlew of the dosage form of drawlng flgure 1 deplctlng a dlfferent lnternal structure embodlment provlded by the lnventlon;

Drawlng flgure 4 ls a graph that deplcts the release rate pattern from one embodlment of the dosage form provlded by the lnventlon and shows the dosage form as belng useful for up to 22 hours; and, C

Z~5~ ~

4a Drawlng flgure 5 ls a graph that deplcts the release rate pattern for a dlfferent embodlment of the dosage form provlded by the lnventlon.
In the drawlng flgures and ln the speclflcatlon llke parts ln related drawlng flgures are ldentlfled by llke numbers. The terms appearlng earller ln the speclflcatlon and ln the descrlptlon of the drawlngs, as well as embodlments thereof, are further descrlbed elsewhere ln the dlsclosure.
DETAILED DISCLOSURE OF THE DRAWING FIGURES
Turnlng now to the drawlng flgures ln detall, whlch drawlng flgures are examples of the dosage forms provlded by thls lnventlon, and whlch examples are not to be construed as llmltlng, one example of the dosage form ls lllustrated ln drawlng flgure 1 and deslgnated by the numeral 10. In drawlng flgure 1, dosage form 10 comprlses a body 11, whlch body member 11 comprlses a wall 12 that surrounds and encloses an lnternal compartment, not seen ln drawlng flgure 1. Dosage form 10 comprlses at least one exlt means 13 for connectlng the lnterlor of dosage form 10 wlth the exterlor envlronment of use.
In drawlng flgure 2, dosage form 10 ls seen ln opened vlew. In drawlng flgure 2, dosage form 10 comprlses a body member 11 comprlslng wall 12, whlch wall surrounds and deflnes an lnternal compartment 14. Wall 12 comprlses at least one exlt means 13 that connects lnternal compartment 14 wlth the exterior of dosage form 10. Dosage form 10 can comprlse more than one exlt means 13. Wall 12 of dosage form C

4b 10 comprlses ln total, or in at least a part, a composltlon that is permeable to the passage of an exterlor fluld present ln the envlronment, and wall 12 ls substantlally lmpermeable to the passage of gllplzlde and other lngredlents present ln compartment 14. The composltlon comprlslng wall 12 ls semlpermeable, lt ls substantlally lnert, and wall 12 malntalns lts physlcal and chemlcal lntegrity durlng the dlspenslng llfe of gllplzlde from C

2~2~02 dosage form 10. The phrase, keeps its physical and chemical integrity," means wall 12 does not lose its structure, and it does not change chemically during the glipizide dispensing life of dosage form 10.
Wall 12, in a presently preferred embodiment, comprises 80 weight percent (wt%) to 100 weight percent of a composition comprising a cellulose polymer. The cellulose polymer comprises a member selected from the group consisting of a cellulose ester, cellulose ether, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, and cellulose triacetate. Wall 12, in another preferred manufacture, comprises from 0 weight percent to 25 weight percent of a member selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose, and from 0 to 20 weight percent of polyethylene glycol, with the total amount of all wall-forming components comprising wall 12 equal to 100 weight percent.
Internal compartment 14 comprises an internal glipizide lamina 15, which glipizide lamina can be defined optionally as a glipizide composition 15. Internal compartment 14 also comprises an internal displacement lamina 16, which displacement lamina can be defined optionally as a displacement composition 16. The glipizide lamina 15 and the displacement lamina 16 initially are in laminar arrangement and they cooperate with each other and with dosage form 10 for the effective delivery of glipizide from dosage form 10.
The glipizide composition 15, in a presently preferred embodiment, as seen in Figure 2, comprises about 2.0 mg to 50 mg of glipizide identified by dots 9; from 100 mg to 320 mg of a polyethylene oxide comprising 80,000 to 350,000 molecular weight and identified by dashes 17; from 5 mg to 50 mg of hydroxypropylmethylcellulose comprising a 9,200 to 22,000 molecular weight and identified by vertical lines 18; and from 0 mg to 7.5 mg of a lubricant such as stearic acid, magnesium stearate, and the like.
The displacement lamina 16, as seen in drawing Figure 2, comprises 70 mg to 125 mg of a polyethylene oxide comprising a 4,000,000 to 8,000,000 molecular weight identified as lines 19; from 2@2:~iQ2 20 mg to 50 mg of an osmagent selected from the group consisting of sodium chloride and potassium chloride identified by wavy line 20;
and from 5 mg to 15 mg of a hydroxypropylmethylcellulose having a 9,000 to 25,000 molecular weight identified by vertical slashes 21.
Displacement lamina 16 optionally comprises from 0.1 mg to 5 mg of ferric oxide and from 0.01 mg to 5 mg of a lubricant such as magnesium stearate or stearic acid.
Drawing figure 3 depicts in opened section another osmotic dosage form 10 provided by the invention. In drawing figure 3, dosage form 10 comprises a body 11, a wall 12, which wall 12 surrounds an internal compartment 14 with an exit passageway 13 in wall 12. Internal compartment 14, in this dosage form, comprises an internal glipizide lamina 15, which glipizide lamina 15 comprises 2 mg to 25 mg of aqueous insoluble drug glipizide identified by dots 9; from 100 mg to 150 mg of a hydroxypropylcellulose comprising a 40,000 to 80,000 molecular weight identified by angle 22; and from 40 mg to 70 mg of a polyvinylpyrrolidone comprising a 30,000 to 70,000 molecular weight and identified by half circle 23. Internal compartment 14 comprises a displacement lamina 16 comprising 30 mg to 150 mg of sodium carboxymethylcellulose having 200,000 to 1,000,000 molecular weight identified by wavy lines 24; from 20 mg to 70 mg of an osmagent selected from the group consisting of sodium chloride and potassium chloride identified by circle 25; and from 0.5 mg to 10 mg of a hydroxypropylmethylcellulose comprising a 9,200 to 22,000 molecular weight identified by squares 26. Displacement lamina 16 optionally comprises from 0 mg to S mg of ferric oxide and optionally 0 mg to 7 mg of a lubricant.
The expression, "exit means 13," as used herein, comprises means and methods suitable for the controlled metered release of glipizide 9 from compartment 14 of dosage form 10. The exit means 13 comprises at least one passageway, orifice, or the like, through wall 12 for communication with glipizide 9 in compartment 14. The expression, "at least one passageway," includes aperture, orifice, bore, pore, or porous element through which glipizide can be released, or hollow fiber, capillary tube, porous overlay, porous insert, and the like. The expression also includes a material that ~3~Q~

erodes or is fluid-leached from wall 12 in a fluid environment of use to produce at least one pore-passageway of governed release rate pore-size in wall 12. Representative materials suitable for forming at least one passageway, or a multiplicity of passageways, comprise 5 an erodible polyglycolic acid, or a polylactic acid member in wall 12, a gelatinous filament, polyvinyl alcohol, leachable materials such as a fluid removable pore forming polysaccharide, salt, oxide, polyol, or the like. A passageway or a plurality of passageways can be formed by leaching a material such as sorbitol, lactose, or the like, from wall 12. The passageway can have any shape such as round, triangular, square, elliptical, and the like, for assisting in the metered release of glipizide 9 from dosage form 10. Dosage form 10 can be constructed with one or more passageways in spaced apart relations, or more than one passageway on a single surface of dosage form 10. Passageways and equipment for forming passageways are disclosed in U.S. Pat. Nos. 3,845,770 issued 11/74 to Theeuwes et al;

3,916,899 issued 11/75 to Theeuwes et al; 4,016,880 issued 4/77 to Theeuwes et al; 4,063,064 issued 12/77 to Saunders et al; 4,088,864 issued 5/78 to Theeuwes et al; and, passageways formed by leaching are disclosed in U.S. Pat. Nos. 4,200,098 issued 4/80 to Ayer et al;

4,235,236 issued 11/80 to Theeuwes; and, 4,285,987 issued to Ayer et al.
Dosage form 10 of this invention is manufactured by standard techniques. For example, in one manufacture the drug glipizide is 25 mixed with other composition-forming ingredients and the mix then pressed into a solid lamina possessing dimensions that correspond to the internal dimensions of the compartment space adjacent to the passageway. In another embodiment the beneficial drug glipizide and other composition forming ingredients and a solvent are mixed into a 30 solid, or into a semisolid, by conventional methods such as ballmilling, calendering, stirring, or rollmilling, and then pressed into a preselected lamina forming shape. Next, a lamina composition comprising the osmopolymer and the osmagent are placed in contact with the lamina comprising the beneficial drug glipizide, and the two 35 lamina comprising the laminate are surrounded with a semipermeable wall. The lamination of the glipizide composition and the 2~0~

osmopolymer displacement composition can be accomplished by using a two-layer tablet press technique. The wall can be applied by molding, spraying, or dipping the pressed shapes into wall-forming formulations. Another preferred technique that can be used for applying the wall is the air suspension coating procedure. This procedure consists in suspending and tumbling the two layered laminate in a current of air until the wall forming composition surrounds the laminate. The air suspension pnocedure is described in U.S. Pat. No. 2,799,241; in J. Pharm. Assoc.. Sci. Ed., Vol. 48 pp 451-59 (1959); and ibid, Vol. 49, pp 82-84, (1960). Other standard manufacturing procedures are described in Modern Plastics EncYcloDedia, Vol. 46, pp 62-70, (1969); and in Pharmaceutical Sciences, by Remington, 14th Ed., pp 1626-1978, (1970), published by Mack Publishing Co., Easton, PA.
Exemplary solvents suitable for manufacturing the wall, the laminate, and laminae, comprise inert inorganic and organic solvents that do not adversely affect the final wall and the final laminates.
The solvents broadly comprise a member selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatics, aromatics, heterocyclic solvents, and mixtures thereof. Typical solvents comprise acetone, diacetone, alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methylpropyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, ethylene dichloride and methanol, and the like.
DETAILED DISCLOSURE OF EXAMPLES
OF THE INVENTION

The following examples are merely illustrative of the present invention, and they should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents 2~2~7~:

g ARC 1753 thereof will become apparent to those versed in the art in the light of the present disclosure, the drawings and the accompanying claims.

An oral dosage form, adapted, designed and shaped as an osmotic drug delivery system for admittance into the gastrointestinal tract of a patient in need of glipizide is manufactured as follows: first, 369 9 of pharmaceutically acceptable hydroxypropylcellulose comprising a 60,000 average molecular weight is passed through a 20 mesh screen, followed by passing through a 40 mesh screen 162 9 of pharmaceutically acceptable polyvinylpyrrolidone comprising a 40,000 average molecular weight. Next, the two screened ingredients are blended with 66 9 of glipizide to form a homogeneous blend. The blend is suspended in a fluidized bed and sprayed with an atomized spray comprising an ethanol:water (70:30 vol:vol) solution until granules are formed of the three ingredients. The freshly prepared granules then are passed through a 20 mesh screen. Finally, the screened granulation is mixed with 3 9 of magnesium stearate in a rollermill for 5 minutes.
Next, a separate hydrogel granulation is prepared as follows:
first, 389 9 of pharmaceutically acceptable sodium carboxymethylcellulose having 700,000 molecular weight, 174 9 of sodium chloride, 30 9 of pharmaceutically acceptable hydroxypropylmethylcellulose comprising a 11,200 molecular weight and 6 9 of ferric oxide separately are screened through a 40 mesh screen.
Then, all the screened ingredients are mixed to produce a homogeneous blend. Next, 300 ml of denatured anhydrous ethanol is added slowly to the blend with continuous mixing for about 5 minutes. The freshly prepared wet granulation is screened through a 20 mesh screen, allowed to dry at room temperature for 16 hours, and again passed through a 20 mesh screen. The screened granulation is mixed with 1.5 9 of magnesium stearate in a rollermill for about 5 minutes.
Next, the glipizide granulation, and the hydrogel granulation are compressed into a bilaminate tablet arrangement. First, 200 mg of the glipizide composition is added to a 0.375 inch (9.5 mm) punch ~02~0~

and tamped, then, 140 mg of the hydrogel granulation is added to the punch and the two laminae are pressed into a solid, contacting arrangement.
Next, the bilaminate is coated with a semipermeable wall. The semipermeable wall-forming composition comprises 93% cellulose acetate having a 39.8% acetyl content, and 7% polyethylene glycol having a 3350 molecular weight. The wall-forming composition is dissolved in a cosolvent comprising acetone: water (90:10 wt:wt) to make a 4% solids solution. The wall-forming composition is sprayed onto and around the bilaminate in an Aeromatic~ Air Suspension Coater.
Then, a 25 mil (0.635 mm) exit orifice is mechanically drilled on the glipizide side of the osmotic dosage form. The residual solvent is removed by drying the osmotic system for 48 hours at 50~C
and 50% humidity. The osmotic systems are dried for 1 hour at 50-C
to remove excess moisture. Attached drawing figure 4 shows the in vitro release rate profile for glipizide from the finished osmotic system as released in distilled water. The error bars represent the standard deviation added to and subtracted from the mean of five osmotic delivery system. An osmotic dosage form provided by the invention comprises 11 wt% glipizide, 61.50 wt% hydroxypropyl-cellulose of 60,000 molecular weight, 27.0 wt% polyvinylpyrrolidone of 40,000 molecular weight, 0.5% magnesium stearate in the glipizide composition; 64.8 wt% sodium carboxymethylcellulose of 700,000 molecular weight, 29 wt% sodium chloride, 5 wt% hydroxypropyl-methylcellulose of 11,200 molecular weight and 1.0 wt% ferric oxide, 0.2% magnesium stearate in the hydrogel composition; and, 93.0 wt%
cellulose acetate having a 39.8% acetyl content, and 7.0 wt%
polyethylene glycol having a 3350 molecular weight in the semipermeable wall formulation.

A dosage form adapted, designed and shaped as an osmotic drug delivery system is manufactured as follows: first, a glipizide composition is provided by blending together into a homogeneous blend 2~2~!~Q~

478 9 of pharmaceutically acceptable polyethylene oxide comprising a 200,000 molecular weight, 66 9 of glipizide and 54 9 of pharmaceutically acceptable hydroxypropylmethylcellulose comprising a 11,200 molecular weight. Then, 425 ml of denatured anhydrous ethanol is added slowly with continuous mixing over 5 minutes. The freshly prepared wet granulation is screened through a 20 mesh screen through a 20 mesh screen, dried at room temperature for 16 hours, and again screened through a 20 mesh screen. Finally, the screened granulation - is mixed with 1.5 9 of magnesium stearate in a rollermill for 5 minutes.
Next, a hydrogel composition is prepared as follows: first, 412.5 g of pharmaceutically acceptable polyethylene oxide comprising a 7,500,000 molecular weight, 150 9 of sodium chloride and 6 9 of ferric oxide separately are screened through a 40 mesh screen. Then, all the screened ingredients are mixed with 30 9 of hydroxypropylmethylcellulose comprising a 11,200 molecular weight to produce a homogeneous blend. Next, 300 mg of denatured anhydrous alcohol is added slowly to the blend with continuous mixing for 5 minutes. The freshly prepared wet granulation is passed through a 20 mesh screen, allowed to dry at room temperature for 16 hours, and again passed through a 20 mesh screen. The screened granulation is mixed with 1.5 9 of magnesium stearate in a rollermill for 5 minutes.
Next, the glipizide composition and the hydrogel composition are compressed into bilaminate tablets. First, 200 mg of the glipizide is added to a 0.375 inch (9.5 mm) punch and tamped, then, 140 mg of the hydrogel composition is added and the laminae are pressed under a pressure head of 2 tons into a contacting laminated arrangement.
Then, the bilaminate arrangements are coated with a semipermeable wall. The wall forming composition comprises 93%
cellulose acetate having a 39.8% acetyl content, and 7% polyethylene glycol having a molecular weight of 3350. The wall-forming composition is dissolved in an acetone:water (90:10 wt:wt) cosolvent to make a 4% solids solution. The wall forming composition is sprayed onto and around the bilaminate in an Aeromatic~ Air Suspension Coater.

2~2~ 2 Next, a 25 mil (0.635 mm) exit passag -~ay is mechanically drilled through the semipermeable wall to connect the glipizide drug lamina with the exterior of the dosage system. The residual solvent is removed by drying for 48 hours at 50OC and 50% humidity. Next, the osmotic systems are dried for 1 hour at 50OC to remove excess moisture. The dosage form produced by this manufacture provides a glipizide composition comprising 11 wt% glipizide, 79.7 wt%
polyethylene oxide of 200,000 molecular weight, 9 wt% hydroxypropyl-methylcellulose of 11,200 molecular weight, and 0.3 wt% magnesium stearate; a hydrogel composition comprising 68.8 wtX polyethylene oxide comprising a 7,500,000 molecular weight, 25 wt% sodium chloride, 5 wt% hydroxypropylmethylcellulose, 1.0 wtZ ferric oxide and 0.2 wt% magnesium stearate; and a semipermeable wall comprising 93 wt% cellulose acetate comprising a 39.8% acetyl content, and 7.0 wt% polyethylene glycol comprising a 3350 molecular weight.
Accompanying drawing figure 5 depicts the in vitro release rate profile of glipizide released from the final dosage form for four dosage forms. The error bars represent the standard deviation added to and subtracted from the mean of the dosage form.~0 DISCLOSURE OF A METHOD
OF USING THE INVENTION

An embodiment of the invention pertains to a method for delivering the beneficial drug glipizide orally at a controlled rate to a warm blooded animal in need of glipizide therapy, which method comprises the steps of: (AJ admitting into the warm-blooded animal a dosage from comprising: (1) a wall surrounding a compartment, the wall comprising at least in part a semipermeable polymeric composition permeable to the passage of fluid and substantially impermeable to the passage of glipizide; (2) a pharmaceutically acceptable composition in the compartment comprising about 2.5 mg to 50 mg of hypoglycemic glipizide for performing an antidiabetic program; (3) a hydrogel composition in the compartment comprising a member selected from the group consisting of a polyethylene oxide having a 4,000,000 to 7,500,000 molecular weight and a sodium 202~50~

carboxymethylcellulose having a 200,000 to 1,000,000 molecular weight for imbibing and absorbing fluid for pushing the glipizide composition from the dosage form; and, (4) at least one passageway in the wall for releasing glipizide; (B) imbibing fluid through the semipermeable wall at a rate determined by the permeability of the semipermeable wall and the osmotic pressure gradient across the semipermeable wall causing the hydrogel composition to expand and swell; and (C) delivering the beneficial glipizide from the dosage form through the exit passage to the warm blooded animal over a prolonged period of time to produce the desired hypoglycemic effect.
In summary, it will be appreciated that the present invention contributes to the art an unexpected and unforseen dosage form that possesses the practical utility for administering aqueous insoluble glipizide from an osmotic dosage form at a dose metered release rate per unit time. While the invention has been described and pointed out in detail with reference to operative embodiments thereof it will be understood that those skilled in the art that various changes, modifications, substitutions and omissions can be made without departing from the spirit of the invention. It is intended, therefore, that the invention embrace those equivalents within the scope of the claims which follow.