HK1172845B - Novel pharmaceutical formulations against drug misuse - Google Patents

Abstract

The present invention relates to granules containing a solid core whereon an active principle is mounted, said core preferably being selected among insoluble substrates, said granules also containing the following compounds, mounted on said solid core: one or more coloring agents, one or more metal pigments, one or more compounds capable of generating a gas evolution, and optionally one or more bittering agents.

Description

Novel pharmaceutical formulations for preventing drug abuse

Technical Field

The aim of the invention is to develop a novel formulation of a medicament for reducing or avoiding drug abuse.

Background

Substance abuse refers to the inappropriate use of a drug. The phenomenon of drug abuse is increasingly serious, and the drug abuse is a big problem which damages the health of the public. The source of drug abuse is the vague understanding of certain active ingredients, which are both used as medicinally tranquillizing drugs and drugs prohibited by law.

The existence of substance abuse behavior has several objective explanations, such as pursuing psychological or physical stimuli; pursuit of pleasure (party or fun); addiction problems after initial use; relieving pain or psychological disorders; chemical control in some cases (e.g., post-drug abuse); and accidental misuse or misuse of drugs in actual therapy (e.g. due to lack of understanding by some elderly people).

The consequences of drug abuse are also manifold: simple side effects, necrosis of local musculature after administration, cardiac abnormalities, dyspnea, addiction, and uncontrolled crimes (in particular rape).

Currently, there are few good methods of controlling drug abuse and are essentially administrative: such as listing controlled drug lists by special legislation; dispensing the medicament according to a safety prescription; controlled dispensing in hospitals and strict dispensing regulations. To prevent drug abuse, some pharmaceutical companies also strive to improve product packaging to prevent drug misuse, particularly by children.

In recent years, some studies have been made with great success in the dosage of drugs.

For example, in the case of drug addiction or psychological control performance, it has been found that most individuals concerned are swallowed directly, or attempt to extract their active ingredients.

They first obtained powder from various combinations of drugs by rolling them. Thus, they can directly swallow or inhale the active ingredient, and the most common extraction is to dissolve the active ingredient by water or alcohol.

Thus, the international application WO 03/013479 describes a combination formulation of an opioid analgesic with an inhibitor thereof, which is effective in blocking the hedonic effect of the opioid analgesic. The two composite medicines can simultaneously exert the drug effect. Of course, there are several disadvantages associated with the formulation of such opioid agonists and inhibitors. In fact, the use of active inhibitors having a pharmacological therapeutic effect may also cause various problems.

Patent application EP 1293209 describes another improved free formulation, namely the use of an ion-exchange resin which limits the masticatory extraction, the inhalation extraction and the injection. However, this formulation does not prevent extraction with solution or physical crushing.

International patent application WO 2005/079760 describes the use of an elastomeric polymer (NE 30D). TheThe formulation uses a plasticizer which is very plastic and therefore difficult to crush. However, even with this formulation, it is difficult to prevent the extraction of the active ingredient with a solvent.

Thus, while there are some tranquilizers in the world today that use different formulations to ameliorate the abuse of such drugs, none of these approaches prevent the illegal extraction of the active ingredient. Therefore, there is a need for a new pharmaceutical agent.

Disclosure of Invention

In view of the above, it is an object of the present invention to provide novel pharmaceutical formulations which are specifically designed to prevent drug abuse.

The present invention aims to provide pharmaceutical formulations which prevent the illegal extraction of active ingredients.

The present invention aims to provide a number of specially designed clinical medications, particularly oral medications, which are specifically designed to maximize abuse resistance and make the treatment safer.

One of the objectives of the present invention is to provide new pharmaceutical formulations that prevent abuse, avoid misuse, inherit and improve existing means of administration.

It is another object of the present invention to provide a pharmaceutical formulation which ensures therapeutic efficacy and only ensures therapeutic efficacy.

It is another object of the present invention to provide a pharmaceutical formulation that is easily shaped and sized for administration and use.

The present invention relates to a granule comprising a solid core carrying an active ingredient, said core being preferably selected from insoluble carriers, in particular selected from the group consisting of polyols (such as sorbitol, xylitol or maltitol), gums, silicon dioxide derivatives, calcium or potassium derivatives, inorganic compounds such as calcium hydrogen phosphate, tricalcium phosphate and calcium carbonate, sucrose, cellulose derivatives, (in particular microcrystalline cellulose, ethyl cellulose and hydroxypropylmethyl cellulose), starch and mixtures of the above carriers; the granules comprise, in addition to an inner core, the following compounds attached to the inner core:

one or more colorants; one or more metallic pigments; one or more gas-releasing compounds; and one or more bittering agents capable of being combined with the active ingredient.

Accordingly, the present invention is directed to a clinical formulation comprising multiple pharmaceutical ingredients that prevents substance abuse by any of the above-described means and approaches. These formulations are based on the granular dosage forms described above, and may be in the form of a monolithic tablet or a compact tablet. Thus, the granules of the invention may comprise multiple layers of carriers, each with a different efficacy.

The term "granules" refers to formulations consisting of dry solid particles, each of which forms aggregates of powder particles of sufficient hardness to allow various manipulations to be performed.

From a physical point of view, the granules are aggregates of different powder particles, either crystalline or amorphous.

The granules of the invention are particularly suitable for oral administration, in particular for direct swallowing.

The granules of the invention have a core-shell characteristic structure, the core not being of the same type as the compound forming the shell.

Thus, these granules have a multilayer structure. In fact, the active ingredient is precipitated on the inner core, forming a layer (or shell) around the inner core (carrier).

The inner core of the granule may also serve as a carrier to which the active ingredient is attached.

The inner core is composed of solid particles and an active ingredient, wherein the active ingredient is a solid carried on the inner core.

Therefore, the core content of the invention is to develop a novel multiparticulate oral dosage form.

The granules of the invention have an obvious active ingredient layer.

Depending on the desired final pharmacological parameters, the active ingredient layer (first layer) may also be coated with other additives, such as various external coating agents currently used (plasticizers, solubilizers, lubricants, antiadherents, etc.).

The granules of the invention comprise a solid core, preferably selected from water-insoluble or alcohol-insoluble carriers. The selection of a water-insoluble or alcohol-insoluble carrier as the core of the granule of the present invention prevents the granule from being crushed and completely dissolved.

The solid core of the granule may also comprise other compounds, in particular insoluble compounds. Including especially mixtures of sucrose and starch or mixtures of silica or calcium derived inorganic compounds.

The solid core may also be composed of a soluble carrier, and certain solid grades of Polyethylene Glycol (PEG, particularly PEG4000 or PEG6000) may be recommended.

The term "silica derivatives" refers to silicas obtained from alkali silicates and precipitated silicas, in particular(fumed silica), or talc, bentonite or kaolin.

The term "calcium derivative" refers to a crystalline excipient derived from calcium hydroxide, which is insoluble in water, and which is used in the medical community as a diluent, or a product of filler and abrasive.

The term "potassium derivative" especially refers to potassium bicarbonate and potassium chloride.

The insoluble carrier which forms the core of the granules of the invention may also comprise a magnesium derivative, in particular a magnesium carbonate or oxide.

The granules of the present invention further comprise one or more colorants. The choice of colorant is determined by its solubility in the solvent. For example, the choice may depend on the solubility of the colorant in alcohol and in water. In fact, these two solvents are generally used to extract or dissolve the active ingredient.

Thus, the color obtained enables one to see malicious additions in the beverage, for example to be able to detect conspiracy in the control of medicaments.

The granules of the invention also comprise one or more metallic pigments.

The presence of the colorant and metallic pigment allows one to see any dissolution after crushing as a medical agent and any subsequent ingestion thereof. Similarly, the same phenomenon can be observed if such granules are chewed.

The colorant and metallic pigment in the granules of the invention may be located in different tablet layers.

For strong precaution, it is particularly desirable to integrate the active ingredient with the colorant or colorants and then coat them with the metallic pigment, in other words, one can see the color of the metallic pigment from the surface of the granule.

The granules of the invention also comprise in their structure one or more compounds that release a gas when the granules are dissolved by water. Thus, when the granules are poured into a liquid, the production and removal of carbon dioxide from the compound causes the granules to float up and down and form a foam on the surface of the liquid.

This phenomenon is even more pronounced if the liquid used is a beverage with boiling characteristics, such as soda water or cola. In fact, we have observed this real effervescence in the cup.

These different formulation methods can bring the most safe clinical medicament form, prevent the abuse of the medicament to the maximum extent and ensure the safety of the medicament.

According to an optimal design, the granules should also comprise a binder.

The binder serves to bind the granules to one another, that is to say to ensure perfect binding of the granules. In this way, the binder ensures a tight bond between the active ingredient and the granule core.

Thus, the binder, like the active ingredient, is precipitated around the inner core of the granule.

The adhesive basically consists of hydrophilic viscous auxiliary materials: such as gum arabic, tragacanth, methylcellulose, carboxymethylcellulose, gelatin, starch, maltodextrin, PEG4000 and PEG6000 in alcoholic solution, povidone in aqueous or alcoholic solution, sucrose, glucose, sorbitol.

The binder used in the granule of the present invention is preferably selected from the group consisting of starch, sucrose, acacia, polyvinylpyrrolidone (PVP or povidone), Hydroxypropylmethylcellulose (HPMC), shellac, Hydroxypropylcellulose (HPC), cellulose, polyol or alginate, and polyethylene glycol glyceryl fatty acid esterOr a hard polyethylene glycol fatty acid glyceride, particularly a stearin polyethylene glycol glyceride, an acrylic acid derivative and a mixture of the above carriers.

Among the polyols, mannitol, sorbitol, maltitol or xylitol are particularly preferred.

According to a particular embodiment, the binder is preferably selected from the group consisting of polyvinylpyrrolidone, shellac, polyol or alginate, polyglycolyzed fatty acid glycerideOr hard polyethylene glycol fatty acid glycerides, particularly stearic acid polyethylene glycol glycerides, and mixtures thereof.

It is also possible to select an adhesive from the above group for specific propertiesFor example, such as acrylic resinL100 or shellac are advantageous as binders for pH-dependent adjuvants. If hydrophobic materials are desired, it is preferred to use polyethylene glycol fatty acid glycerides

According to a preferred embodiment, the granules of the invention may further comprise one or more bittering agents.

The bitterant is selected from the group consisting of denatonium benzoate, gentian extract, quinine, caffeine, strychnine, quassin, Propylthiouracil (PROP), Phenylthiourea (PTC), astringents such as tannin, grapefruit flavor, and bitter cocoa bean flavor.

The bitter agent (or bitter taste promoter, e.g.)Denatonium benzoate) with the active ingredient, making accidental chewing very difficult, if not impossible, even after extraction and/or dissolution. In fact, the bittering agent has been incorporated into the active ingredient and is difficult to separate.

The bitter medicine can prevent people from intentionally adding medicines in the cocktail, and effectively warn the behavior of intentionally adding medicines in the wine (cubic ice/vodka and the like).

For the selection of the gas-releasing compound in the granules according to the invention, preference is given to the group consisting of carbonates and bicarbonates.

More specifically, they should be sodium bicarbonate, sodium carbonate, sodium aminoacetate carbonate, potassium bicarbonate, magnesium carbonate and calcium carbonate.

As the colorant in the granule of the present invention, a water-soluble colorant and an alcohol-soluble colorant are preferably used.

Among the colorants dissolved in alcohol, the following are particularly preferred: medium red, orange blue FDC, etc.

Among the colorants dissolved in water, conventional food colorants are preferably used. The colorant used in the present invention is the related colorant listed in directive No. 95/45/CE No. 26/7/1995, which is useful for food products (directive No. 2006/33/CE No. modified on 20/3/2006). The use of E100 to E180 colorants is particularly preferred.

A colorant E131 which is soluble in both water and alcohol can also be used (patent blue).

According to a particularly preferred embodiment, the metallic pigment in the granules according to the invention is a titanium dioxide-based metallic pigment present on the surface of the granules.

It has been shown that these metallic pigments based on titanium (e.g. titanium pigments)) The use of (A) is necessary: can make the granule very obvious in color even in very dark beverage (such as beverage)) They may also exhibit gloss.

The coated granule also has one or more layers of coating containing various adjuvants.

The coating of the granules of the invention is a shell consisting of a coating agent.

The granules of the present invention may further comprise a coating agent selected from the group consisting of wax derivatives, plasticizers (film forming agents), shellac, polyvinylpyrrolidone, polyethylene glycol, cellulose derivatives (such as HPMC or HPC), sucrose, alginate, fatty acid glycerides, and methacrylic acid polymers.

The term "wax derivative" refers to natural or synthetic esters of fatty acids and alcohols, which are typically solid at room temperature and have different uses in the preparation of pharmaceuticals.

The granules of the invention may also be coated with a film to which one or more excipients, such as lubricants, pigments, sweeteners, plasticizers or antiadherents, may be added.

The granules according to the invention may also comprise an enteric coating which consists of a methacrylic acid polymer, in particularL, shellac, or HPMCP (hydroxypropylmethylcellulose phthalate).

Thus, enteric coated granules are resistant to gastric acid.

The presence of an enteric coating may affect the physiological absorption of the active ingredient, and in particular may prevent degradation of the active ingredient in an acidic environment.

The granules of the invention may also comprise a slow release coating.

Such granules may alter or delay the release of the active ingredient (slow release granules).

Such coatings employ coating compositions consisting essentially of copolymers of methacrylates and acrylatesS100 (acrylic resin), shellac, cellulose derivatives (especially ethyl cellulose) and other acrylic derivatives.

The presence of such a slow-release coating may in particular influence the apparent half-life of the active ingredient.

The granules produced according to the invention may also comprise lubricants and/or flavourings and/or sweeteners.

Among the lubricants which the present invention allows to use, particular advantages are obtainedSelected from talc, magnesium stearate, silicon dioxide derivatives (especially) And wax.

Among the flavors allowed for the present invention, we used flavors commonly used in food additives.

Specifically, sweeteners useful in the present invention are those edible relevant sweeteners listed in directive 94/35/CE No. 30/6/1994 (modification of directive 2006/25/CE No. 5/7/2006). In particular, it is particularly preferred to use E951 aspartame, E420 sorbitol, E421 mannitol, E950 acesulfame potassium, E954 saccharin, stevia or thaumatin.

The granules of the invention may contain any active ingredient drug for use in therapy and combinations thereof. Preferred active ingredients are analgesics and analgesics.

The analgesic active agent can relieve pain of patients. Among the analgesics, central morphine analgesics (morphine derivatives), central non-morphine analgesics, peripheral nerve analgesics, and other analgesics (e.g., benzodiazepines) are mainly selected.

The active ingredient of the granules of the present invention may preferably be selected from the group consisting of morphine sulfate, oxycodone, gamma-hydroxybutyric acid or salts thereof, buprenorphine, modafinil, dextropropoxyphene, methadone, tramadol, nalbuphine, tetrahydrocannabinol and benzodiazepines.

According to a particular embodiment, the granules of the invention may be free of inhibitors of the active ingredient. The benefits of the granules of the invention thus produced are: contains no inhibiting components capable of changing the therapeutic effect of the active components.

Thus, the granules of the invention, which do not contain an inhibitor of an active ingredient, ensure the desired therapeutic effect for the patient and only aim at this, in other words, the invention does not use other active ingredients (e.g. inhibitors containing an active ingredient).

According to another preferred embodiment, the granules according to the invention may not comprise an ion-exchange resin.

The granules of the invention preferably comprise from 0.5% to 60% of active ingredient relative to the total weight of the granules.

The granules of the invention preferably comprise from 0.2% to 4% of a colouring agent, relative to the total weight of the granules.

The granules of the invention preferably comprise from 0.1% to 5% of metallic pigment, relative to the total weight of the granules.

The granules of the invention preferably comprise from 5% to 20% of the gas-releasing compound, relative to the total weight of the granules.

The granule core of the present invention preferably comprises from 10% to 85% relative to the total weight of the granule.

The invention is a pharmaceutical composition containing the above granules.

The invention also comprises a process for the manufacture of a granulate as defined above, characterised by the step of subjecting the active ingredient to a powdering treatment and spraying it onto the insoluble core.

One preferred process according to the invention is: the active ingredient is mixed with a colorant, a metallic pigment and a gas-releasing compound, and the active ingredient mixture is subjected to a powdering treatment and sprayed onto the insoluble core.

The process of the invention also comprises a granule coating step following the powdering and spraying step: comprises applying a coating film to the granules, optionally with the addition of a step of mixing with lubricants and/or flavorings and/or sweeteners and/or pigments (metallic pigments).

The structure of the granules of the invention is closely related to the particular process carried out above, so that granules of core-shell structure are obtained.

Different auxiliary materials commonly used in the industry are used for direct processing and manufacturing, and the results of comparative experiments prove that: the granules themselves are satisfactory to manufacture, achieving good criteria in terms of appearance, friability and ease of disintegration. However, the granules obtained by this simple process have a very large body surface area, which requires a large amount of coating polymer according to conventional techniques.

Thus, another significant feature of the granules of the invention is that its body surface area is reduced. And from the appearance, the granules are smoother and have regular appearance.

The pulverization step in the preparation process of the granules also comprises the step of spraying an alcoholic solution, a hydroalcoholic solution or an aqueous solution of the binder.

Preferably, the spraying step is carried out simultaneously or alternately with the powdering step.

More preferably, the simultaneous operation of spraying the dissolved binder while powdering is carried out.

This has the advantage of ensuring that the active ingredient is tightly bound to the core.

Therefore, the process of the present invention is advantageous in that the powdered active ingredient is tightly adhered to the core, and the spraying operation of dissolving the adhesive is performed simultaneously while pulverizing.

The process of the invention may further comprise, after the powdering step, one or more steps of coating the granules, in particular by applying a coating agent in the form of a film to the granules by film coating.

The small-surface granule specially made from the granule of the invention reduces the use amount of the coating agent, thereby greatly reducing the dilution of the coating agent to the active ingredients in the granule.

The preferred process of practice of the invention comprises, after the coating step, a further step of mixing the lubricant and/or flavoring and/or sweetening agents, which may themselves be preformed into granules which are ultimately mixed with the active particles.

Of course, these lubricants, flavors, sweeteners may also be added prior to the powdering step described above.

Detailed Description

The following examples are specific pharmaceutical formulations made according to the above granule definitions of the present invention.

Example 1: morphine sulfate-based tablets

The tablets are obtained by the following operating process:

using denatonium benzoateSilicone (A)972) Talc, sodium bicarbonate (gas-releasing compound) and patent blue (colorant) make the initial mixture (mixture 1). Mixing the above components inMix in the mixer for 10 minutes.

The powdered active ingredient was poured into a mixer to make a second mixture (mixture 2). The mixture was then mixed with HPMC with stirring for 20 minutes.

Subsequently, mixture 1 was introduced into mixture 2 and mixed for another 20 minutes.

The resulting mixture is then directly compressed on a Korch3 tablet press, and the finished tablet is produced.

Then, the tablet is made to containCoating solution of LP, pigment and magnesium stearate is used for suspension coating and spraying.

Example 2: oxycodone-based granules

The granules are obtained by the following operation processes:

first, an active suspension is prepared, i.e. a suspension is prepared comprising the active ingredient (oxycodone), binder (PVP), pigment and bittering agentA suspension of (a).

The suspension is then sprayed onto the carrier (mannitol particles in a fluidized air bed) and the particles are then dried in the fluidized air bed.

An initial mixture (mixture 1) was prepared from granules based on mannitol, microcrystalline cellulose and sodium glycine carbonate (gas releasing compound).

Then, a second mixture (mixture 2) is prepared on the basis of the above-mentioned granules containing the active ingredient. The granules were air dried and then reintroduced into the mixer, followed by addition of the pigment and lubricant.

Finally, the mixture 1 and the mixture 2 are stirred and mixed, and measurement and quality inspection are carried out.

Example 3: buprenorphine-based capsules

The capsule is obtained according to the following operation process:

the neutral carrier (sugar/starch) was placed in a conventional mixer and an aqueous suspension containing the active ingredient (buprenorphine), binder and bittering agent was prepared. Sodium bicarbonate (a gas-releasing compound) is attached to the sugar and starch carriers by a powdering process, alternating the powdering process and the suspension spraying step.

Next, the obtained pellets were subjected to a drying treatment in a blender.

Then, a coating treatment was carried out with an ethyl cellulose aqueous suspension containing a plasticizer, a pigment and talc.

The granules are then further dried to harden the film.

Finally, the capsule particles are subpackaged.

Example 4: modafinil-based capsules

The capsule can be obtained by the following operation process:

the cellulose was placed in a conventional blender.

After the powdering treatment, the active ingredient is mixed with sodium carbonate; this mixture was then sprayed by atomization onto a rotating carrier in an agitator.

Then, we will containAnd pigment, and adding an alcoholic solution containing a PVP binder. This solution was then atomized onto a carrier, and the atomization was carried out while the pulverization treatment was carried out.

The granules obtained are then subjected to a drying treatment to eliminate the solvents used in the powdering stage of the active ingredient.

Preparation of the coating suspension: i.e., a suspension of methacrylate polymer is prepared, followed by the addition of plasticizer, lubricant, and pigment. The suspension is then stirred and sprayed onto the previously prepared granules.

The coated granules obtained in this way are dried again and then portioned.

Example 5: GHB (gamma-hydroxybutyric acid) granules

Microgranules of example 5 can be prepared by loading the active ingredient (GHB) onto sugar spheres.

Mixing the active components of gamma-hydroxybutyric acid and sodium bicarbonate(magnesium aluminum silicate) compound. The mixture thus produced was already well fused.

Meanwhile, a solution was prepared from shellac resin and ethanol, and this solution was added to the above mixture. Sugar spheres were then added.

Next, all ingredients are dried and dissolved in water and in alcoholAndthe coating agent is used for coating treatment.

The whole is then dried again and coated a second time with a mixture of shellac and talc dissolved in water and in alcohol.

Finally, the granules thus obtained are dried and talc is added as a lubricant.

Claims (16)

1. A granule comprising a solid inner core carrying an active ingredient, wherein the inner core is selected from insoluble carriers,

the granules comprise, in addition to an inner core, the following compounds attached to the inner core:

one or more colorants;

one or more metallic pigments;

one or more gas-releasing compounds;

and optionally one or more bittering agents.

2. A granule according to claim 1, wherein the insoluble carrier is selected from the group consisting of polyols, gums, sucrose, starch and mixtures thereof.

3. A granulate according to claim 1, wherein the insoluble carrier is selected from calcium hydrogen phosphate, tricalcium phosphate and calcium carbonate.

4. The granule according to claim 1, wherein the insoluble carrier is selected from the group consisting of microcrystalline cellulose, ethyl cellulose, hydroxypropyl methylcellulose.

5. A granulate according to any one of claims 1 to 4, containing a gas-releasing compound selected from the group consisting of carbonates and bicarbonates.

6. A granulate according to claim 5, wherein the gas-releasing compound is selected from the group consisting of sodium bicarbonate, sodium carbonate, sodium aminoacetate carbonate, potassium bicarbonate, magnesium carbonate and calcium carbonate.

7. A granule according to any of claims 1 to 4, characterized in that the metallic pigment is a titanium dioxide based pigment attached to the surface of the granule.

8. The granule according to any of claims 1 to 4, wherein the active ingredient is selected from the group consisting of analgesics and painkillers.

9. A granulate according to any one of claims 1 to 4, wherein the active ingredient is selected from the group consisting of morphine sulfate, oxycodone, gamma-hydroxybutyric acid or salts thereof, buprenorphine, modafinil, dextropropoxyphene, methadone, tramadol, nalbuphine, tetrahydrocannabinol, and benzodiazepines.

10. A granule according to any of claims 1 to 4, characterized in that the bitterant is selected from the group consisting of denatonium benzoate, gentian extract, quinine, caffeine, strychnine, quassin, propylthiouracil, phenylthiourea, tannin, grapefruit flavour and bitter cocoa bean flavour.

11. A granule according to any one of claims 1 to 4, characterized in that the active ingredient is present in an amount of 0.5 to 60% by weight relative to the total weight of the granule.

12. A granule according to any of claims 1 to 4, characterized in that the colorant is present in an amount of from 0.2% to 4% by weight, relative to the total weight of the granule; the weight content of the metal pigment is 0.1-5%; the gas-releasing compound is present in an amount of 5 to 20% by weight.

13. A granule according to any of claims 1 to 4, wherein the solid inner core is present in an amount of from 10 to 85% by weight, relative to the total weight of the granule.

14. A pharmaceutical composite tablet comprising the granule according to any one of claims 1 to 13.

15. A process for the manufacture of a granulate according to any of claims 1 to 13, comprising the step of subjecting the active ingredient to a powdering treatment and spraying it onto an insoluble carrier.

16. A process for the manufacture of a granulate according to claim 15, comprising the steps of mixing the active ingredient with a colorant, a metallic pigment and a gas-releasing compound, followed by powdering and spraying onto an insoluble carrier.