U.S. patent application number 13/879479 was filed with the patent office on 2013-08-08 for phosphate binder formulation for simple dosing.
This patent application is currently assigned to FRESENIUS MEDICAL CARE DEUTSCHLAND GMBH. The applicant listed for this patent is Johannes Bartholomaeus, Eva Fries-Schaffner, Astrid Oppermann, Friedrich Schulze, Kai Strothmann. Invention is credited to Johannes Bartholomaeus, Eva Fries-Schaffner, Astrid Oppermann, Friedrich Schulze, Kai Strothmann.
Application Number | 20130202699 13/879479 |
Document ID | / |
Family ID | 43567532 |
Filed Date | 2013-08-08 |
United States Patent
Application |
20130202699 |
Kind Code |
A1 |
Strothmann; Kai ; et
al. |
August 8, 2013 |
PHOSPHATE BINDER FORMULATION FOR SIMPLE DOSING
Abstract
The invention relates to a pharmaceutical composition in the
form of pourable granules or a chewable tablet containing at least
one phosphate binding substance and at least one effervescent
agent. The composition may be taken orally without adding
water.
Inventors: |
Strothmann; Kai; (Wuerselen,
DE) ; Schulze; Friedrich; (Neu-Anspach, DE) ;
Bartholomaeus; Johannes; (Aachen, DE) ;
Fries-Schaffner; Eva; (Bad Vilbel, DE) ; Oppermann;
Astrid; (Frankfurt/Main, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Strothmann; Kai
Schulze; Friedrich
Bartholomaeus; Johannes
Fries-Schaffner; Eva
Oppermann; Astrid |
Wuerselen
Neu-Anspach
Aachen
Bad Vilbel
Frankfurt/Main |
|
DE
DE
DE
DE
DE |
|
|
Assignee: |
FRESENIUS MEDICAL CARE DEUTSCHLAND
GMBH
Bad Homburg
DE
|
Family ID: |
43567532 |
Appl. No.: |
13/879479 |
Filed: |
October 11, 2011 |
PCT Filed: |
October 11, 2011 |
PCT NO: |
PCT/EP2011/005069 |
371 Date: |
April 15, 2013 |
Current U.S.
Class: |
424/466 ;
424/400; 424/43; 424/490 |
Current CPC
Class: |
A61P 13/12 20180101;
A61K 33/06 20130101; A61K 9/0056 20130101; A61K 31/19 20130101;
A61K 9/1652 20130101; A61K 31/77 20130101; A61K 9/0007 20130101;
A61K 33/10 20130101; A61K 31/7004 20130101; A61K 9/1617 20130101;
A61K 9/1635 20130101; A61K 31/225 20130101 |
Class at
Publication: |
424/466 ; 424/43;
424/490; 424/400 |
International
Class: |
A61K 31/19 20060101
A61K031/19; A61K 33/10 20060101 A61K033/10 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 13, 2010 |
EP |
10013578.9 |
Claims
1. A pharmaceutical composition in the form of pourable granules or
a chewable tablet containing at least one phosphate binding
substance and at least one effervescent agent which contains a
carbonate and a solid organic edible acid or the acidic salt
thereof for use in treatment of renally insufficient patients,
where the composition is administered orally without adding
water.
2. The composition according to claim 1, characterized in that the
carbonate is an alkali or alkaline earth carbonate or an alkali or
alkaline earth bicarbonate.
3. The composition according to claim 1, characterized in that the
phosphate-binding substance is a calcium salt, a magnesium salt, an
ion exchanger polymer, a lanthanum compound or an iron
compound.
4. The composition according to claim 1, characterized in that the
phosphate binding substance is calcium acetate.
5. The composition according to claim 1, characterized in that the
phosphate-binding substance is present in granulated form.
6. The composition according to claim 1, characterized in that the
phosphate binding substance is provided with a taste-masking
coating.
7. The composition according to claim 6, characterized in that the
coating is prepared by a spray coating method in a fluidized
bed.
8. The composition according to claim 7, characterized in that the
coating is a melt coating.
9. The composition according to claim 7, characterized in that the
coating is a spray coating of suspensions and/or solutions.
10. The composition according to claim 1, characterized in that the
composition contains magnesium carbonate.
11. The composition according to claim 1, characterized in that the
effervescent agent is contained in a coating of the
phosphate-binding substance.
12. The composition according to claim 1, characterized in that it
contains at least one sugar alcohol.
13. The composition according to claim 1, characterized in that the
phosphate-binding substance constitutes 15-80% of the weight of the
composition.
14. The composition according to claim 1, characterized in that the
effervescent agent constitutes 3-60% of the weight of the
composition.
15. The composition according to claim 1, characterized in that the
oral cavity is rerinsed with water after oral administration of the
composition.
16. The composition according to claim 1, characterized in that it
is taken in a dose of 0.5-5 g three or four times daily, preferably
with meals.
17. The composition according to claim 1, characterized in that the
average particle size of the granules is 100-3500 .mu.m.
18. A stickpack containing 0.5-4 g of a composition according to
claim 1.
19. A pharmaceutical composition in the form of untableted granules
containing at least one effervescent agent and containing calcium
acetate and magnesium carbonate in a weight ratio of 1:1 to 4:1.
Description
[0001] The invention relates to pharmaceutical compositions
containing phosphate binders, which may be taken orally without
adding water. The pharmaceutical composition here is preferably in
the form of granules or a chewable tablet containing an
effervescent agent.
[0002] Renally insufficient patients and dialysis patients in
particular often suffer from a hyperphosphatemia requiring
treatment. Hyperphosphatemia is a pathophysiological elevation in
the blood phosphate level. Hyperphosphatemia occurs with a massive
intake of phosphate, massive release of phosphate due to tissue
destruction, reduced phosphate elimination in advanced renal
failure and/or conditions with an increased phosphate resorption
through the kidneys. The rise in serum phosphate may lead to
deposition of calcium phosphate in blood vessels and other tissues.
Chronic hyperphosphatemia can lead to calcification of tissues and
blood vessels, which may result in circulation disorders,
myocardial infarction and/or a stroke. Therefore renally
insufficient patients must usually take phosphate binders to
control their serum phosphate levels. The phosphate binders should
be taken with meals to bind the phosphate contained in food in the
form of sparingly soluble salts or unabsorbable complexes in the
intestine and therefore eliminate them with the feces. To do so,
the patients must take a large quantity of the phosphate binder,
usually in the form of a large number of tablets, for example, 1 to
5 tablets three times daily with each meal. To be able to take
large quantities more easily or with fewer tablets, it is either
necessary to take an even larger number of tablets in the case of
smaller tablets or much larger tablets that are more difficult to
take may be administered in the case of fewer tablets. However,
this large number of tablets is only a portion of the total oral
medication taken by a renally insufficient patient. In a recent
study on 233 dialysis patients, they were taking an average of 11
different medications, resulting in 19 tablets to be taken per day
as the median (Chiu, Y. W. 2009). Of these, approximately 50% were
phosphate binders.
[0003] In addition, renally insufficient patients and in particular
dialysis patients are allowed to drink only a small amount of water
per day, so that the tablets cannot be swallowed easily. Renally
insufficient patients cannot eliminate excess fluid from the body
via the urine or can do so only to a limited extent. Therefore,
most renally insufficient patients suffer from a permanent fluid
excess in the body which has a negative influence on their
well-being as well as their mortality. Excess fluid can cause
hypertension, which can damage the cardiovascular system and in
particular the function of the left ventricle and thus can
contribute indirectly toward an increased mortality of renally
insufficient patients due to cardiovascular diseases. Furthermore,
a large percentage of renally insufficient patients suffer from
anemia and receive hematopoietic medication in the form of Epogen
or analogs and in the form of iron preparations. A fluid excess
reduces the concentration of the hematopoietic medications and thus
makes suitable dosing of these medications much more difficult.
Therefore, control of fluid intake is extremely important in
renally insufficient patients. In most cases, the goal is to
minimize fluid intake in renally insufficient patients.
[0004] This is complicated by the fact that dialysis patients have
approximately half as much saliva as healthy control groups
(Bayraktar, G., 2004). Compliance in taking medication is therefore
influenced in a negative sense. In contrast with the number of
different medications prescribed, the number of phosphate binder
tablets prescribed must be seen in conjunction with patient
compliance in particular (Arnas, M. D., 2010). If dialysis patients
are asked which medication they would most prefer to omit if they
had a choice, phosphate binders would be listed in first place
(Arenas, M. D. 2010). An improved dosage form that is patient
friendly and better-tasting phosphate binders would make a
significant contribution toward meeting patients' requests
(Lindberg, M., 2008).
[0005] U.S. Pat. No. 7,465,465 discloses chewable tablets with
lanthanum as a phosphate binder which must be chewed before
swallowing to remedy these problems. This may be difficult for a
dialysis patient who has reduced saliva. Crushing the tablet and
then distributing it on food or a spoon is associated with the risk
of taking too little of the active ingredient because of losses in
preparation and/or incomplete ingestion of the foodstuff.
[0006] EP 1 924 246 discloses powder preparations with a suspension
stabilizer for taking the powder after suspending it in water. This
is associated with the disadvantage of the larger quantity of water
of the suspension against the water restrictions for dialysis
patients. It is customary to suspend such a powder in at least 40
mL-60 mL water before it is taken. Thus the total quantity of water
ingested adds up to approximately 120-300 mL per day for
administration of the phosphate binder alone. To supply the total
dose of the phosphate binder more reliably, it is also necessary to
use more water to rinse off the powder particles adhering to the
edge, which remain on the glass wall after taking the suspension
and then to also drink this water.
[0007] To reduce the water ingested with the phosphate binder, WO
2008/011126 discloses concentrated solutions of calcium acetate
with large quantities of polyols, sweeteners and taste-masking
substances. In such formulations, a portion of the bad inherent
taste of calcium phosphate remains perceptible overall on the one
hand, and on the other hand, a number of patients reject the
intense, always uniform taste of the sweeteners and flavorings,
which do not correspond to all meals. For combination products with
readily water-soluble calcium acetate and sparingly soluble
magnesium carbonate, there is the additional disadvantage of dosing
inaccuracy because it is difficult to dose magnesium in suspended
form by means of a dropper, etc.
[0008] All the approaches toward simpler dosing described here have
the additional disadvantage that in any case the product is
distributed involuntarily in wide areas of the oral cavity,
producing an unwanted taste. This taste becomes more intense when
parts of the product remain in parts of the oral cavity for an even
longer period of time.
[0009] Therefore, the object of the invention is to make available
a dosage form for phosphate binders that will allow renally
insufficient patients to easily take the required large quantities
of phosphate binders without any additional quantities of water. In
a second aspect, the dosage forms should mask any poor taste of the
phosphate binder and should impart a pleasant feel in the mouth. In
another aspect the object of the invention is to make available a
composition which will be distributed involuntarily in the oral
cavity as little as possible and will allow accurate doing.
[0010] These objects are achieved through the composition according
to Claim 1 and its application as well as through the subject
matters of the additional independent claims.
[0011] Additional objects are achieved by preferred embodiments of
the invention which are the subject matter of the dependent
claims.
[0012] A pharmaceutical composition in the form of pourable
granules or a chewable tablet containing at least one phosphate
binding substance and at least one effervescent agent which in turn
contains an alkali carbonate or an alkaline earth carbonate or an
alkali bicarbonate or alkaline earth bicarbonate and a solid
organic edible acid or the acid salt thereof is used in the
treatment of renally insufficient patients and is characterized in
that the granules are administered orally without adding water or
another liquid and can then be swallowed. In this way, the
medication can be taken without any additional intake of fluid.
Washing it down with water is not absolutely ruled out but is not
necessary. It is decisive that the composition is taken first in
the mouth without water. The effervescent agent has the effect of
masking the taste and imparts a pleasant feeling in the mouth. In
this way, the pharmaceutical composition can be partially dissolved
in saliva and swallowed mostly completely by the tongue.
[0013] The pharmaceutical composition is ideally administered from
a stickpack directly to the tongue. In the case of an active
ingredient with a bad taste, it may additionally be coated in the
granules to mask the taste if a simple flavoring and/or the
effervescent agent is not sufficient to mask the taste.
[0014] Phosphate binders are substances which interact with
phosphate ions including crotonated phosphate ions and thereby
hinder them in being taken up from the gastrointestinal tract into
the blood stream and thus into the body to ensure the elimination
of phosphates in the feces.
[0015] Phosphate binders that may be used include in particular
calcium, magnesium, aluminum, iron, lanthanum and bismuth salts,
whose solubility products are larger than those of the
corresponding phosphate salts of these cations. In addition,
phosphate-binding organic polymers having an anion exchanger
function such as sevelamer, AMG 223 (Amgen) and MCI-196
(Colestilan, Mitsubishi) are suitable substances for the invention.
Suitable aluminum salts include all the pharmaceutically tolerable
salts which fulfill the above requirements, especially preferably
oxides, in particular algedrate and/or hydroxides. All the
pharmaceutically acceptable salts which fulfill the above
requirements, in particular lanthanum carbonate including its
hydrates are suitable as the lanthanum salts. All the
pharmaceutically acceptable salts which fulfill the above
requirements, preferably chlorides, sulfates, hydroxides, oxides,
carbonates and in particular heavy magnesium carbonate are suitable
as the magnesium salts. Preferred phosphate binders based on metal
salts include iron hydroxides, iron oxide hydroxides and iron
citrates, in particular iron preparations, which are stabilized by
carbohydrates or humic acid or are bound to them or form sheet
salts with magnesium, for example, fermagates and calcium salts,
preferably calcium carbonate and/or calcium chloride and especially
preferably calcium acetate. Calcium acetate is preferred in
comparison with calcium carbonate because of its high solubility
but it has the disadvantage of an extremely unpleasant taste. Of
the metal salts, calcium salts are especially good phosphate
binders and have a favorable price. However, as a disadvantage it
is discussed that calcium preparations can cause hypercalcemia in
many patients, i.e., elevated blood calcium levels. Chronic
hypercalcemia is associated with the risk of calcification of the
blood vessels and thus in turn with the risk of cardiovascular
diseases. Replacing some of the calcium in such phosphate binders
with magnesium which itself functions as a phosphate binder reduces
the risk of development of hypercalcemia. It has been demonstrated
that by adding magnesium salts, in particular magnesium carbonate
to phosphate binding calcium acetate, hypercalcemia and therefore
calcification can be largely prevented and no negative effects can
be detected in comparison with patients treated with calcium-free
phosphate binders (de Francisco, A. L. M. et al., Nephrol Dial
Transplant 2010). To achieve this effect, a preferred weight ratio
of calcium acetate to magnesium carbonate of 1:1 to 4:1 is assumed,
but a ratio of 1.2:1 to 3:1 is especially preferred and a ratio of
1.5:1 to 2:1 is most especially preferred. Magnesium salts also
have an independent phosphate binding effect, so that in the
presence of magnesium salts, the quantity of phosphate binder based
on calcium required can be reduced. A combination of calcium
acetate and magnesium carbonate thus constitutes an especially
preferred composition in the sense of the present invention.
Another special advantage of this combination is derived from the
fact that magnesium carbonate is also a preferred ingredient of the
effervescent agent inasmuch as magnesium carbonate can fulfill two
functions at the same time within the composition. The weight and
the volume of the composition per dose to be taken by the patient
are further reduced in this way. A daily dose ideally contains 100
mg to 3000 mg calcium and 0 mg to 1500 mg magnesium abased on the
weight of the metal ions, but 300 mg to 1800 mg calcium is
preferred and 180 mg to 750 mg magnesium, 450-1350 mg calcium and
180-540 mg, magnesium being most preferred. In the absence of
magnesium, the preferred quantities for calcium are increased by a
factor of 1.5.
[0016] For ion exchange polymers, in particular sevelamer, the
ideal daily dose is 500-12,000 mg preferably 2000-10,000 mg and
especially preferably 5000-8000 mg.
[0017] For phosphate binders based on lanthanum, the ideal daily
dose based on lanthanum is 250-5000 mg preferably 750-4000 mg,
1500-3000 mg.
[0018] The daily dose is usually divided among 3 to 15 individual
doses to be taken with each meal. It is customary to take 1 to 4
individual doses with the three main meals per day.
[0019] Because of the large quantity in which phosphate binders
must still be taken, one goal of the present invention is to
minimize the weight and the volume of the final composition. The
admixture of other excipients should be limited to a minimum. The
composition according to the invention preferably contains 15% to
80% of the phosphate binding active ingredient, especially
preferably 20% to 70% and most especially preferably 25% to
60%.
[0020] All the aforementioned phosphate binders must be taken in
large quantities and the object of the present invention is to make
it possible for these quantities to be taken without additional
intake of fluid. Tablets of this size or capsules containing the
active ingredient are virtually impossible to swallow without
taking some fluid at the same time. The only remaining options are
a chewable tablet or granules. For both dosage forms it is of
crucial importance for the dosage form to taste good and to impart
a pleasant feeling in the mouth because both dosage forms have a
large surface area in the mouth when taken and have the potential
to distribute themselves throughout the entire mouth. An unpleasant
taste or an unpleasant feeling in the mouth is thus perceived
especially strongly with these dosage forms. All the aforementioned
phosphate binders in the form of granules or a chewable tablet that
disintegrates in the mouth impart an unpleasant "chalky" or "sandy"
feeling in the mouth and in particular impart a dry feeling. The
dry feeling in the mouth is further exacerbated in renally
insufficient patients who often suffer from a lack of saliva.
Furthermore, some of the active ingredients, for example, calcium
acetate have a very unpleasant inherent taste.
[0021] According to the invention, an effervescent agent is
therefore added to the composition. The effervescent agent is
dissolved by saliva in the mouth, thereby releasing carbon dioxide
in a chemical acid-base reaction. The carbon dioxide thereby
released stimulates additional formation of saliva, especially in
cooperation with flavorings and is also perceived as fresh and
pleasant in the mouth. Due to the increased salivation, the feeling
of dryness disappears and the composition can be swallowed more
easily after being mixed with saliva. In addition, the carbon
dioxide thereby released has a taste-masking effect per se.
[0022] The effervescent agent contains at least one solid organic
edible acid and/or its salt and at least one salt which released
carbon dioxide, in particular a carbonate, preferably selected from
the group of alkali salts and alkaline earth salts and their metal
hydrogen salts. Especially suitable are sodium carbonate, sodium
bicarbonate, potassium carbonate, potassium bicarbonate, magnesium
carbonate and/or calcium carbonate. Magnesium carbonate is
especially preferred because in addition to the effervescent
function it also acts as an active ingredient against hypercalcemia
and has phosphate binding properties. Calcium carbonate is also
preferably used because the calcium supplied in the effervescent
agent has a phosphate-binding effect and thus makes it possible to
reduce the amount of active ingredient. The effervescent reaction
also counteracts the disadvantage of the low solubility of calcium
carbonate. Suitable acids include in particular citric acid,
tartaric acid, malic acid, adipic acid, succinic acid, fumaric
acid, ascorbic acid, maleic acid and ascorbic acid as well as
partial salts of these acids in the case of polybasic acids, for
example, monosodium tartrate. Such acids, which additionally
stimulate salivation and/or have a pleasant inherent taste, are
also especially preferred to facilitate swallowing of the slightly
foaming preparation and also to improve the taste of the
composition. Tartaric acid, citric acid, ascorbic acid, sodium and
potassium tartrate, sodium hydrogen citrate and sodium ascorbate
are especially suitable for this purpose.
[0023] The effervescent formulations according to the invention may
be produced by conventional methods that are known in the state of
the art. For example, the acids and carbonates are granulated
separately, preferably by moist granulation, during which the
active ingredients are added to one of the granules. After mixing,
soluble lubricants such as sodium benzoate or polyethylene glycols
are added to the carefully dried granulates and compressed.
According to another method, all acids, carbonates and active
ingredients are mixed together and heated in a reactor until the
citric acid releases its water of crystallization, for example, and
granules are formed. Repeated stirring is necessary to obtain a
uniform composition, which is then screened rapidly and dried
carefully. Good drying is absolutely essential to avoid gradual
disintegration of the granules due to reaction of the acids with
the carbonates. To achieve rapid drying, for example, vacuum drying
cabinets or so-called one-pot granulators with vacuum-assisted
drying are used. In another variant of production, the initial
reaction of the acid with basic components and subsequent drying
takes place in a vacuum. The resulting effervescent granules
according to the invention are pressed with additional ingredients
of the composition to form chewable tablets or are packed into
stickpacks. The dosage of the effervescent formulation plays an
important role for the invention. On the one hand enough
effervescent agent must be present to permit a perceptible release
of carbon dioxide which produces the pleasantly fresh feeling in
the mouth and masks the taste. On the other hand the composition
should not foam too much in the mouth because most patients do not
perceive this as pleasant. The proportion of effervescent agent in
the composition is therefore ideally 3-60% of the total weight,
preferably 5-45% and especially preferably 10-30%.
[0024] There are various methods with which those skilled in the
art are familiar which make it possible to incorporate phosphate
binding active ingredients into granules. The active ingredient
here, optionally with the addition of excipients, is preferably
itself in the form of granules which represent the final granulated
composition or are a component thereof. On incorporation into
granules, both pregranulated active ingredients and powdered active
ingredients which are then granulated in subsequent steps may be
used. The dosage forms may contain excipients which are bound into
the granular structure as well as being added in the form of a
powder to the particles of granules. The excipients used may
include in particular fillers, sweeteners, acidifying agents,
flavorings, coating agents, flow regulating agents and parting
compounds. Granulation methods that may be used include in
particular moist granulation, dry granulation and melt granulation,
although other methods are not ruled out. In moist granulation,
aqueous methods are preferred for environmental reasons and for
reasons of occupational safety, but methods using organic solvents
are also possible. For moist granulation and melt granulation,
fluidized bed methods and high speed mixer methods are preferred
(e.g., Diosna mixer or Granumat from Bohle) but alternative methods
are also possible. Granulation methods which yield the densest
possible granules to reduce the volume of the dose taken are
preferred. In addition granules having a smooth surface with little
porosity, which permit uniform moistening by saliva and impart a
pleasant feeling in the mouth due to their smoothness are also
preferred. Preferred granulation methods include moist granulation
of the active ingredients with binders and subsequent drying in a
fluidized bed and melt granulation.
[0025] In preferred embodiments, additional advantageous excipients
are added to the active ingredient in granulation. Various
excipients--such as fillers, parting compounds, binders,
disintegrants, flow regulators, sweeteners and/or flavorings--are
used for technical and pharmaceutical reasons in granulation and
are very familiar to those skilled in the art. However, within the
scope of the present invention, the excipients also ideally
contribute toward improving the feeling in the mouth and the taste
of the granules.
[0026] The fillers may be all pharmaceutically conventional tablet
and granular fillers in particular inert compounds such as
celluloses, starches and/or lactose. Sugars such as sucrose,
glucose or fructose which improve the taste of the formulation and
thus function as sweeteners at the same time are preferred within
the scope of this invention. Sugar alcohols are especially
preferred because they mask the unpleasant taste of the active
ingredients with a pleasantly sweet inherent taste while on the
other hand being easy to moisten with saliva. This leads to the
desired effect of increased salivation and contributes toward a
pleasant cool feeling in the mouth. Within the scope of the present
invention, sugar alcohols may preferably be selected from the group
comprising mannitol, inositol, erythritol, lactitol, xylitol,
maltitol, malbitol, sorbitol, inulin and isomalt.
[0027] The sugar alcohols mentioned above may also be used as
preferred binders in melt granulation. Other preferred binders
within the scope of the invention in granulation with taste-masking
properties at the same time include: cyclodextrin, alginic acid,
Eudragit E-100, polacrilin, microcrystalline cellulose, beeswax,
glycerol esters, triglycerides, polyglycerol esters of long-chain
fatty acids, PEG, fatty alcohol PEG esters, fatty alcohol PEG
ethers, PVP and derivatives, polyacrylic acid, polyacrylates,
polymethacrylates and any combinations thereof. Low-melting binders
which allow granulation at low temperatures and binders which are
simultaneously hydrophilic or even to form hydrogels are especially
preferred because they impart a better feeling in the mouth.
[0028] Sweeteners, e.g., aspartame, saccharine, cyclamate,
acesulfam, neohesperidine, trehalose, alitame, dihydrochalcone,
thaumatin and sucralose may also be used for additional sweetening
because these sweeteners can also stimulate salivation in addition
to having a sweetening effect.
[0029] In addition to a simple sweetening, flavorings and
taste-improving substances are used to mask the taste, to produce a
pleasant taste and to increase salivation. Fruit aromas and
especially preferably citrus fruit aromas are preferred here
because these impart an especially fresh taste and a cool feeling
in the mouth. For the same reasons, mint flavorings are also
preferred.
[0030] Flow regulators that may be used include those substances
which allow an easy and uniform flow of the granules such as in
particular highly disperse silicon dioxide, precipitated silicon
dioxide and talc.
[0031] Fatty acids and their salts, e.g., stearic acid, magnesium
stearate, calcium stearate, behenic acid and calcium behenate,
fatty alcohols, e.g., stearyl alcohol, fats, e.g., hardened
triglycerides and hardened castor oil, sodium fumaryl stearate,
polyethylene glycol with a molecular weight of >1500 Dalton as
well as talc are suitable parting compounds.
[0032] In another preferred embodiment, the active ingredient
granules are coated with a substance to mask the taste. Those
skilled in the art are familiar with many coatings and coating
methods for taste-masking coatings. For example, the following
materials are suitable for taste-masking coatings in the sense of
this invention:
[0033] Cellulose acetate or cellulose acetate butyrate with PVP,
Eudragit RD 100 with carboxymethyl cellulose, polyvinyl alcohol and
polyethylene glycol copolymer, Eudragit 100 and PVP, polyvinyl
acetate and pharmaceutically acceptable hydrophilic polymers,
Eudragit E100 and pharmaceutically acceptable acids, polyacrylates,
polymethacrylates, polymethacrylic esters, combinations of enteric
polymers with hydrophilic gel-forming polymers such as polyvinyl
acetate or polyvinylpyrrolidone (PVP).
[0034] The preferred coating method is spray coating in a fluidized
bed. In principle, both top spray and bottom spray methods are
customary here. The bottom spray method is preferred here for
coating particles and granules thereof. Typical representatives of
devices in this field include those available from the following
companies: Glatt, Aeromatic, Diosna and Bohle. A so-called Wurster
insert is preferred for the bottom spray method. Another preferred
type of bottom spray fluidized coating device is the ball coater
and/or those from the Mycrolab, Unilab, Pilotlab family and/or HDGC
from the company Oyster Huttlin. As those skilled in the art are
aware, in all these systems the coating is performed by spraying a
solution of suspension of a polymer in water and/or another organic
solvent is applied by means of a nozzle to a fluidized bed of
particles and/or granules or pellets, where the fluidized bed is
produced by introducing air, usually heated, and then drying.
[0035] In addition to traditional methods in which the coating is
dissolved in water or an organic solvent and then dried in a
fluidized bed, the melt coating method is considered and is
especially preferred. In the melt coating method, low melting
binders are used, additional substances being dissolved or
suspended in their melt. The melt is sprayed in the fluidized bed
and the coating hardens on cooling. Ideally binders which
themselves have a taste-masking effect and cause a pleasant
perception in the mouth are used, for example, lipophilic
substances selected from the group of lipids, waxes, glycerol
esters, triglycerides, polyglycerol esters of long-chain fatty
acids, PEG, fatty alcohol PEG esters, fatty alcohol PEG ethers and
PVP and derivatives, polyacrylic acids and polyacrylates,
polymethacrylates and combinations thereof. Low-melting binders
which allow granulation at low temperatures and binders which are
hydrophilic at the same time or even tend to form hydrogels are
especially preferred because this imparts a better feeling in the
mouth.
[0036] A surface modifier which produces a smooth surface that is
easy to moisten and thus additionally improves the feeling in the
mouth is preferably added to the coating. Examples of surface
modifiers include sorbitan fatty acid esters, polyoxyethylalkyl
esters, polyoxyethylalkyl ethers, polyoxyethyl sorbitan fatty acid
esters, polyoxyethyl stearates and copolymers thereof.
[0037] If a taste-masking coating is used within the scope of the
present invention, then the effervescent agent should essentially
not be present in the active ingredient granules because the
taste-masking coating would prevent moistening of the effervescent
agent by saliva on the one hand and would thus delay the release of
carbon dioxide while on the other hand any carbon dioxide that
might be formed could at least partially break open the
taste-masking coating. In such a case the effervescent agent may be
added in the form of additional granules or as a powder to the
composition. In another embodiment, the effervescent agent may be
present in the outer layer of the coating. This may be the same
layer as the taste-masking coating or an additional layer.
[0038] The same thing also applies to sweeteners and flavorings
which cannot manifest their taste-improving properties in the core
of the coated active ingredient granules as for the effervescent
agent. Sweeteners and flavorings are also preferably added in the
form of additional granules or as a powder, where these may be the
granules containing the effervescent agent or they may especially
preferably be part of an outer coating.
[0039] The composition may be supplied in the form of free-flowing
granules or a chewable tablet. The chewable tablet offers the
advantages of ease of administration and accurate doseability as a
tablet. Nevertheless within the scope of the invention, the
pourable granular form is preferred. One reason for this is that
the chewable tablet must be chewed. Therefore taste-masking
coatings, for one thing, may be destroyed and for another thing
chewing produces a large volume distribution in the mouth and may
result in the substance sticking to the teeth, which makes rapid
and complete swallowing difficult. The granules may be applied
directly to the tongue and dissolved there, resulting in a
comparatively minor distribution of the particles in the mouth
between the tongue and gums and the granules can be swallowed
completely. Within the scope of the invention, it has been found
that particles with an average particle size of 100-3500 .mu.m
preferably 250-2500 .mu.m and especially preferably 400-2000 .mu.m
are perceived as being especially pleasant for this application.
(The average particle size can be determined by the shaking screen
method according to DIN 53477.) Particles of this size are often
combined in the mouth to form a particularly pasty consistency
which is easy to swallow. Larger particles prevent this
advantageous pasty consistency from being formed whereas smaller
particles in the mouth are perceived as dusty. Smaller particles
because of their larger total surface area adsorb more saliva so
more saliva is needed for initial dissolving, which promotes the
unwanted effect of dryness in the mouth.
[0040] The phosphate binder in a daily total dose of 40-10,000 mg
may be packaged as a single dose or as multiple doses. The daily
dose should be divided among meals, usually three, and taken with
meals. The precise dosing is preferably adjusted according to the
patient's phosphate levels in the course of treatment. It is thus
advisable to package the most common dose per meal in individual
packages. Patients having a low demand for phosphate binders would
then take less than the total contents of one package per meal or
would divide the contents of one package among several meals.
Patients having a high demand could take more than the contents of
one package.
[0041] For a phosphate binder based on calcium, preferably 70-700
mg calcium and 0-300 mg magnesium, based on the weight of the metal
ions, preferably 100-450 mg calcium and 50-240 mg magnesium and
most especially preferably 150-300 mg and 80-160 mg magnesium are
packaged individually.
[0042] For a phosphate binder based on an ion exchanger, preferably
150-3000 mg of the active ingredient, preferably 300-2500 mg and
most especially preferably 600-1700 mg are packaged
individually.
[0043] For a phosphate binder based on lanthanum, preferably
40-1000 mg lanthanum, based on the weight of the metal ions,
preferably 50-750 mg and most especially preferably 80-500 mg is
packaged individually.
[0044] Suitable packages for the preparations according to the
invention in the form of granules include in particular packages
containing the dose of phosphate binder to be administered and from
which the preparation can be applied directly to the mouth,
preferably to the tongue. A bag package, especially preferably a
so-called stickpack package in which the preparation is enclosed in
a tubular package, is preferred. The tubular package is preferably
produced by placing the material, preferably a film, around a round
guide sleeve and connecting it at the sides of the material that
come in contact. The resulting tube is sealed at its lower end,
filled with the preparation which is then preferably dosed through
the guide sleeve and then sealed at its upper end. In the case of a
film tube, the welding of the upper part of the package preferably
takes place together with the welding of the lower part of the
following package and the separation of the two packages. After
being cut or torn open on a short side of the bag, the stickpack
has a small opening of preferably less than 1 cm diameter out of
which the preparation can be administered into the mouth out of the
bag, preferably following gravity. The granules pour out of the
package into the mouth and the granules may be supplied in portions
in the case of larger filling quantities in the bag. Smaller
filling quantities may be administered all at once as a bulk
dose.
[0045] The filling quantity of a stickpack is based on the quantity
which contains an adequate amount of the active ingredient on the
one hand and on the other hand the quantity that is still perceived
as pleasant by the patient when taking it in the mouth. Such a
stickpack therefore preferably contains 0.5-8 g of the total
composition; especially preferably the stickpack contains 0.75-5 g
of the composition, and most especially preferably 1-3.5 g.
EXAMPLES
Example 1
[0046] A granular preparation containing 110 mg calcium and 60 mg
magnesium per dose can be prepared by the following method:
TABLE-US-00001 Calcium acetate (according to the 435 g requirements
of the European Pharmacopoeia)* Heavy magnesium carbonate
(according to the 235 g requirements of the European Pharmacopoeia)
Mannitol 338 g Sodium bicarbonate 67 g Monosodium dihydrogen
citrate 67 g Citric acid 13 g Aspartame 5 g Orange flavoring 30 g
Highly-disperse silicon dioxide 10 g *For anhydrous calcium
acetate, for hydrated calcium acetate, the initial weight must be
adjusted, based on the water content and more calcium acetate must
be added. This step must be taken into account for all examples
using calcium acetate.
[0047] Calcium acetate, heavy magnesium carbonate, sodium hydrogen
phosphate and 750 of the mannitol are converted to granules by
roller compacting and subsequent screening for a 1.5 mm screen.
[0048] Monosodium hydrogen citrate, citric acid and the remaining
25% of the mannitol are also converted to granules by means of
roller compacting and then screening through a 1.5 mm screen.
[0049] Granules, aspartame, orange flavoring and highly disperse
silicon dioxide are mixed in a container mixer and then packaged in
stickpacks with a filling weight of 1200 mg each.
Example 2
[0050] A granular preparation with 110 mg calcium and 60 mg
magnesium per dose can also be prepared by the following
method:
[0051] Effervescent granules:
TABLE-US-00002 Citric acid 75 g Monosodium citrate 75 g Sodium
bicarbonate 150 g Sodium cyclamate 20 g Sucrose palmitate 2 g
Hydroxypropylmethyl cellulose 5 g
[0052] Other ingredients:
TABLE-US-00003 Calcium acetate (according to the 435 g requirements
of the European Pharmacopoeia), granulated (Paul Lohmann) Heavy
magnesium carbonate (according to the 262 g requirements of the
European Pharmacopoeia), granulated with approximately 10%
cornstarch (magnesium carbonate DC90 S/C Paul Lohmann) Aspartame 10
g Sorbitol 200 g Xylitol 136 g Orange flavoring 30 g
[0053] For the effervescent granules, citric acid, monosodium
citrate, sodium bicarbonate, sodium cyclamate, sucrose palmitate
and hydroxypropyl cellulose are mixed in a Diosna mixer with a
1-liter container and sprayed slowly with 5 g ethanol through a
nozzle while stirring. Next granulation is continued for 10
minutes. Then the composition is spread on a metal sheet and dried
for 60 minutes in a vacuum drying cabinet at 30.degree. C. and a
final pressure of <50 mbar.
[0054] The resulting effervescent granules are pressed through a 1
mm screen and mixed with the other ingredients in a 5-liter cube
mixer.
[0055] The mixture is welded into an aluminum stickpack in portions
of 1400 mg.
Example 3
[0056] A granular preparation with 167 mg calcium per dose can be
prepared by the following method:
TABLE-US-00004 Calcium acetate (according to the 660 g requirements
of the European Pharmacopoeia), granulated (Paul Lohmann) Aspartame
10 g Sorbitol 200 g Xylitol 100 g Orange flavoring 30 g Finished
effervescent granules from Example 2 200 g
[0057] All the ingredients are mixed in a 5-liter cube mixer. The
mixture is welded into an aluminum stickpack in portions of 1200 mg
each.
Example 4
[0058] A granular preparation with 167 mg calcium per dose can also
be prepared by the following method:
[0059] Calcium acetate with a taste-masking coating:
TABLE-US-00005 Calcium acetate (according to the 1980 g
requirements of the European Pharmacopoeia), granulated (Paul
Lohmann) Glycerol palmitostearate (Precirol .RTM. ATO 5, 220 g
Gattefosse)
[0060] Other ingredients:
TABLE-US-00006 Aspartame 30 g Sorbitol 600 g Xylitol 320 g Orange
flavoring 100 g Finished effervescent granules 650 g from Example
2
[0061] The calcium acetate is moved in a fluidized bed apparatus
(Unilab 05 from Huttlin) at an inlet air temperature of 35.degree.
C. and coated at a spray rate of 6 g/min with a melt of glycerol
palmitostearate heated to 80.degree. C. and atomized through a
spray nozzle of 1 mm at an atmospheric pressure of 1 bar by means
of spray air heated to 60.degree. C. Then the coated granulates are
cooled to 25.degree. C. for 10 minutes in the ball coater.
[0062] The coated calcium acetate is passed through a 2 mm screen,
mixed with the other ingredients in a 10-liter cube mixer and then
welded in aluminum stickpacks in portions of 1300 mg each.
Example 5
[0063] A granular preparation with 220 mg calcium and 120 mg
magnesium per dose can be prepared by the following method:
TABLE-US-00007 Calcium acetate from Example 4 with a taste- 1450 g
masking coating (calcium acetate content 90%) Heavy magnesium
carbonate (according to the 785 g requirements of the European
Pharmacopoeia), granulated with approximately 10% cornstarch
(magnesium carbonate DC90 S/C Paul Lohmann) Aspartame 30 g Sorbitol
600 g Xylitol 400 g Orange flavoring 100 g Finished effervescent
granules from Example 2 625 g
[0064] All the ingredients are mixed in a 10-liter cube mixer and
welded into aluminum stickpacks in portions of 2660 mg each.
Example 6
[0065] A granular preparation with 220 mg calcium and 120 mg
magnesium per dose can be prepared by the following method:
TABLE-US-00008 Calcium acetate from Example 4 with a taste- 1450 g
masking coating (calcium acetate content 90%) Heavy magnesium
carbonate (according to the 785 g requirements of the European
Pharmacopoeia), granulated with approximately 10% cornstarch
(magnesium carbonate DC90 S/C Paul Lohmann) Aspartame 30 g Sorbitol
550 g Xylitol 400 g Sodium carboxymethyl cellulose 50 g Orange
flavoring 100 g Finished effervescent granules from Example 2 625
g
[0066] All the ingredients are mixed in a 10-liter cube mixer and
welded into aluminum stickpacks in portions of 2660 mg.
Example 7
[0067] The finished mixture from Example 4 can be filled into
stickpacks of a corresponding filling volume (adaptable through the
width and especially the length of the stickpacks) in the following
portions to prepare different calcium doses:
TABLE-US-00009 Corresponding weight of calcium acetate Filling
amount of Calcium dose (anhydrous) stickpacks 50 mg 198 mg 389 mg
100 mg 395 mg 778 mg 150 mg 593 mg 1168 mg 200 mg 791 mg 1557 mg
250 mg 988 mg 1946 mg 300 mg 1186 mg 2335 mg 350 mg 1384 mg 2725 mg
400 mg 1582 mg 3114 mg 500 mg 1977 mg 3892 mg
Example 8
[0068] A granular preparation with 220 mg calcium and 110 mg
magnesium per dose can be prepared by the following method:
TABLE-US-00010 Calcium acetate from Example 4 with a taste- 1450 g
masking coating (calcium acetate content 90%) Heavy magnesium
carbonate (according to the 720 g requirements of the European
Pharmacopoeia), granulated with approximately 10% cornstarch
(magnesium carbonate DC90 S/C Paul Lohmann) Aspartame 30 g Sorbitol
550 g Xylitol 375 g Sodium carboxymethyl cellulose 50 g Orange
flavoring 100 g Finished effervescent granules from Example 2 625
g
[0069] All the ingredients are mixed in a 10-liter cube mixer and
welded into aluminum stickpacks in portions of 2600 mg each.
Example 9
[0070] The finished mixture from Example 8 can be filled into
stickpacks of a corresponding filling volume (adjustable through
the width and especially the length of the stickpacks) to produce
different doses of calcium and magnesium in the following portions,
each in a 2:1 ratio (Ca:Mg):
TABLE-US-00011 Filling amount of Calcium dose Magnesium dose
stickpacks 50 mg 25 mg 591 mg 100 mg 50 mg 1182 mg 150 mg 75 mg
1773 mg 200 mg 100 mg 2364 mg 250 mg 125 mg 2955 mg 300 mg 150 mg
3545 mg 350 mg 175 mg 4136 mg
Example 10
[0071] The finished mixture from Example 4 can be used to produce
different calcium doses with different dosing ratios of calcium to
magnesium. This yields the following filling quantities in
stickpacks of a corresponding filling volume (adjustable through
the width and especially the length of the stickpacks):
TABLE-US-00012 Corresponding Corresponding weight of the weight of
mixture from magnesium Example 4 to be carbonate DC90 Filling used
per S/C to be used amount of Magnesium stickpack for for magnesium
the Ca:Mg ratio Calcium dose dose calcium per stickpack stickpacks
4:1 100 mg 25 mg 778 mg 28 mg 806 mg 2:1 100 mg 50 mg 778 mg 56 mg
834 mg 1:1 100 mg 100 mg 778 mg 111 mg 889 mg 3:1 150 mg 50 mg 1168
mg 56 mg 1224 mg 2:1 150 mg 75 mg 1168 mg 83 mg 1251 mg 1.5:1 150
mg 100 mg 1168 mg 111 mg 1279 mg 4:1 200 mg 50 mg 1557 mg 56 mg
1613 mg 2:1 200 mg 100 mg 1557 mg 111 mg 1668 mg 1.33:1 200 mg 150
mg 1557 mg 167 mg 1724 mg 1:1 200 mg 200 mg 1557 mg 222 mg 1779 mg
5:1 250 mg 50 mg 1946 mg 56 mg 2002 mg 2.5:1 250 mg 100 mg 1946 mg
111 mg 2057 mg 2:1 250 mg 125 mg 1946 mg 139 mg 2085 mg 1.67:1 250
mg 150 mg 1946 mg 167 mg 2113 mg 1:1 250 mg 250 mg 1946 mg 278 mg
2224 mg 3:1 300 mg 100 mg 2335 mg 111 mg 2446 mg 2:1 300 mg 150 mg
2335 mg 167 mg 2502 mg 1.5:1 300 mg 200 mg 2335 mg 222 mg 2557 mg
1:1 300 mg 300 mg 2335 mg 333 mg 2668 mg
Example 11
[0072] A granular preparation with 167 mg calcium per dose can also
be prepared by the following method:
[0073] Calcium acetate with a taste-masking coating:
TABLE-US-00013 Calcium acetate (according to the 1980 g
requirements of the European Pharmacopoeia), granulated (Paul
Lohmann) Basic butylated methacrylate copolymer, Ph. 400 g Eur.
(Eudragit EPO .RTM., Evonik) Sodium dodecyl sulfate 40 g Stearic
acid 60 g Talc 160 g
[0074] Other ingredients:
TABLE-US-00014 Aspartame 30 g Sorbitol 600 g Xylitol 320 g Orange
flavoring 100 g Finished effervescent granules 810 g from Example
2
[0075] First, a film coating suspension with an excess of 25% is
added to the ingredients of the coating material as listed above.
The excess covers the spray losses during production so that the
planned quantity of a coating of 20% methacrylate polymer can be
applied. To do so, first 50 g sodium dodecyl sulfate is dissolved
in 3.5 L of purified water at room temperature (approximately
20.degree. C.). After 5 minutes, 75 g stearic acid is dispersed in
the solution while stirring further using an UltraTurrax. After
another 5 minutes, 500 g Eudragit EPO is distributed in the
dispersion while stirring further and is further dispersed for 30
minutes intensely using the UltraTurrax. In parallel, 200 g talc is
dispersed in 1.5 L purified water at room temperature
(approximately 20.degree. C.) while stirring with an UltraTurrax
and then stirring is continued intensely for 20 minutes more. The
two dispersions are mixed together and then applied to the
granulated calcium acetate by means of a fluidized bed device with
a Wurster insert (Glatt GCPG2 LabSystem) in the bottom spray
method. The dispersions are applied in two partial batches, each
using half of the materials. The inlet air temperature is set at
approximately 50.degree. C., so that a product temperature of
approximately 30.degree. C. is established during film coating. The
suspension is applied to the calcium acetate through a 1.2 mm
nozzle at an air pressure of approximately 1.5 bar and at a feed
rate of 10 g per minute. The process is terminated when the weight
of the granules has increased by approximately 33%. The coated
granules from the two partial batches is passed through a 2 mm
screen and mixed with the other ingredients in a 10 liter cube
mixer and then welded in aluminum stickpacks in portions of 1500 mg
each.
Example 12
[0076] A granular preparation with 110 mg calcium and 60 mg
magnesium per dose can be prepared by the following method:
TABLE-US-00015 Calcium acetate from Example 11 with a taste- 1740 g
masking coating (calcium acetate content 75%) Heavy magnesium
carbonate (according to the 785 g requirement of the European
Pharmacopoeia), granulated with approximately 10% cornstarch
(magnesium carbonate DC90 S/C Paul Lohmann) Aspartame 30 g Sorbitol
600 g Xylitol 400 g Orange flavoring 100 g Finished effervescent
granules from Example 2 695 g
[0077] All the ingredients are mixed in a 10-liter cube mixer and
welded in aluminum stickpacks in portions of 1450 mg each.
Example 13
[0078] A granular preparation with 220 mg calcium and 120 mg
magnesium per dose can be packaged in aluminum stickpacks by
filling the finished mixture from Example 12 into aluminum
stickpacks in portions of 2900 mg each.
Example 14
[0079] A preparation containing 125 mg lanthanum (=238.5 mg
lanthanum hydroxycarbonate) per dose can be prepared by the
following method:
TABLE-US-00016 Lanthanum hydroxycarbonate 715 g (lanthanum content
52.4%) Aspartame 10 g Sorbitol 200 g Xylitol 100 g Orange flavoring
30 g Finished effervescent granules 220 g from Example 2
[0080] All the ingredients are mixed in a 5-liter cube mixer. The
mixture is welded in an aluminum stickpack in portions of 425 mg
each.
Example 15
[0081] Preparations containing 250 mg, 500 mg, 750 mg and 1000 mg
lanthanum per dose can be obtained by filling the mixture from
Example 14 into aluminum stickpacks according to the following
table:
TABLE-US-00017 Corresponding Filling amount of weight of stickpacks
with lanthanum finished mixture Lanthanum dose hydroxycarbonate
from Example 14 250 mg 477 mg 850 mg 500 mg 954 mg 1700 mg 750 mg
1431 mg 2550 mg 1000 mg 1908 mg 3400 mg
Example 16
[0082] A preparation with 800 mg sevelamer hydrochloride per dose
can be prepared by the following method:
TABLE-US-00018 Sevelamer hydrochloride, dried 800 g Aspartame 10 g
Sorbitol 200 g Xylitol 100 g Orange flavoring 40 g Finished
effervescent granules 250 g from Example 2
[0083] All the ingredients are mixed in a 5-liter cube mixer. The
mixture is welded in an aluminum stickpack in portions of 1400 mg
each.
Example 17
[0084] Preparations with 1600 mg and 2400 mg sevelamer per dose can
be packaged in aluminum stickpacks by filling the mixture from
Example 16 into aluminum stickpacks according to the following
table:
TABLE-US-00019 Filling amount of Sevelamer stickpacks with finished
dose mixture from Example 16 1600 mg 2800 mg 2400 mg 4200 mg
Example 18
[0085] A preparation with 800 mg sevelamer hydrochloride per dose
can be prepared by the following method:
TABLE-US-00020 Sevelamer hydrochloride, dried 800 g Povidone K30 50
g Aspartame 10 g Sorbitol 200 g Xylitol 100 g Orange flavoring 40 g
Finished effervescent granules 250 g from Example 2
[0086] Povidone K30 is dissolved in 150 mL of a mixture of 90%
ethanol and 10% purified water. Sevelamer hydrochloride is
granulated with the povidone solution in a fluidized bed granulator
(Glatt GCPG2 LabSystem) in the top spray method. The granules are
passed through a 1 mm screen and mixed with the other ingredients
in a 5-liter cube mixer. The mixture is welded in an aluminum
stickpack in portions of 1450 mg each.
* * * * *