disclosure of Invention
The traditional Chinese medicine preparation gallbladder warming tablet has various medicinal materials, complex components and complicated process links, and a method for detecting the process stability is not available at present. The inventor of the invention surprisingly finds that the process stability of the warming-in-container tablet can be detected by measuring the synephrine transfer rate of the warming-in-container tablet, thereby well controlling the product quality stability of the warming-in-container tablet.
The seven medicinal materials for producing the gallbladder warming tablet of the invention have the following proportions: 800 parts of bamboo shavings, 700 parts of rhizoma pinellinae praeparata, 700 parts of radix curcumae, 300 parts of liquorice, 100 parts of dried orange peel, 800 parts of poria cocos and 800 parts of immature bitter orange.
Specifically, 750 parts by weight of caulis bambusae in taeniam, 600 parts by weight of rhizoma pinellinae praeparata in 450-.
Preferably, 660 parts of caulis bambusae in taeniam, 550 parts of rhizoma pinellinae praeparata, 550 parts of radix curcumae, 165 parts of liquorice, 165 parts of dried orange peel, 550 parts of poria cocos and 660 parts of immature bitter orange. Or 500 parts of caulis bambusae in taeniam, 450 parts of rhizoma pinellinae praeparata, 500 parts of radix curcumae, 150 parts of liquorice, 200 parts of pericarpium citri reticulatae, 600 parts of poria cocos and 700 parts of immature bitter orange.
The preparation method of the gallbladder warming tablet comprises the following steps: mixing radix Curcumae, rhizoma Pinelliae Preparata, fructus Aurantii Immaturus, pericarpium Citri Tangerinae, Glycyrrhrizae radix, caulis Bambusae in Taenia and Poria at above ratio, soaking in water for half an hour, heating to boil, reflux-extracting for 1-2h, extracting twice, condensing during extraction to collect volatile oil, filtering the extractive solution, concentrating, precipitating with ethanol, filtering, concentrating the supernatant to obtain soft extract, adding adjuvants to make into granule, spraying volatile oil, and tabletting. The collected volatile oil contains the components of the raw medicinal materials and is also an effective component for exerting the drug effect.
The gallbladder warming tablet is produced by seven medicinal materials, wherein the content determination and the chemical component research of rhizoma pinellinae praeparata, radix curcumae, caulis bambusae in taeniam and poria cocos are not related in pharmacopoeia of the people's republic of china (2010 edition). Only the literature can be found that rhizoma Pinelliae Preparata contains trigonelline, radix Curcumae contains curcumin, and caulis Bambusae in Taenia contains tricin.
The inventor researches the three components and the raw medicinal materials and finds that: when the medicinal material curcuma aromatica is curcuma aromatica, the curcuma aromatica does not contain curcumin; the content of the tricin in the bamboo shavings is only 0.0087%, and the content is too low to be detected easily; in addition to rhizoma Pinelliae Preparata, radix Glycyrrhizae also contains trigonelline and has a content higher than that of rhizoma Pinelliae Preparata, and has poor specificity of trigonelline component, and radix Glycyrrhizae is a messenger drug, and its component is not suitable as index; accordingly, none of the above three components is suitable as a detection index.
The inventor carries out intensive research on two medicinal materials of the tangerine peel and the immature bitter orange, and finds that the tangerine peel and the immature bitter orange both contain hesperidin and synephrine, and the chemical components of the tangerine peel and the immature bitter orange are close. The inventor researches the quality stability and the process stability of the warming gallbladder tablets by taking hesperidin and synephrine as detection indexes respectively, and finds that the transfer rate of the hesperidin is too low in the process of preparing the warming gallbladder tablets, so that the detection is easy to cause inaccuracy and is not suitable for serving as the index, and the synephrine transfer rate is higher and is suitable for serving as the detection index.
The invention relates to a method for detecting the process stability of a lining warming tablet, which comprises the step of measuring the synephrine transfer rate of the lining warming tablet.
In one embodiment of the method of the invention, when the synephrine transfer rate is more than or equal to 40.8%, the process stability is qualified; specifically, the process stability is qualified when the synephrine transfer rate is more than or equal to 41%, more than or equal to 42%, more than or equal to 43.5%, more than or equal to 44%, more than or equal to 45.4%, more than or equal to 46%, more than or equal to 47%, more than or equal to 48%, more than or equal to 49%, more than or equal to 50%, or more than or equal to 50.21%.
In one embodiment of any of the methods of the invention, the synephrine transfer rate is 100% × synephrine mass in fel tablet (μ g)/synephrine mass in the drug (μ g).
In one embodiment of any of the methods of the invention, the amount of synephrine in the herbal material (μ g) is the amount of synephrine in the prescribed citrus aurantium (μ g) + the amount of synephrine in the prescribed citrus peel (μ g); specifically, the mass (μ g) of synephrine in the prescription fructus aurantii immaturus is equal to the mass (g) of the prescription fructus aurantii immaturus multiplied by the content (μ g/g) of synephrine in the prescription fructus aurantii immaturus; specifically, the mass (μ g) of synephrine in the prescribed pericarpium citri reticulatae is equal to the mass (g) of the prescribed pericarpium citri reticulatae multiplied by the content (μ g/g) of synephrine in the prescribed pericarpium citri reticulatae.
In one embodiment of any of the methods of the invention, the determination of synephrine content in the prescription citrus aurantium is made in accordance with pharmacopoeia of the people's republic of china (2010 version), p 230; specifically, the method for measuring the content of synephrine in the tangerine peel comprises the steps of mixing the tangerine peel and methanol, and measuring the content of the synephrine in an extracting solution by liquid chromatography.
In any embodiment of the methods of the invention, the determination of the synephrine content of citrus peel comprises any one or more of the following (1) to (4),
(1) before mixing, crushing the dried orange peel into medium powder;
(2) adding 50-100mL of methanol into per gram of dried orange peel;
(3) mixing under ultrasound; specifically, after ultrasonic treatment, methanol is used for complementing loss weight loss;
(4) filtering the extractive solution; specifically, the filter pore size is 0.22. mu.m.
In one embodiment of any of the methods of the present invention, the liquid chromatography detection conditions for measuring the content of citrus peel synephrine are any one or more of the following (1) to (7),
(1) the chromatographic column is a normal phase silica gel bonded diol-based chromatographic column;
(2) the detection wavelength is 275 nm;
(3) the flow rate of the mobile phase is 0.6-1.2 mL/min;
(4) the theoretical plate number is more than or equal to 14000;
(5) the liquid chromatography is high performance liquid chromatography;
(6) column temperature: 35 ℃;
(7) mobile phase a was a 5mM ammonium acetate solution, mobile phase B was acetonitrile, the mobile phase A, B volume percent changes are as follows,
in any embodiment of the method of the present invention, the quality measurement of synephrine in the Winterian tablets comprises the steps of mixing the Winterian tablets with methanol and measuring the content of synephrine in the extract by liquid chromatography.
In any of the embodiments of the methods of the invention, the Wencandine synephrine assay comprises any one or more of the following (1) to (5),
(1) before mixing, crushing the warm gall pieces;
(2) mixing under ultrasound; specifically, after ultrasonic treatment, methanol is used for complementing loss weight loss;
(3) the methanol concentration is 50-100% v/v;
(4) adding 50-100mL of methanol into each gram of gallbladder warming tablets;
(5) filtering the extractive solution; specifically, the filtrate is further purified; the preferred purification step is evaporation of the filtrate to dryness, dissolution of the residue and elution through a polyamide column.
In any embodiment of the method of the present invention, the conditions for the liquid chromatography detection of the content of the Chondrus crispus are any one or more of the following (1) to (6),
(1) the chromatographic column is a normal phase silica gel bonded diol-based chromatographic column;
(2) acetonitrile and ammonium acetate solution are used as mobile phases; preferably, acetonitrile is used as the mobile phase A, and 5mmol/L ammonium acetate solution is used as the mobile phase B; more preferably, the volume ratio of mobile phase a to mobile phase B is (60-95): (5-40);
(3) the detection wavelength is 275 nm;
(4) the flow rate of the mobile phase is 0.6-1.2 mL/min;
(5) the theoretical plate number is more than or equal to 14000;
(6) the liquid chromatography is high performance liquid chromatography.
In the present invention, the term "process stability" refers to the ability of the process to withstand fluctuations in materials and process and equipment changes without negative quality impact (ICH process robustness).
In the present invention, the term "medium powder" means powder which can pass through the sieve No. four in its entirety, but mixed with powder which can pass through the sieve No. five by not more than 60%.
In the present invention, the term "theoretical plate number" refers to one of column efficiency parameters of chromatography, and is used to quantitatively express the separation efficiency of a chromatography column.
Advantageous effects of the invention
(1) The stability of the gallbladder warming tablet process is detected by the synephrine transfer rate value of the gallbladder warming tablet.
(2) The invention further takes the synephrine transfer rate of the warming gallbladder tablets to be more than or equal to 40.8 percent as the qualified standard of the process stability of the warming gallbladder tablets, thereby realizing the control of the product quality of the warming gallbladder tablets.
(3) The liquid chromatography detection of the invention uses the normal phase silica gel bonded diol-based chromatographic column, which can better retain the synephrine component, and has the advantages of shorter equilibrium time, higher determination speed, higher sensitivity and higher separation degree.
In addition, the normal phase silica gel bonded diol-based chromatographic column does not need to be added with an ion pair reagent, so that the damage to the chromatographic column is reduced, and the synephrine component can be better kept on the chromatographic column.
(4) The sample extraction method is simple, the impurity content of the sample is low, the interference on a liquid chromatograph is reduced, and the detection accuracy is improved.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Preparation of Yiwendan tablets
Preparation example 1
Mixing 660 parts of seven medicinal materials including bamboo shavings, 550 parts of rhizoma pinellinae praeparata, 550 parts of radix curcumae, 165 parts of liquorice, 165 parts of dried orange peel, 550 parts of poria cocos and 660 parts of immature bitter orange in proportion, adding water to soak for half an hour, heating to boil, performing reflux extraction for 1.5 hours, extracting twice, condensing and collecting volatile oil in the extraction process, filtering the extracting solution, concentrating at 80 ℃, performing ethanol precipitation and filtration, concentrating the supernatant into thick paste at 80 ℃, adding dextrin to prepare granules, spraying the volatile oil, and tabletting to obtain the first batch of gallbladder warming tablets.
Preparation example 2
Mixing 550 parts by weight of seven medicinal materials of bamboo shavings, 450 parts by weight of rhizoma pinellinae praeparata, 450 parts by weight of radix curcumae, 150 parts by weight of liquorice, 150 parts by weight of dried orange peel, 450 parts by weight of poria cocos and 550 parts by weight of immature bitter orange in proportion, adding water for soaking for half an hour, heating to boil, performing reflux extraction for 1.5h, extracting twice, collecting volatile oil in the extraction process, filtering the extracting solution, concentrating at 80 ℃, performing ethanol precipitation and filtration, concentrating the supernatant into thick paste at 80 ℃, adding dextrin to prepare granules, spraying the volatile oil, and tabletting to obtain the second batch of the gallbladder warming tablets.
Preparation example 3
Mixing 750 parts by weight of seven medicinal materials of bamboo shavings, 600 parts by weight of rhizoma pinellinae praeparata, 600 parts by weight of radix curcumae, 250 parts by weight of liquorice, 250 parts by weight of dried orange peel, 600 parts by weight of poria cocos and 700 parts by weight of immature bitter orange in proportion, adding water for soaking for half an hour, heating to boil, performing reflux extraction for 1.5h, extracting twice, collecting volatile oil in the extraction process, filtering the extracting solution, concentrating at 80 ℃, performing ethanol precipitation and filtration, concentrating the supernatant into thick paste at 80 ℃, adding dextrin to prepare granules, spraying the volatile oil, and tabletting to obtain the third batch of gallbladder warming tablets.
Method for measuring synephrine transfer rate and hesperidin transfer rate of Wendan tablets
The synephrine standard and the hesperidin standard used for the determination are provided by China food and drug testing research institute, and the batch numbers are 110727-.
Method for measuring synephrine transfer rate of Wendan tablet
(1) Quality determination of synephrine in Wendan tablet
Firstly, extracting a sample by a gallbladder warming sheet:
taking 10 warm gallbladder tablets (about 0.25 g/tablet) per batch, crushing, grinding into fine powder, weighing 1g of the warm gallbladder tablet fine powder, adding 50-100mL of 50-100% (v/v) methanol, weighing, carrying out ultrasonic treatment for 10-60min, cooling to room temperature, weighing again, supplementing the lost weight with 50-100% (v/v) methanol, cooling, filtering, precisely taking 10mL of subsequent filtrate, evaporating to dryness, dissolving the residue with 10mL of water, loading the residue into a column by a dry method through polyamide (60-90 meshes, 2.5g, the inner diameter of the residue is 1 cm), eluting with 25mL of water, collecting the eluate, transferring to a 25mL volumetric flask, adding water to the scale, and shaking uniformly to obtain the product;
measurement of synephrine content of the sample:
detecting the sample by using high performance liquid chromatography (Shimadzu LC-20AT high performance liquid chromatograph; SPD-M20A ultraviolet detector; Labsolutions data processing software system), wherein the chromatographic conditions are as follows: sample introduction amount: 10 mu l of the mixture; a chromatographic column: normal phase silica gel bonded Diol-based chromatography column (YMC-Pack Diol-120-NP, 250 × 4.6mm, 5 μm, 12 nm); mobile phase: acetonitrile is used as a mobile phase A, a 5mmol/L ammonium acetate solution is used as a mobile phase B, and the volume ratio of the mobile phase A to the mobile phase B is 80: 20; the detection wavelength is 275nm, the flow rate is 1.0mL/min, and the theoretical plate number is not less than 14000.
③ the method for calculating the synephrine mass in the Wendan tablet:
adding water into synephrine standard substance to prepare 7 standard solutions of 7.44 mug/mL, 14.88 mug/mL, 29.76 mug/mL, 59.52 mug/mL, 89.28 mug/mL, 119.04 mug/mL and 148.8 mug/mL respectively, detecting the 7 standard solutions according to the method, performing linear regression by taking the concentration of the standard solutions as an abscissa and the chromatographic peak area as an ordinate to obtain a linear equation y of 5218.2x-1829.9 and R of 0.9999, substituting the chromatographic peak area of the sample into the linear equation to calculate the synephrine content of the sample, and calculating the synephrine mass in the WEN-DAN tablet according to the following formula.
The quality of synephrine (μ g) ═ the synephrine content in the wendan tablet (μ g/mL) x 25mL × dilution times × the quality of each batch of wendan tablet (g)/the quality of wendan tablet fine powder (g)
The dilution factor was equal to the initial methanol volume (mL)/10 mL.
(2) And (3) measuring the quality of synephrine in medicinal materials:
in the formula I, both the immature bitter orange and the dried orange peel contain synephrine, the synephrine content in the immature bitter orange in the formula is determined according to pages 230-231 of pharmacopoeia of the people's republic of China (2010 edition), and page number difference can be caused due to different printing batches.
II, measuring the content of synephrine in the tangerine peel with the prescription:
i. extracting a sample from dried orange peel:
precisely weighing 3 parts (used for calculating the average value) of the dried orange peel medium powder, wherein each part is about 1g, respectively placing the dried orange peel medium powder into 200mL conical bottles with stoppers, precisely adding 100mL of methanol, weighing, and ultrasonically treating for 1 h. Weighing, adding methanol to complement weight loss, shaking, and filtering with 0.22 μm microporous membrane.
A sample detection method:
the determination of synephrine quality in the Wendan tablet is carried out according to the second step.
The difference lies in that: column temperature: 35 ℃; mobile phase a was 5mM ammonium acetate solution, mobile phase B was acetonitrile, and mobile phase A, B volume percent change is shown in table 1.
TABLE 1
A method of calculation:
dissolving synephrine standard with chromatographic pure methanol to obtain standard solution with synephrine content of 0.036mg/ml, and measuring the standard solution according to the above method. Calculating by adopting an external standard method to obtain the synephrine content of the sample, and calculating according to the following formula to obtain the synephrine content in the tangerine peel of the prescription.
The content of synephrine (mug/g) in the tangerine peel of the prescription is sample synephrine (mug/mL) multiplied by 100 mL/tangerine peel medium powder mass (g)
III, calculating the quality of the synephrine in the medicinal materials according to the following formula.
The mass (mug) of synephrine in the medicinal materials is equal to the mass (g) of prescription immature bitter orange multiplied by the synephrine content (mug/g) in the prescription immature bitter orange, the mass (g) of prescription dried orange peel multiplied by the synephrine content (mug/g) in the prescription dried orange peel
(3) Calculating the synephrine transfer rate of the Wendan tablets:
the synephrine transfer rate of the Wendan tablets is calculated according to the following formula.
Synephrine transfer rate of 100% × synephrine mass (μ g) in fel tablet/synephrine mass (μ g) in medicinal material
Method for measuring hesperidin transfer rate of (II) wendan tablets
(1) Measuring the quality of hesperidin in the gallbladder warming tablet:
firstly, extracting a sample by a gallbladder warming sheet:
grinding fel Ursi in mortar, precisely weighing 0.5g, placing in conical flask with plug, precisely adding 50mL methanol, sealing, weighing, ultrasonic treating (power 250W, frequency 59kHz) for 30min, cooling, weighing again, supplementing the weight loss with methanol, shaking, filtering, and collecting the filtrate.
Measuring the content of hesperidin in the sample:
detecting a sample by using high performance liquid chromatography, wherein the chromatographic conditions are as follows: sample introduction amount: 10 mu l of the mixture; octadecylsilane chemically bonded silica is used as a filling agent; acetonitrile-0.1% phosphoric acid (volume ratio 20: 80) is used as a mobile phase; the detection wavelength is 285 nm; column temperature: 35 ℃; the theoretical plate number is not less than 15000 in terms of hesperidin peak.
③ the method for calculating the content of hesperidin in the gallbladder warming tablet:
taking a proper amount of hesperidin standard, dissolving with pure water to prepare a standard solution of 0.11mg/mL, detecting the standard solution according to the method, and calculating the hesperidin quality in the gallbladder warming tablet by adopting an external standard method and according to the following formula.
The quality of hesperidin in the warm gallbladder tablet is V sample multiplied by A sample multiplied by C standard multiplied by m batch/(A standard multiplied by m sample)
Wherein, the sample V is the total volume (mL) of the sample, the sample A is the peak area of the sample, the sample C is the concentration (mu g/mL) of the standard solution, the sample A is the peak area of the standard solution, the sample m is the sampling amount (g) of the warm-gallbladder tablets, and the batch m is the mass (g) of each warm-gallbladder tablet.
(2) The quality of hesperidin in the medicinal materials is determined:
the immature bitter orange and the tangerine peel in the formula contain hesperidin, the hesperidin content in the tangerine peel in the formula is determined according to pages 176-177 of pharmacopoeia of the people's republic of China (2010 version), and page number difference can be caused due to different printing batches.
II, measuring the content of hesperidin in the immature bitter orange with the prescription:
i. extracting a sample from immature bitter orange:
reference (i) · (2). ii. i) the sample is extracted from dried orange peel. Except that the immature bitter orange middle powder is used for replacing the dried orange peel middle powder.
A sample detection method:
the samples were examined by high performance liquid chromatography. The chromatographic conditions are as follows: sample introduction amount: 10 mu L of the solution; a chromatographic column: YMC-Pack, ODS-AM, 4.6 x 250mm,5 μm; a detector: an ultraviolet detector; detection wavelength: 283 nm; column temperature: 35 ℃; flow rate: 1.0 mL/min; mobile phase A: water, mobile phase B acetonitrile, and the volume ratio of A to B is 80: 20.
a method of calculation:
dissolving hesperidin standard with chromatographic pure methanol to obtain standard solution with hesperidin content of 0.080mg/mL, and detecting the standard solution according to the above method. And calculating to obtain the hesperidin content of the sample by adopting an external standard method, and calculating to obtain the hesperidin content in the immature bitter orange in the formula by referring to the step (I) - (2), the step (II) and the step (iii).
III, calculating the mass of the hesperidin in the medicinal materials according to the following formula.
The weight (μ g) of hesperidin in the medicinal materials is multiplied by the weight (g) of prescription immature bitter orange and the content (μ g/g) of hesperidin in prescription immature bitter orange, and the weight (g) of prescription dried orange peel is multiplied by the content (μ g/g) of hesperidin in prescription dried orange peel
(3) Calculating the hesperidin transfer rate of the swertia mileensis tablet:
the transfer rate of the hesperidin in the gallbladder warming tablet is calculated according to the following formula.
The hesperidin transfer rate is 100% multiplied by the hesperidin quality (mu g) in the fel warming tablet/the hesperidin quality (mu g) in the medicinal materials
Thirdly, evaluating the stability of the process
The respective rates of synephrine transfer and hesperidin transfer were measured in accordance with II for batches of the Wendan tablets I, II and III of preparation examples 1 to 3, and the results are shown in Table 2.
TABLE 2
As can be seen from Table 2, the synephrine transfer rate in the production of the warming gallbladder tablets is far greater than the hesperidin transfer rate, and the synephrine transfer rate is easier to measure accurately and is suitable for being used as an index for evaluating the process stability. Moreover, the synephrine transfer rate of the preparation examples 1-3 is more than or equal to 40.8%, which indicates that the preparation process of the fel warming tablets of the preparation examples 1-3 has high stability.
In addition, 10 batches of the warming gallbladder tablets prepared according to preparation examples 1 to 3 were prepared, and 10 batches produced according to preparation example 1 were named as warming gallbladder tablets I1-Ⅰ1010 batches produced according to preparation example 2 and named as Wendan tablets II1-Ⅱ1010 batches produced in preparation example 3 and named as Wendan tablets III1-Ⅲ10. The synephrine transfer rate of each batch of the gallbladder warming tablets is measured according to the second criterion, and the result shows that the gallbladder warming tablets I1-Ⅰ10The synephrine transfer rate is close to 50.68%; warming gallbladder tablet II1-Ⅱ10The synephrine transfer rate is close to 51.94%; warming gallbladder tablet III1-Ⅲ10The synephrine transfer rate was close to 50.21%. The synephrine transfer rate is more than or equal to 40.8 percent, and the preparation process of the gallbladder warming tablet is stable.
In addition, when measuring the synephrine mass in the Wendan tablet I, two mobile phases A and B with the volume ratio of 80:20 and 90:10 are respectively adopted for sample detection, and the obtained liquid chromatogram is respectively shown in figures 1 and 2.
As can be seen from comparison of FIG. 1 and FIG. 2, the volume ratio of mobile phase A to B is 80:20, and the peak time is earlier than that of the mobile phase A to B when the volume ratio is 90:10, so that the detection speed is faster, the separation degree is better, and the base line is more stable.
Fourth, research on methodology for detecting process stability of gallbladder warming tablet
(1) Precision:
the prepared synephrine standard solution with the concentration of 29.76 mu g/mL is measured according to the two (one) (1) and (II) method, sample introduction is repeated for 6 times, and RSD is calculated, and the result is 1.41%, which indicates that the precision of the instrument is good.
(2) Stability:
the sample is extracted from the Winterepha I according to the method in the second (first) to the method in the first (1), the sample is measured for 5 times, 10 mu l of the sample is injected into the high performance liquid chromatography at the time points of the beginning, 6h, 12h, 24h and 36h respectively, the synephrine chromatographic peak area is measured, the RSD of the chromatographic peak area is calculated for 5 times to be 1.85, and the result shows that the extracted sample is stable within 36 hours.
(3) Reproducibility:
6 parts of samples of the swertia mileensis I are prepared and measured according to the method in the second (first) to (1), and the RSD of the content of synephrine in the swertia mileensis is 1.92, which indicates that the method has good reproducibility.
(4) And (3) sample recovery rate:
crushing and grinding 10 pieces of fel warming tablets I (the measured synephrine content is 3.80mg/g) into fine powder, weighing 6 parts of fel warming tablets 0.5g, respectively adding synephrine standard substance of about 1.9mg into a bottle with a corkscrew, respectively measuring the synephrine content of the added standard substance by a two.
The sample adding recovery rate is (adding standard substance synephrine content-wendan tablet I synephrine content)/standard substance adding amount is multiplied by 100%
As a result, the average value of the sample recovery rate of synephrine is 97.6%, the RSD is 0.96%, and the sample recovery rate meets the requirement, which shows that the method has higher accuracy.
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.